WO2007083146A2

WO2007083146A2 - The treatment of cognitive and psychotic disorders

Info

Publication number: WO2007083146A2
Application number: PCT/GB2007/000193
Authority: WO
Inventors: Sabine Bahn; Christopher Robin Lowe
Original assignee: Cambridge Enterprise Limited
Priority date: 2006-01-20
Filing date: 2007-01-22
Publication date: 2007-07-26
Also published as: WO2007083146A3; GB0601179D0

Abstract

An anti-diabetic agent such as insulin is useful for the treatment of a psychotic disorder such as a schizophrenic disorder.

Description

THE TREATMENT OF COGNITIVE AND PSYCHOTIC DISORDERS Field of the Invention

The present invention relates to the treatment of schizophrenia, related psychotic disorders and cognitive disorders. The invention also relates to agents and medicaments adapted for delivery to the central nervous system, in particular via the intranasal route. Background of the Invention

Schizophrenia, bipolar disorder (manic depression) and severe clinical depression are a group of mental illnesses, termed psychotic disorders, which often manifest themselves with psychotic states characterized by disruption of basic perceptual, cognitive, affective and judgmental processes. Individuals experiencing a psychotic episode may experience auditory or visual hallucinations, hold paranoid or delusional beliefs, experience personality changes and exhibit disorganised thinking. These symptoms are sometimes accompanied by features such as a lack of insight into the unusual or bizarre nature of their behaviour, difficult social interactions and impairment in carrying out basic activities of daily living. For example, patients with schizophrenia often hear voices, or believe that others are reading their minds, controlling their thoughts or plotting to harm them. These terrifying symptoms may render them fearful and withdrawn, and their speech and behaviour can be so disorganised that they may be incomprehensible or frightening to others.

The clinical syndrome of schizophrenia typically has its onset in late adolescence or early adulthood and presents as a constellation of positive (hallucination, delusions, disorganization of thought and bizarre behaviour), negative (loss of motivation, restricted range of emotional experience and expression and reduced hedonic capacity) and cognitive impairments with extensive variation between individuals (Lewis, 2000). In addition, many patients with schizophrenia experience difficulties with depression and substance abuse contributing to the 10-15% lifetime incidence of suicide. No single symptom is unique to schizophrenia and/or is present in every case. Psychotic episodes, for example, are not uncommon in cases of brain injury, learning disability, substance abuse, a range of metabolic disorders and may occur after chronic psychological stress and vary in duration between individuals. Psychosis is thus a descriptive term for a complex group of behaviours and experiences. Individuals with schizophrenia can have long periods without psychosis and similarly those with bipolar disorder, or depression, can have mood symptoms without psychosis. Unfortunately, the current diagnosis and classification of schizophrenia is based solely on the physicians experience in interpreting clinical indications presented by the patient.

Schizophrenia and bipolar affective disorder are a major burden to affected individuals, their families and to society at large, affecting at least 2% of the population worldwide and costing hundreds of billions in healthcare provision, treatments and lost earnings. Schizophrenia is found at similar prevalence in both sexes and throughout diverse cultures and geographic zones. The World Health Organization found schizophrenia to be the world's fourth leading cause of disability that accounts for 1.1% of the total DALYs (Disability Adjusted Life Years) and 2.8% of YLDs (years of life lived with disability). It was estimated that the economic cost of schizophrenia exceeded US$ 19 billion in 1991 , more than the total cost of all cancers in the United States. Effective treatments used early in the course of schizophrenia can improve prognosis and help reduce the costs associated with this illness. The current mix of therapeutic interventions reduces the burden by only 13% (Saha et al., 2005). The ICD-10 Classification of Mental and Behavioural Disorders, published by the World Health Organization in 1992, is the manual most commonly used by European psychiatrists to diagnose mental health conditions. The manual provides detailed diagnostic guidelines and defines the various forms of schizophrenia: schizophrenia, paranoid schizophrenia, hebrephrenic schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, post-schizophrenic schizophrenia, residual schizophrenia and simple schizophrenia.

The Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM IV) published by the American Psychiatric Association, Washington D.C., 1994, has proven to be an authoritative reference handbook for health professionals both in the United Kingdom and in the United States in categorizing and diagnosing mental health problems. This describes the diagnostic criteria, subtypes, associated features and criteria for differential diagnosis of mental health disorders, including schizophrenia, bipolar disorder and related psychotic disorders.

Antipsychotic medications have been available since the mid-1950s. However, current antipsychotic drugs do not cure schizophrenia, or even ensure that there will be no further psychotic episodes, and most schizophrenics continue to suffer some symptoms throughout their lives; Less than one in five patients recovers. Medications and other treatments, when used regularly and as prescribed, can help reduce and control the distressing symptoms of the illness. However, some patients are not greatly helped by available treatments or may prematurely discontinue treatment because of unpleasant side effects, residual symptoms, lost opportunities or stigma. The newer antipsychotic drugs, the so-called "atypicals", such as clozapine and olanzapine, can treat certain of the positive symptoms of schizophrenia, particularly hallucinations and delusions, but may not be as helpful with the more negative symptoms of reduced motivation and emotional expressiveness. Furthermore, the long-term side effects of even these newer atypical antipsychotic drugs may pose serious problems with sedation, weight gain, new onset diabetes (both type 2 and diabetic ketoacidosis) and hypertriglyceridaemia (Livingstone et al., 2003), and, if given at high dose, may lead to social withdrawal and induce Parkinsonian symptoms which are a prominent side-effect of typical antipsychotic drugs (Holt et al., 2004). A recent large-scale study (1500 patients) aimed to determine the effectiveness of antipsychotic drugs in patients with chronic schizophrenia showed that between 69-82% of patients discontinued using their medication owing to inefficacy or intolerable side effects. Interestingly there was no significant difference in the discontinuation rate between typical and atypical antipsychotic medication (Lieberman et al., 2005). Schizophrenia remains an elusive multifaceted disorder with ail evidence of its onset and aetiology pointing to the implication of a complex interplay of genetic, nutritional, environmental and developmental factors.

It has been known since 1922, well before the era of antipsychotic medications, which are known to change glucose and lipid levels, that schizophrenia is associated with impaired insulin action (Lorenz, 1922). Early studies have also shown a positive correlation between insulin resistance and the duration of hospitalization for schizophrenic patients (Schimmelbusch et al., 1971 ).

Patients with schizophrenia exhibit prominent impairments in memory and attention (Saykin et al., 1994; Paulsen et al., 1995) which can substantially affect functional outcome in the community (Green, 1996). Glucose regulation is known to be inherently impaired in schizophrenic patients, which show reduced glucose tolerance and abnormal movements (Braceland et al., 1945; Franzen & Nilsson, 1968; Brambilia et al., 1976; Schultz et al., 1999; Newcomer et al., 2002). It has been suggested that since glucose is the principal energy substrate for the brain, and alterations in glucose availability may affect neuronal function, including cognitive performance, that altered glucose metabolism may play a role in schizophrenia (Fucetola et al., 1999; Newcomer et al., 1999). Recent research indicates that the schizophrenia disease process is associated with abnormalities in energy metabolism and glucoregulatory disturbances in the brain (Holt et al., 2004). It is known that glucose administration improves memory performance in older rodents (Gold & Stone, 1988), in old and young human subjects (Hall et al., 1989; Craft et al., 1994; Kaplan θt al., 2000) and in patients with Alzheimer's disease (AD) (Craft et al., 1992, 1993, 1996).

Age- and dose-dependent glucose-induced increases in memory and attention have been observed in schizophrenics (Fucetola et al., 1999). More recent studies have shown that verbal declarative memory and other cognitive functions could be improved when glucose administration was used as an adjunct to clozapine therapy (Stone et al., 2003). The underlying biochemical basis for these observations has yet to be established.

WO2005/013978 discloses indole-4-sulfonamides and their use as 5-HT-6 modulators.

There is an urgent clinical need for safer, more effective and less side-effect- prone therapies to treat psychotic disorders, in particular schizophrenic disorders. Summary of Invention

The present invention is based on a novel approach to treat/ameliorate the symptoms of schizophrenia, especially the incapacitating cognitive defects. A parallel transcriptomics, proteomics and metabolomics study on human brain tissue identified altered proteins, transcriptional and metabolite perturbations associated with glucoregulatory responses. Furthermore, cluster analysis of the transcriptome revealed that the genes relating to energy metabolism and oxidative stress differentiated -90% of schizophrenia patients from controls (Prabakaran et al., 2004). ¹H-NMR spectroscopy in conjunction with computerised pattern recognition analysis revealed elevated glucose levels in the CSF of first-onset drug-naϊve schizophrenic patients, but not in the serum samples of the same patients, suggesting that the glucoregulatory changes are brain-specific (Holmes et al., 2006). According to the present invention, an anti-diabetic agent is used for the treatment of a psychotic disorder. The invention further relates to a method of treatment of a psychotic disorder, in particular a schizophrenic disorder, comprising administration to a subject of an anti-diabetic agent or medicament as described herein. Preferably the anti-diabetic agent and/or medicament is formulated for delivery to the CNS, most preferably as an intranasal formulation.

Further evidence may be provided by a clinical study coupled with parallel preclinical investigations of animal models of schizophrenia (PCP rat model). The novel treatment may be beneficial alone or in conjunction with established antipsychotic drug regimes and may also prove beneficial in the treatment of other conditions that present with cognitive decline and deficits, such as dementias and learning disabilities. This invention can utilise agents specifically targeting the glucoregulatory defects in the schizophrenic brain using antidiabetic drugs similar to those used in the treatment of diabetes mellitus. Despite well-established and accepted compounds for the treatment of diabetes, such as insulin, metformin and the sulphonylureas, there are a variety of new approaches and agents under development. The key approaches and classes of drugs to be tested include those shown in Figure 1. Brief Description of the Drawings

Figure 1 shows approaches to the treatment of schizophrenia through modulation of glycoregulation. Figure 2 shows elevated CSF glucose levels in patients with schizophrenia (52) with respect to healthy volunteers (84).

Figure 3 shows serum insulin levels in 20 drug-naive schizophrenic patients and 18 healthy volunteers (p = 0.02). Description of the Invention The term "psychotic disorder" encompasses schizophrenic disorders and also, bipolar disorders, neuropsychiatric (psychotic depression and other psychotic episodes) and neurodevelopmental disorders (especially Autistic spectrum disorders) which can present with psychotic or other schizophrenia-like symptoms. References may be made to ICD-ID and DSM IV classifications. A medicament according to the invention is preferably formulated for administration to the central nervous system (CNS). A medicament according to the present invention preferably delivers an anti-diabetic agent into the CNS (i.e. the brain or spinal cord) rather than to the circulatory system. By circumventing the blood-brain barrier (BBB), administration to the CNS obviates drug delivery problems imposed by the BBB and facilitates delivery of agents that are either poorly transported across, or are unable to cross, the BBB. Delivery of agents to the CNS using a formulation of the invention increases the efficiency of delivery and minimizes the possibility of unwanted side effects associated with systemic delivery, e.g. following oral administration.

More specifically, the invention provides medicaments formulated for delivering an anti-diabetic agent to the CNS by way of neural pathways associated with the olfactory or trigeminal nerve. The olfactory region is located within the upper one-third of the nasal cavity. An alternative embodiment of the invention involves administering a polynucleotide agent to a tissue that is innervated by the trigeminal nerve. Transport through or by way of a neural pathway includes intracellular axonal transport and extracellular transport through intercellular clefts in the olfactory neuroepithelium, as well as transport that occurs through or by way of fluid-phase endocytosis by a neuron, through or by way of a lymphatic channel running with a neuron, through or by way of a perivascular space of a blood vessel running with a neuron or neural pathway, through or by way of a mucosal or epithelial cell layer, through or by way of an adventitia of a blood vessel running with a neuron or neural pathway, and transport through the hemangiolymphatic system.

Medicaments according to the invention include those formulated for administration of an anti-diabetic agent to tissue innervated by the olfactory nerve. The anti-diabetic agent can be delivered to the olfactory area via delivery to the nasal cavity. Preferably, the anti-diabetic agent is contacted with the olfactory region of the nasal cavity by instilling the agent to the upper third of the nasal cavity or to the olfactory epithelium. Anti-diabetic agents contacted with the olfactory region of a mammal's nasal cavity may thus be delivered to the CNS via an olfactory nerve pathway, an olfactory epithelium pathway, a perivascular channel, or a lymphatic channel running along the olfactory nerve. Fibres of the olfactory nerve are unmyelinated axons of olfactory receptor cells that are located in the very top (i.e., superior one-third) of the nasal cavity just under the cribiform plate of the ethmoid bone that separates the nasal and cranial cavities. The olfactory epithelium is the only site in the body where an extension of the CNS comes into direct contact with the external microenvironment. The dendrites of these sensory neurons extend into the nasal cavity, and the axons collect into nerve bundles that project to the olfactory bulb. The olfactory receptor cells are bipolar neurons with swellings covered by immobile hair-like cilia that project into the nasal cavity. At the other end, axons from these cells collect into aggregates and enter the cranial cavity at the roof of the nose. Surrounded by a thin tube of pia, the olfactory nerves cross the subarachnoid space containing cerebral spinal fluid (CSF) and enter the inferior aspects of the olfactory bulbs. Once the anti-diabetic agent is dispensed into/contacted with the nasal cavity, particularly to the upper third of the nasal cavity, the anti-diabetic agent can be transported through the nasal mucosa and into the olfactory bulb. The olfactory bulb has widespread connections with various anatomical regions of the brain including but not limited to the anterior olfactory nucleus, frontal cortex, hippocampal formation, amygdaloid nuclei, nucleus of Meynert and the hypothalamus.

In some embodiments the medicament is formulated to administer an antidiabetic agent to such that the agent is transported to the CNS along an olfactory pathway (e.g., an olfactory nerve pathway, an olfactory epithelial pathway, or an olfactory region lymphatic channel) originating in the olfactory region of the nasal cavity. Delivery through an olfactory pathway can employ movement of an agent into or across mucosa (e.g., epithelium), through or by way of the olfactory nerve, through or by way of a lymphatic channel, or by way of a perivascular space surrounding a blood vessel that travels with the olfactory nerve to the brain and from there into meningial lymphatics associated with various anatomical regions of the CNS. Olfactory neurons provide a direct connection to the CNS, brain, and/or spinal cord due, it is believed, to their role in olfaction. CNS delivery through or by way of the olfactory nerve relies on the anatomical connection of the nasal submucosa and the subarachnoid space. An anti-diabetic agent that enters a receptor cell can be transported by way of the fascicles of the olfactory nerve to the rhinoencephalon, which is the portion of the brain that contains the olfactory bulb and structures of the limbic system as well as most of the forebrain. More specifically, medicaments according to the invention can administer anti-diabetic agents via mechanisms that employ extracellular or intracellular (e.g., transneuronal) axonal transport including anterograde (away from the cell body and toward the axon terminal) and retrograde (from the axonal terminal to the cell body) transport.

The olfactory mucosa (epithelium) comprises pseudo-stratified columnar epithelium comprised of three principal cell types: receptor cells, supporting cells, and basal cells. The receptor cell is also referred to as the olfactory cell or primary olfactory neuron. In an embodiment, an anti-diabetic agent formulated into a medicament for nasal administration to the upper third of the nasal cavity in a region located between the central nasal septum and the lateral wall of each main nasal passage. Application of the anti-diabetic agent to a tissue innervated by the olfactory nerve can deliver the agent to damaged or diseased neurons or cells of the CNS, brain, and/or spinal cord. For example, an agent contacted with a nasal cavity tissue innervated by the olfactory nerve can be absorbed or transported through the tissue and be delivered to an anatomical region of the CNS such as the brain stem, the cerebellum, the spinal cord, the olfactory bulb, and cortical or subcortical structures.

Medicaments manufactured according to the invention can deliver agents to the CNS via an olfactory mucosal (epithelial) pathway by receptor-mediated transcytosis or by paracellular transport. Alternatively an anti-diabetic agent administered according to the method of the invention may be delivered to the CNS via a supporting cell by pinocytosis or diffusion. An anti-diabetic agent may enter the lamina propia via a paracellular mechanism that permits access to the intercellular fluid. The perivascular pathway and/or a hemangiolymphatic pathway, such as lymphatic channels running within the adventitia of cerebral blood vessels, provides another possible pathway for the transport of anti-diabetic agents to the brain and spinal cord from tissue innervated by the olfactory nerve.

In an alternative embodiment a medicament manufactured in accordance with the invention can be formulated to permit administration of an anti-diabetic agent to a tissue innervated by the trigeminal nerve. The medicament can thus be used to administer an anti-diabetic agent to a tissue that is located within or outside of the nasal cavity and which is innervated by one or more of the branches of the trigeminal nerve. Branches of the trigeminal nerve that innervate tissues outside the nasal cavity include the ophthalmic nerve, the maxillary nerve, and the mandibular nerve. In addition to innervating tissues of the nasal cavity (located primarily in the lower two thirds of the cavity), the trigeminal nerve innervates tissues of a mammal's (e.g., a human's) head including skin of the face and scalp, oral tissues, and tissues of and surrounding the eye. Tissues located outside of the nasal cavity that are innervated by the trigeminal nerve include extranasal tissue that is innervated by the trigeminal nerve and extranasal tissue that surrounds the trigeminal nerve.

A medicament manufactured in accordance with the invention may be formulated to administer an anti-diabetic agent to tissue innervated by the ophthalmic nerve branch of the trigeminal nerve. The ophthalmic nerve innervates tissues including superficial and deep parts of the superior region of the face, such as the eye, the lachrymal gland, the conjunctiva, and skin of the scalp, forehead, upper eyelid, and nose.

The ophthalmic nerve has three branches known as the nasociliary nerve, the frontal nerve, and the lachrymal nerve. A medicament manufactured in accordance with the invention can administer an anti-diabetic agent to tissue innervated by the one or more of the branches of the ophthalmic nerve. The frontal nerve and its branches innervate tissues including the upper eyelid, the scalp, particularly the front of the scalp, and the forehead, particularly the middle part of the forehead. The nasociliary nerve forms several branches including the long ciliary nerves, the ganglionic branches, the ethmoidal nerves, and the infratrochlear nerve. The long ciliary nerves innervate tissues including the eye. The posterior and anterior ethmoidal nerves innervate tissues including the ethmoidal sinus and the inferior two-thirds of the nasal cavity. The infratrochlear nerve innervates tissues including the upper eyelid and the lachrymal sack. The lachrymal nerve innervates tissues including the lachrymal gland, the conjunctiva, and the upper eyelid. Medicaments manufactured according to the invention can be formulated to administer an anti-diabetic agent to tissue innervated by the maxillary nerve branch of the trigeminal nerve. The maxillary nerve innervates tissues including the roots of several teeth and facial skin, such as skin on the nose, the upper lip, the lower eyelid, over the cheekbone, and over the temporal region. The maxillary nerve has branches including the infraorbital nerve, the zygomaticofacial nerve, the zygomaticotemporal nerve, the nasopalatine nerve, the greater palatine nerve, the posterior superior alveolar nerves, the middle superior alveolar nerve, and the interior superior alveolar nerve. Medicaments manufactured according to the invention can administer the agent to tissue innervated by the one or more of the branches of the maxillary nerve.

The infraorbital nerve innervates tissue including skin on the lateral aspect of the nose, upper lip, and lower eyelid. The zygomaticofacial nerve innervates tissues including skin of the face over the zygomatic bone (cheekbone). The zygomaticotemporal nerve innervates tissue including the skin over the temporal region. The posterior superior alveolar nerves innervate tissues including the maxillary sinus and the roots of the maxillary molar teeth. The middle superior alveolar nerve innervates tissues including the mucosa of the maxillary sinus, the roots of the maxillary premolar teeth, and the mesiobuccal root of the first molar tooth. The anterior superior alveolar nerve innervates tissues including the maxillary sinus, the nasal septum, and the roots of the maxillary central and lateral incisors and canine teeth. The nasopalantine nerve innervates tissues including the nasal septum. The greater palatine nerve innervates tissues including the lateral wall of the nasal cavity.

Medicaments manufactured in accordance with the invention can be formulated to administer an anti-diabetic agent to tissue innervated by the mandibular nerve branch of the trigeminal nerve. The mandibular nerve innervates tissues including the teeth, the gums, the floor of the oral cavity, the tongue, the cheek, the chin, the lower lip, tissues in and around the ear, the muscles of mastication, and skin including the temporal region, the lateral part of the scalp, and most of the lower part of the face.

The mandibular nerve has branches including the buccal nerve, the auriculotemporal nerve, the inferior alveolar nerve, and the lingual nerve. Medicaments manufactured in accordance with the invention can formulated to administer an anti- diabetic agent to one or more of the branches of the mandibular nerve. The buccal nerve innervates tissues including the cheek, particularly the skin of the cheek over the buccinator muscle and the mucous membrane lining the cheek, and the mandibular buccal gingiva (gum), in particular the posterior part of the buccal surface of the gingiva. The auriculotemporal nerve innervates tissues including the auricle, the external acoustic meatus, the tympanic membrane (eardrum), and skin in the temporal region, particularly the skin of the temple and the lateral part of the scalp. The inferior alveolar nerve innervates tissues including the mandibular teeth, in particular the incisor teeth, the gingiva adjacent the incisor teeth, the mucosa of the lower lip, the skin of the chin, the skin of the lower lip, and the labial mandibular gingivae. The lingual nerve innervates tissues including the tongue, particularly the anterior two-thirds of the tongue, the floor of the mouth, and the gingivae of the mandibular teeth.

Medicaments of the invention can be formulated to administer a anti-diabetic agent to any of a variety of tissues innervated by the trigeminal nerve. For example, for administration of the anti-diabetic agent to skin, epithelium, or mucosa or around the face, the eye, the oral cavity, the nasal cavity, the sinus cavities, or the ear. Thus, in an embodiment, a medicament manufactured in accordance with the invention administers an anti-diabetic agent to skin innervated by the trigeminal nerve, e.g. to skin of the face, scalp, or temporal region. Suitable skin of the face includes skin of the chin; the upper lip, the lower lip; the forehead, particularly the middle part of the forehead; the nose, including the tip of the nose, the dorsum of the nose, and the lateral aspect of the nose; the cheek, particularly the skin of the cheek over the buccinator muscle or skin over the cheek bone; skin around the eye, particularly the upper eyelid and the lower eyelid; or a combination thereof. Suitable skin of the scalp includes the front of the scalp, scalp over the temporal region, the lateral part of the scalp, or a combination thereof. Suitable skin of the temporal region includes the temple and scalp over the temporal region.

In another embodiment, a medicament of the invention may be formulated to administer an anti-diabetic agent to mucosa or epithelium innervated by the trigeminal nerve, e.g. to mucosa or epithelium of or surrounding the eye, such as mucosa or epithelium of the upper eyelid, the lower eyelid, the conjunctiva, the lachrymal system, or a combination thereof. Medicaments of the invention may also be formulated to administer the anti-diabetic agent to mucosa or epithelium of the sinus cavities and/or nasal cavity, such as the inferior two-thirds of the nasal cavity and the nasal septum. Medicaments of the invention may also administer the agent to mucosa or epithelium of the oral cavity, such as mucosa or epithelium of the tongue; particularly the anterior two-thirds of the tongue and under the tongue; the cheek; the lower lip; the upper lip; the floor of the oral cavity; the gingivae (gums), in particular the gingiva adjacent the incisor teeth, the labial mandibular gingivae, and the gingivae of the mandibular teeth; or a combination thereof.

In a further embodiment, a medicament manufactured in accordance with the invention may be formulated to administer an anti-diabetic agent to mucosa or epithelium of the nasal cavity. Other preferred regions of mucosa or epithelium for administering the anti-diabetic agent include the tongue, particularly sublingual mucosa or epithelium, the conjunctiva, the lachrymal system, particularly the palpebral portion of the lachrymal gland and the nasolacrimal ducts, the mucosa of the lower yield, the mucosa of the cheek, or a combination thereof. In other embodiments, a medicament of the invention may be formulated to administer an anti-diabetic agent to nasal tissues innervated by the trigeminal nerve. For example, the medicament may be formulated to administer an agent to nasal tissues including the sinuses, the inferior two-thirds of the nasal cavity, and the nasal septum. Preferably, the nasal tissue for administering the agent includes the inferior two-thirds of the nasal cavity and the nasal septum.

A medicament of the invention may be formulated for administration of an antidiabetic agent to oral tissues innervated by the trigeminal nerve, e.g. to administer the agent to oral tissues such as the teeth, the gums, the floor of the oral cavity, the cheeks, the lips, the tongue, particularly the anterior two-thirds of the tongue, or a combination thereof. Suitable teeth include mandibular teeth, such as the incisor teeth. Suitable portions of the teeth include the roots of several teeth, such as the roots of the maxillary molar teeth, the maxillary premolar teeth, the maxillary central and lateral incisors, the canine teeth, and the mesiobuccal root of the first molar tooth, or a combination thereof. Suitable portions of the lips include the skin and mucosa of the upper and lower lips. Suitable gums include the gingiva adjacent the incisor teeth, and the gingivae of the mandibular teeth, such as the labial mandibular gingivae, or a combination thereof. Suitable portions of the cheek include the skin of the cheek over the buccinator muscle, the mucous membrane lining the cheek, and the mandibular buccal gingiva (gum), in particular the posterior part of the buccal surface of the gingiva, or a combination thereof. Preferred oral tissue for administering the antidiabetic agent includes the tongue, particularly sublingual mucosa or epithelium, the mucosa inside the lower lip, the mucosa of the cheek, or a combination thereof.

In another embodiment, a medicament of the invention may be formulated to administer an anti-diabetic agent to a tissue of or around the eye that is innervated by the trigeminal nerve, e.g. to administer the agent to tissue including the eye, the conjunctiva, the lachrymal gland including the lachrymal sack, the skin or mucosa of the upper or lower eyelid, or a combination thereof. An anti-diabetic agent that is administered conjunctival^ but not absorbed through the conjunctival mucosa can drain through nasolacrimal ducts into the nose, where it can be transported to the CNS, brain, and/or spinal cord as though it had been intranasally administered. Furthermore, a medicament of the invention may be formulated to administer an anti-diabetic agent to a tissue of or around the ear that is innervated by the trigeminal nerve, e.g. to administer the agent to tissue including the auricle, the external acoustic meatus, the tympanic membrane (eardrum), and the skin in the temporal region, particularly the skin of the temple and the lateral part of the scalp, or a combination thereof.

Thus, in some embodiments a medicament of the invention is formulated to administer an anti-diabetic agent to a mammal in a manner such that the agent is transported into the CNS, including the brain, and/or spinal cord along a trigeminal neural pathway originating in a tissue that can be located either within or outside of the nasal cavity. Typically, this can be achieved by administering the anti-diabetic agent to a tissue located outside the nasal cavity (i.e., extranasal tissue), which is innervated by the trigeminal nerve. The trigeminal neural pathway innervates various tissues of the head and face, as described above. In particular, the trigeminal nerve innervates the nasal, sinusoidal, oral and conjunctival mucosa or epithelium, and the skin of the face. Application of the agent to a tissue innervated by the trigeminal nerve can deliver the agent to damaged or diseased neurons or cells of the CNS, including the brain, and/or spinal cord. Trigeminal neurons innervate these tissues and can provide a direct connection to the CNS, brain, and/or spinal cord due. Delivery through the trigeminal neural pathway can employ lymphatic channels that travel with the trigeminal nerve to the pons, olfactory area and other brain areas and from there into dural lymphatics associated with portions of the CNS, such as the spinal cord. A perivascular pathway and/or a hemangiolymphatic pathway, such as lymphatic channels running within the adventitia of cerebral blood vessels, provides an additional mechanism for the transport of therapeutic agents to the spinal cord from tissue innervated by the trigeminal nerve.

The trigeminal nerve includes large diameter axons, which mediate mechanical sensation, e.g., touch, and small diameter axons, which mediate pain and thermal sensation, both of whose cell bodies are located in the semilunar (or trigeminal) ganglion or the mesencephalic trigeminal nucleus in the midbrain. Certain portions of the trigeminal nerve extend into the nasal cavity, oral, and conjunctival mucosa and/or epithelium. Other portions of the trigeminal nerve extend into the skin of the face, forehead, upper eyelid, lower eyelid, dorsum of the nose, side of the nose, upper lip, cheek, chin, scalp and teeth. Individual fibres of the trigeminal nerve collect into a large bundle, travel underneath the brain and enter the ventral aspect of the pons. Another portion of the trigeminal nerve enters the CNS in the olfactory area of the brain. . A medicament of the invention may be formulated to administer an anti-diabetic agent to the trigeminal nerve, for example, through the nasal cavity's, oral, lingual, and/or conjunctival mucosa and/or epithelium; or through the skin of the face, forehead, upper eyelid, lower eyelid, dorsum of the nose, side of the nose, upper lip, cheek, chin, scalp and teeth. Such administration can employ extracellular or intracellular (e.g., transneuronal) anterograde and retrograde transport of the agent entering through the trigeminal nerves to the brain and its meninges, to olfactory area of the brain, the brain stem, or to the spinal cord. Once the agent is dispensed into or onto tissue innervated by the trigeminal nerve, it may transport through the tissue and travel along trigeminal neurons into areas of the CNS.

Delivery through the trigeminal neural pathway can employ movement of an agent across skin, mucosa, or epithelium into the trigeminal nerve or into a lymphatic, a blood vessel perivascular space, a blood vessel adventitia, or a blood vessel lymphatic that travels with the trigeminal nerve to the olfactory area of the brain and/or pons and from there into meningial lymphatics associated with portions of the CNS such as the spinal cord. Blood vessel lymphatics include lymphatic channels that are around the blood vessels on the outside of the blood vessels; this also is referred to as the hemangiolymphatic system.

A medicament of the invention is preferably formulated for the delivery of anti- diabetic agents to the CNS by intranasal administration. Intranasal administration can accomplish delivery of the anti-diabetic agent to the brain stem, cerebellum, spinal cord, and cortical and subcortical structures. A carrier or other transfer-promoting factors may be included in the medicament to assist in delivery of the anti-diabetic agent to the CNS, e.g. via the trigeminal and/or olfactory neural pathway. Intranasal administration allows the anti-diabetic agent to bypass the BBB and travel directly from the nasal mucosa and/or epithelium to the brain and spinal cord.

In other embodiments, a medicament of the invention may be formulated to deliver of a anti-diabetic agent by transdermal (i.e., through or by way of the skin) or sublingual (applied to the underside of the tongue) administration, which can deliver the agent to the CNS by way of a neural pathway, e.g., a trigeminal neural pathway, after. Transdermal or sublingual administration can result in delivery of an agent into a blood vessel perivascular space or a lymphatic that travels with the trigeminal nerve to the olfactory bulb, pons, and other brain areas, and from there into meningeal lymphatics associated with portions of the CNS such as the spinal cord. Transport along the trigeminal nerve may also deliver transdermal^ or sublingually administered agents to the midbrain, diencephalon, medulla, and cerebellum. The ethmoidal branch of the trigeminal nerve enters the cribriform region. A transdermal^ or sublingually administered agent can enter the ventral dura of the brain and may travel in lymphatic channels within the dura.

The perivascular pathway and/or an hemangiolymphatic pathway, such as a lymphatic channel running within the adventitia of a cerebral blood vessel, provide an additional mechanism for transport of the anti-diabetic agent to the spinal cord from the skin or from underneath the tongue. An anti-diabetic agent transported by the hemangiolymphatic pathway does not necessarily enter the circulation. Blood vessel lymphatics associated with the circle of Willis as well as blood vessels following the trigeminal nerve can also be involved in the transport of the agent.

Transdermal or sublingual formulations can deliver an anti-diabetic agent to the brain stem, cerebellum, spinal cord, and cortical and subcortical structures. A carrier or other transfer-promoting factors may assist in the transport of the agent into and along the trigeminal neural pathway. Transdermal or sublingual administration of a therapeutic agent can bypass the BBB through a transport system from the skin to the brain and spinal cord.

Suitably the medicament is formulated for intranasal, buccal, sublingual, transdermal, ocular, intrathecal or intracranial administration.

In medicaments of the invention, the total amount of anti-diabetic agent administered per dose should be in a range sufficient to deliver a biologically relevant amount of the agent. The medicament is preferably formulated to provide a unit dose of anti-diabetic agent and can be in the form of a solution, suspension, emulsion, powder, microparticle, or a sustained-release formulation. The total volume of the medicament per unit dose will generally be in the range from about 10 μl to about 1000 μl. For example, a single dose of an aqueous solution administered to the olfactory region of the nasal cavity, can range from about 10 μl to about 200 μl. Nasal administration may require the administration of more than one dose, for example two or more doses may be administered.

The total amount of agent administered as a unit dose to a particular tissue will depend upon the nature of the medicament, that is whether the medicament is formulated as, for example, a solution, a suspension, an emulsion, a powder, a microparticle, or a sustained-release formulation.

Needle-free subcutaneous administration to an extranasal tissue innervated by the trigeminal nerve may be accomplished by use of a device that employs a supersonic gas jet as a power source to accelerate an agent that is formulated as a powder or a microparticle into the skin. Subcutaneous delivery of an aqueous composition can be accomplished in a needle-free manner by employing a gas-spring powered hand-held device to produce a high force jet of fluid capable of penetrating the skin. A skin patch formulated to mediate a sustained release of a composition can be employed for the transdermal delivery of an agent to a tissue innervated by the trigeminal nerve. The medicament may a therapeutically effective amount of an agent, or a combination of agents.

As used herein the terms "effective amount" and "therapeutically effective dose" refer to achieving a level of therapeutic agent that is sufficient to prevent, treat, reduce, and/or ameliorate the symptoms and/or underlying causes of a psychotic disorder, in particular a schizophrenic disorder.

For medicaments administered by way of an intranasal route, the anti-diabetic agent may be capable of at least partially dissolving in the fluids that are secreted by the mucous membrane that surrounds the cilia of the olfactory receptor cells of the neuroepithelium. The medicament can include, for example, any pharmaceutically acceptable additive, carrier, or adjuvant that facilitates dissolution or transport of the anti-diabetic agent, and which is suitable for administration to a tissue innervated by the olfactory and/or trigeminal nerves. Thus the medicament may comprise an antidiabetic agent in combination with a pharmaceutical carrier, additive, and/or adjuvant, which may promote the transfer of the agent within or through tissue innervated by the olfactory and/or trigeminal nerves. Alternatively, the agent may be combined with substances that may assist in transporting the agent to sites of nerve cell damage.

The medicament will typically contain a pharmaceutically acceptable carrier mixed with the anti-diabetic agent and other components in the pharmaceutical composition. The term "pharmaceutically acceptable carrier" includes carriers conventionally used in the art to facilitate the storage or administration of the agent. A suitable carrier should be stable and should not produce significant local or systemic adverse effect in recipients at the dosages and concentrations employed for treatment.

Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly (when isotonic) for solutions. The carrier can be selected from various oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like.

Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The medicament may contain conventional pharmaceutical additives, such as preservatives, stabilizing agents, wetting, or emulsifying agents, salts for adjusting osmotic pressure, buffers, and the like.

A medicament formulated for intranasal delivery may optionally comprise an odorant. An odorant agent may provide an odorliferous sensation, and/or to encourage inhalation of the intranasal preparation to enhance delivery of the anti-diabetic agent to the olfactory neuroepithelium. The odorliferous sensation provided by the odorant agent may be pleasant, obnoxious, or otherwise malodorous. A lipophilic odorant agent having moderate to high affinity for odorant binding protein (OBP) may be used. OBP has an affinity for small lipophilic molecules found in nasal secretions and may act as a carrier to enhance the transport of a lipophilic odorant substance and active agent to the olfactory receptor neurons.

A suitable odorant agent may be one which is capable of associating with lipophilic additives, such as liposomes and micelles within the preparation, to further enhance delivery of the active agent by means of OBP to the olfactory neuroepithelium.

OBP may also bind directly to lipophilic agents to enhance transport of the anti-diabetic agent to olfactory neural receptors.

Suitable odorants having a high affinity for OBP include terpenoids such as cetralva and citronellol, aldehydes such as amyl cinnamaldehyde and hexyl cinnamaldehyde, esters such as octyl isovalerate, jasmines such as C1S-jasmine and jasmal, and musk 89. Other suitable odorant agents include those which may be capable of stimulating odorant-sensitive enzymes such as adenylate cyclase and guanylate cyclase, or which may be capable of modifying ion channels within the olfactory system to enhance absorption of the anti-diabetic agent. Other acceptable components that may be comprised in medicaments of the invention include, but are not limited to, pharmaceutically acceptable agents that modify isotonicity, including water, salts, sugars, polyols, amino acids, and buffers. Examples of suitable buffers include phosphate, citrate, succinate, acetic acid, and other organic acids or their salts. Typically, the pharmaceutically acceptable carrier also includes one or more stabilizers, anti-oxidants and/or anti-oxidant chelating agents. The use of buffers, stabilizers, reducing agents, anti-oxidants and chelating agents in the preparation of medicaments is well known in the art.

Suitable buffers include acetate, adipate, benzoate, citrate, lactate, maleate, phosphate, tartrate, borate, tris(hydroxymethyl aminomethane), succinate, glycine, histidine, the salts of various amino acids, or the like, or combinations thereof. Suitable salts and isotonicifiers include sodium chloride, dextrose, mannitol, sucrose, trehalose, or the like. Where the carrier is a liquid, it is preferred that the carrier is hypotonic or isotonic with oral, conjunctival, dermal fluids or CSF and has a pH within the range of 4.5-8.5. Where the carrier is in powdered form, it is preferred that the carrier is also within an acceptable non-toxic pH range.

Suitable antioxidants include sodium bisulfite, sodium sulfite, sodium metabisulfite, sodium thiosulfate, sodium formaldehyde sulfoxylate, and ascorbic acid.

Suitable chelating agents, which chelate trace metals to prevent the trace metal catalyzed oxidation of reduced cysteines, include citrate, tartrate, ethylenediaminetetraacetic acid (EDTA) and its disodium, tetrasodium, and calcium disodium salts, and diethylenetriaminepentaacetic acid (DTPA).

A medicament in accordance with the invention can include one or more preservatives such as phenol, cresol, p-aminobenzoic acid, BDSA, sorbitrate, chlorhexidine, benzalkonium chloride, or the like. Suitable stabilizers include carbohydrates such as trehalose or glycerol. The composition can include a stabilizer such as one or more of microcrystalline cellulose, magnesium stearate, mannitol, sucrose.

Suitable suspending additives include carboxymethyl cellulose, hydroxypropyl methylcellulose, hyaluronic acid, alginate, chondroitin sulfate, dextran, maltodextrin, dextran sulfate, or the like. The composition can include an emulsifier such as polysorbate 20, polysorbate 80, pluronic, triolein, soybean oil, lecithins, squalene and squalanes, sorbitan treioleate, or the like.

The composition can include an antimicrobial such as phenylethyl alcohol, phenol, cresol, benzalkonium chloride, phenoxyethanol, chlorhexidine, thimerosol, or the like. Suitable thickeners include natural polysaccharides such as mannans, arabinans, alginate, hyaluronic acid, dextrose, or the like; and synthetic ones like the

PEG hydrogels of low molecular weight and aforementioned suspending agents.

The composition can include an adjuvant such as cetyl trimethyl ammonium bromide, BDSA, cholate, deoxycholate, polysorbate 20 and 80, fusidic acid, or the like. Suitable sugars include glycerol, threose, glucose, galactose, mannitol, and sorbitol. A suitable protein is human serum albumin.

Medicaments may comprise one or more of a solubility enhancing additive, preferably a cyclodextrin; a hydrophilic additive, preferably a mono succinamide or oligosaccharide; an absorption promoting additive, preferably a cholate, a deoxycholate, a fusidic acid, or a chitosan; a cationic surfactant, preferably a cetyl trimethyl ammonium bromide; a viscosity enhancing additive, preferably to promote residence time of the composition at the site of administration, preferably a carboxymethyl cellulose, a maltodextrin, an alginic acid, a hyaluronic acid, or a chondroitin sulphate; or a sustained release matrix, preferably a polyanhydride, a polyorthoester, a hydrogel, a particulate slow release depo system, preferably a polylactide co-glycolides (PLG), a depo foam, a starch microsphere, or a cellulose derived buccal system; a lipid-based carrier, preferably an emulsion, a liposome, a niosome, or a micelle. The composition can include a bilayer destabilizing additive, preferably a phosphatidyl ethanolamine; a fusogenic additive, preferably a cholesterol hemisuccinate. Other medicaments for sublingual administration may include, for example, a bioadhesive to retain the agent sublingually; a spray, paint, or swab applied to the tongue; retaining a slow dissolving pill or lozenge under the tongue; or the like.

Preferred compositions for transdermal administration include a bioadhesive to retain the agent on or in the skin; a spray, paint, cosmetic, or swab applied to the skin; or the like.

These lists of carriers and additives is by no means complete and a worker skilled in the art can choose excipients from the GRAS (generally regarded as safe) list of chemicals allowed in the pharmaceutical preparations and those that are currently allowed in topical and parenteral formulations. The medicament can be formulated in a unit dosage and in a form such as a solution, suspension, or emulsion.

A medicament formulated for administration to tissue innervated by the trigeminal and/or olfactory neurons may be provided as a powder, a granule, a solution, a cream, a spray (e.g., an aerosol), a gel, an ointment, an infusion, an injection, a drop, or sustained release composition, such as a polymer disk.

For buccal administration, the medicament can take the form of tablets or lozenges formulated in a conventional manner.

For administration to the eye or other external tissues, e.g., mouth and skin, the medicament can be applied to the as a topical ointment or cream. The anti-diabetic agent can be presented in an ointment, for instance with a water-soluble ointment base, or in a cream, for instance with an oil-in-water cream base. For conjunctival applications, the agent can be administered in biodegradable or non-degradable ocular inserts. The anti-diabetic agent may be released by matrix erosion or passively through a pore as in ethylene-vinylacetate polymer inserts. For other mucosal administrations, such as sublingual, powder discs may be placed under the tongue and active delivery systems may for in situ by slow hydration as in the formulation of liposomes from dried lipid mixtures or pro-liposomes.

Other preferred forms of medicament for administration include a suspension of a particulate, such as an emulsion, a liposome, an insert that releases the anti-diabetic agent slowly, and the like.

Powder or granular forms of a medicament may be combined with a solution and with a diluting, dispersing, or surface-active agent.

Medicaments may include a bioadhesive to retain the agent at the site of administration; a spray, paint, or swab applied to the mucosa or epithelium; a slow dissolving pill or lozenge; or the like.

The medicament can be in the form of lyophiljzed powder, which can be converted into a solution, suspension, or emulsion before administration.

The medicament may be sterilized, e.g. by membrane filtration and stored in unit-dose or multi-dose containers such as sealed vials or ampoules.

Medicaments for intrathecal or intracranial administration are most suitably presented in the form of solutions and include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives.

Methods for formulating medicaments are well known in the art, for example see Remington's Pharmaceutical Sciences (18th Ed.; Mack Publishing Company, Eaton, Pa., 1990).

The anti-diabetic agents of the present invention can be formulated in a sustained-release medicament. Many methods of preparation of a sustained-release formulation are known in the art and are disclosed in Remington's Pharmaceutical Sciences (supra).

Sustained release formulations may involve impregnation of the agent in semipermeable matrices of solid hydrophobic polymers. Such matrices can be shaped into films or microcapsules. Examples of such matrices include, but are not limited to, polyesters, copolymers of L-glutamic acid and gamma ethyl-L-glutamate, polylactides, polylactate polyglycolate (PLGA) such as polylactide-co-glycolide, hydrogels , non- degradable ethylene-vinyl acetate (e.g., ethylene vinyl acetate disks and poly(ethylene- co-vinyl acetate)), degradable lactic acid-glycolic acid copolymers such as the Lupron Depot(TM), poly-D-(-)-3-hydroxybutyric acid, hyaluronic acid gels, alginic acid suspensions, and the like. Suitable microcapsules can also include hydroxymethylcellulose or gelatin- microcapsules and polymethyl methacrylate microcapsules prepared by coacervation techniques or by interfacial polymerization. In addition, microemulsions or colloidal drug delivery systems such as liposomes and albumin microspheres, may also be used.

Other suitable sustained-release compositions employ a bioadhesive to retain the agent at the site of administration.

Among the optional substances that may be combined with the anti-diabetic agent in the medicament are lipophilic substances that can enhance absorption of the agent through the mucosa or epithelium of the nasal cavity, or along a neural, lymphatic, or perivascular pathway to damaged nerve cells in the CNS. The agent may be mixed with a lipophilic adjuvant alone or in combination with a carrier, or may be combined with one or several types of micelle or liposome substances. Among the preferred lipophilic substances are cationic liposomes including one or more of the following: phosphatidyl choline, lipofectin, DOTAP, a lipid-peptoid conjugate, a synthetic phospholipid such as phosphatidyl lysine, or the like. These liposomes may include other lipophilic substances such as gangliosides and phosphatidylserine (PS). Also suitable are micellar additives such as GM-1 gangliosides and phosphatidylserine (PS), which may be combined with the anti-diabetic agent either alone or in combination.

Medicaments of the invention can be formulated for administration of a therapeutically effective dose of an anti-diabetic agent in a continuous manner, as for example with a sustained-release formulation, or it may be achieved according to a desired daily dosage regimen, as for example with one, two, three or more administrations per day.

In particularly preferred embodiments the medicament is formulated for intranasal administration. With the exception of insulin per se, there are no reports in the literature of the intranasal administration of anti-diabetic agents. Many drugs are not effectively delivered to the brain or CNS due to a number of factors, especially the blood-brain barrier. Intranasal drug delivery is one of the focused delivery options for brain targeting as the brain and nose compartments are connected via the olfactory route and peripheral circulation (Vyas et al., 2005). Intranasal administration allows therapeutic substances to enter the CSF from the nasal mucosa via intercellular clefts along the nervus olfactorius and the bulbus olfactorius (Sakane et al., 1991 ; Ilium, 2000; Ilium, 2002). Studies on nasal bioavailabilities of 25 compounds in rats suggested good availability (-70%) without adjuvants for all molecules with molecular masses <1000 with a decline in availability above this value (McMartin et al., 1987). With the use of adjuvants, this limit could be extended to at least 6000. The anti-diabetic agent (which may be a single anti-diabetic agent or combination of anti-diabetic agents and may be in the form of a pro-drug or linked to an oligomeric group that enhances avidity of said agent for the desired target in the CNS). A preferred agent is insulin. In addition to insulin, other preferred agents for use in the invention include a

GLP-1 agonist, a DPPIV inhibitor, insulin sensitisers (particularly a PPAR agonist), a dual PPAR agonist, an insulin secretagogue, an HGP inhibitor, a glucosidase inhibitor or a prandial glucose regulator (PGR). Other are exendin (1-9) GLP-1 analogues and other peptidal and peptoidal GLP-1 analogies. GLP-1 Agonists: Anti-diabetic agents include insulinotropic hormone glucagon- like peptide (GLP)-I and its agonists. GLP-1 (30 amino acids) is believed to serve an important physiological function in the regulation of glucose metabolism. It stimulates the expression of the homeodomain transcription factor IDX-1 which is critical for the regulation of the glucose-responsive insulin gene transcription together with transcription of the β-cell genes GLUT2, glucokinase and islet amyloid polypeptide (Staffers et al., 2000). Glucagon-like peptide-1 (7-36) amide [GLP-1 (7-36)] amide is a post-translationally modified pro-glucagon neuropeptide produced in the brain which is a basis for the development of an antihyperglycaemic agent. Because GLP-1 is known to have a relatively short half-life in plasma (<3 min) due to proteolysis by dipeptidyl peptidase IV (DPP IV; CD26), long acting versions of GLP-1 , such as exendin-4, discovered in the venom of the GiIa monster Heloderma suspectum, and acylated GLP-1 (NN2211) (Aziz & Anderson, 2002; Rolin et al., 2002) have been developed for oral administration for the treatment of diabetes.

DPPIV inhibitors: These compounds increase GLP-1 bioactivity by inhibiting the enzyme responsible for its degradation in vivo. Dipeptidyl peptidase IV (EC 3.4.14.5), or lymphocyte surface glycoprotein CD26, is a member of the prolyl oligopeptidase family of serine proteases and is unique among this group of membrane ectoenzymes in that it is able to liberate X-Pro and less efficiently X-AIa dipeptides from the N-terminus of peptide hormones, chemokines and neuroculatory peptides such as GLP-1, substance P, peptide YY and neuropeptide Y. DPPIV-mediated cleavage of the N-terminal His-Ala of GLP-1 results in biological inactivation in vivo; hence administration of specific DPPIV inhibitors closes this route of hormone degradation and greatly enhances insulin secretion. Known DPPIV inhibitors have been developed for oral or intravenous administration for the treatment of diabetes (see Demuth et al (2005) Biochimica et Biophysica Acta, 1751 , 33-44, the contents of which are incorporated herein by reference). DPP IV inhibitors include:

(i) reversible product analogue inhibitors (such as pyrrolidines or thiazolidines), e.g. P32/98 or a pro-drug, derivative or metabolite thereof;

(ii) covalently modifying product analogue inhibitors (such as cyanopyrrolidines), e.g. NVP-DPP728, LAF-237 or BMS-47718 or a pro-drug, derivative or metabolite thereof; and

(iii) reversible non-peptidic heterocyclic inhibitors (such as xanthines and aminomethylpyrimidines) e.g. is MK-0431 or a pro-drug, derivative or metabolite thereof. Known pyrrolidine DPPIV inhibitors generally have an alpha amino acid pyrrolidine core, to which substituents are added to enhance potency, selectivity, bioavailability and duration of action. BDPX (7-Benzyl-1 ,3-dimethyl-8- piperazinoxanthine) is a competitive inhibitor of DPPIV, which has served as a lead structure and has been substituted at the Ri, R₇ and R₈ positions (Formula I) to provide a series of DPPIV inhibitors with low nanomolar affinity, a favourable pharmacokinetic profile and high DPPIV selectivity.

BDPX

Formula I In Formula I above: R₁ and R₇ are the same or different and each is selected from the group consisting of a hydrogen atom, an alkyl group as defined below (said alkyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined below, an acyl group as defined below and an alkoxy group as defined below), an alkenyl group as defined below (said alkenyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined below, an acyl group as defined below and an alkoxy group as defined below), an alkynyl group as defined below, an acyl group as defined below, a dienyl group as defined below and an aryl group as defined below; and

R₈ is selected from the group consisting a hydrogen atom, an alkyl group as defined below (said alkyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined below, an acyl group as defined below and an alkoxy group as defined below), an alkenyl group as defined below (said alkenyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined below, an acyl group as defined below and an alkoxy group as defined below), an alkynyl group as defined below, a hydroxy group, an alkoxy group as defined below, an amino group [which may be unsubstituted or substituted with one or two substituents, which may be the same or different and selected from the group consisting of an alkyl group as defined below (said alkyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined below, an acyl group as defined below and an alkoxy group as defined below), an aryl group as defined below and an acyl group as defined below], a heterocyclic group as defined below [said heterocyclic group may be unsubstituted or substituted with at least one substituent selected from the group consisting of an alkyl group as defined below (said alkyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined below, an acyl group as defined below and an alkoxy group as defined below), an aryl group as defined below and an acyl group as defined below], an acyl group as defined below, a dienyl group as defined below and an aryl group as defined below. The alkyl groups in the definitions of substituents Ri, R₇ and R₈ above are straight or branched alkyl groups having from 1 to 6 carbon atoms. Alkyl groups having from 1 to 4 carbon atoms are preferred, e.g. methyl, ethyl and propyl groups.

The alkenyl groups in the definitions of substituents R₁, R₇ and R₈ above are straight or branched alkenyl groups having from 2 to 6 carbon atoms, e.g. alkenyl groups having 2 or 3 carbon atoms.

The alkynyl groups in the definitions of substituents R₁, R₇ and R₈ above are straight or branched alkynyl groups having from 2 to 6 carbon atoms, e.g. alkynyl groups having 2 or 3 carbon atoms.

The dienyl group in the definition of R₁, R₇ and R₈ above are straight or branched dienyl groups having from 4 to 10 carbon atoms, e.g. those having from 4 to 6 carbon atoms such as 1 ,3-butadienyl groups. The halogen atoms in the definitions of R-i, R₇ and R₈ above include fluorine, chlorine, bromine and iodine atoms.

The alkoxy groups in the definition of R₈ above are alkyl groups as defined and exemplified above which are bonded to an oxygen atom. The alkoxy groups are preferably straight or branched alkoxy groups having 1 to 4 carbon atoms, such as methoxy, ethoxy and propoxy groups.

The aryl groups in the definitions of R₁, R₇ and R₈ above are aryl groups that may optionally be substituted with at least one substituent selected from the group consisting of an alkyl group as defined above, an alkenyl group as defined above, an alkynyl group as defined above, a halogen atom, a cyano group, a group of formula -

NR¹R" (wherein R' and R" are the same or different and each is a hydrogen atom or an alkyl group as defined above), a hydroxyl group and an alkoxy group as defined above, said aryl groups being aromatic hydrocarbon groups having from 6 to 14 carbon atoms in one or more rings. They preferably have from 6 to 10 carbon atoms, e.g. phenyl and naphthyl.

The acyl groups in the definitions of R₁, R₇ and R₈ above are selected from aliphatic acyl groups, aromatic acyl groups and alkoxycarbonyl groups as defined and exemplified below:

(i) aliphatic acyl groups, examples of which include alkyicarbonyl groups having from 1 to 25 carbon atoms, e.g. acetyl, halogenated alkyicarbonyl groups having from 1 to 25 carbons in which the alkyl moiety thereof is substituted by at least one halogen atom, e.g. chloroacetyl, alkoxyalkylcarbonyl groups which comprise an alkyicarbonyl group having from 1 to 25 carbon atoms in which the alkyl moiety thereof is substituted with at least one alkoxy group as defined above, e.g. methoxyacetyl, and unsaturated alkyicarbonyl groups having from 1 to 25 carbon atoms, e.g. acryloyl;

(ii) aromatic acyl groups, examples of which include arylcarbonyl groups which comprise a carbonyl group which is substituted with an aryl group as defined above, e.g. benzoyl, halogenated arylcarbonyl groups which comprise an arylcarbonyl group as defined above which is substituted with at least one halogen atom, e.g. 4- chlorobenzoyl, alkylated arylcarbonyl groups which comprise an arylcarbonyl group as defined above which is substituted with at least one alkyl group as defined above, e.g. 2,4,6- trimethylbenzoyf, alkoxylated arylcarbonyl groups which comprise an arylcarbonyl group as defined above which is substituted with at least one alkoxy group as defined above, e.g. 4-anisoyl, nitrated arylcarbonyl groups which comprise an arylcarbonyl group as defined above which is substituted with at least one nitro group, e.g. 4-nitrobenzoyl, alkoxycarbonylated arylcarbonyl groups which comprise an arylcarbonyl group as defined above which is substituted with a carbonyl group which is itself substituted with an alkoxy group as defined above, e.g. 2-(methoxycarbonyl)benzoyl, and arylated arylcarbonyl groups which comprise an arylcarbonyl group as defined above which is substituted with at least one aryl group as defined above, e.g. 4- phenylbenzoyl;

(iii) alkoxycarbonyl groups, examples of which include alkoxycarbonyl groups which comprise a carbonyl group substituted with an alkoxy group as defined above, e.g. methoxycarbonyl, and alkoxycarbonyl groups as defined above which are substituted with at least one substituent selected from the group consisting of halogen atoms and trialkylsilyl groups (wherein said alkyl groups are as defined above), examples of which include 2,2,2- trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl.

Said heterocyclic group in the definition of R₈ above is a 5- to 10-membered monocyclic or bicyclic heterocyclic group containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms, said group being a heteroaryl group, a fully saturated heterocyclic group or a partially saturated heterocyclic group.

For heteroaryl groups, in the case where the group is a bicyclic ring system, one of them at least is a heterocyclic ring. In the case of a bicyclic ring system, the group is a condensed ring, and either one ring is a heterocyclic ring and the other is a carbocyclic ring, or both of the rings are heterocyclic rings. The heterocyclic ring is a 5- or 6-membered ring and contains from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms. The carbocyclic ring is an aryl group as defined above. The monocyclic heteroaromatic group can be, for example, a pyrrolyl group, a furyl group, a pyridyl group , an imidazolyl group, a pyrazolyl group, an oxazoiyl group, an isoxazolyl group, a thiazoiyl group, an isothiazolyl group, a triazolyl group, a thiadiazolyl group, a tetrazolyl group, a pyrimidinyl group, a pyrazinyl group, an oxazinyl group or a thiazinyl group. The condensed aromatic heterocyclic ring group can be, for example, an indolyl group, an indazolyl group, a benzofuranyl group, a benzothiophenyl group, a benzimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, a quinolyl group such, an isoquinolyl group, a benzoxazinyl group, a benzothiazinyl group, an imidazopyridyl group or a thiazolopyridyl group.

The saturated heterocyclic ring group above is a 4-7 membered saturated heterocyclic ring group containing at least one ring atom selected from nitrogen, oxygen and sulfur atoms. Examples of said saturated heterocyclic ring group are 4- membered saturated heterocyclic rings such as azetidyl, etc.; 5-membered saturated heterocyclic rings such as pyrrolidyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidyl, oxazolidyl, isoxazolidyl, thiazolidyl, isothiazolidyl, etc.; 6-membered saturated heterocyclic rings such as piperidino, tetrahydropyranyl, tetrahydrothiopyranyl, piperazino, morpholino, thiomorpholino, etc.; and 7-membered saturated heterocyclic ring groups such as homopiperazino, etc.

Insulin sensitisers: Such compounds act by enhancing insulin action in muscle, fat and other tissues. The most widely used are PPAR agonists include PPARy agonists, such as thiazolidinediones (TZDs) e.g. the "glitazones" troglitazone, roziglitazone and piaglitazone and oxazolidinediones (OZD), which are relatively new classes of oral anti-diabetic drugs that agonise the peroxisome proliferator-activated nuclear receptor (PPARy) and are able to reduce insulin resistance by binding to helix 12 of PPAR causing key conformational changes that are necessary to initiate a series of events leading to the regulation of gene expression. The formulae of pioglitazone, rosiglitazone and other suitable compounds of this type are:

A further example of a thiazolidinedione PPARy agonist is a carbon tethered aryl thiazolidine dione of Formula II:

In Formula Il above:

X and Y are the same or different and each is CH₂ or O;N is an integer from 1 to 6; and

R is selected from the group consisting a hydrogen atom, an alkyl group as defined above (said alkyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined above, an acyl group as defined above and an alkoxy group as defined above), an alkenyl group as defined above (said alkenyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined above, an acyl group as defined above and an alkoxy group as defined above), an alkynyl group as defined above (said alkynyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined above, an acyl group as defined above and an alkoxy group as defined above), a hydroxy group, an alkoxy group as defined above, an amino group [which may be unsubstituted or substituted with one or two groups, which may be the same or different selected from the group consisting of an alkyl group as defined above (said alkyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined above, an acyl group as defined above and an alkoxy group as defined above), an aryl group as defined above or an acyl group as defined above], a heterocyclic group as defined above [said group may be unsubstituted or substituted with at least one substituent selected from the group consisting of an alkyl group as defined above (said alkyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined above, an acyl group as defined above and an alkoxy group as defined above), an aryl group as defined above or an acyl group as defined above], an acyl group as defined above, a dienyl group as defined above and an aryl group as defined above.

Dual PPAR agonists: Such compounds may be used in this invention, since Type 2 diabetes is frequently associated with other features such as obesity, dyslipidaemia and hypertension; as a result, approximately 75-80% of such patients die from coronary heart disease or cerebrovascular damage. Consequently, it has been proposed that dual treatment with PPAR α/γ agonists will reduce triglyceride levels and improve insulin sensitivity in the treatment of type 2 diabetes, providing glycaemic control by PPARy activation and lipid profile management by PPARq activation. PPARα/γ agonists include thiazolidinedione compounds (TZDs), which are believed to reduce insulin resistance by increasing the expression of insulin-sensitive genes activated by PPARα/γ, although additional mechanisms may be possible.

Other PPARα/γ agonists which show excellent anti-hyperglycaemic efficacy in a db/db mouse model of type 2 diabetes without the side effects of typical PPARy agonists include tetrazole series compounds of Formula III or IV and o-arylmandelic acid of Formula V. There are no reports of the use of any of these PPARα/γ agonists in intranasal therapy for the treatment of schizophrenia.

Formula III

Formula IV

In Formula III and Formula IV above: each of m-i , m₂, p and q is the same or different and is an integer from 1 to 6; and R₂ is selected from the group consisting of a hydrogen atom, an alkyl group as defined above (said alkyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined above, an acyl group as defined above and an alkoxy group as defined above), an alkenyl group as defined above (said alkenyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined above, an acyl group as defined above and an alkoxy group as defined above), an alkynyl group as defined above (said alkynyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined above, an acyl group as defined above and an alkoxy group as defined above), an acyl group as defined above, a dienyl group as defined above and an aryl group as defined above;

Formula V

Formula V

In Formula V above:

R₃ and R₄ are the same or different and each is selected from the group consisting a hydrogen atom, an alkyl group as defined above (said alkyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined above, an acyl group as defined above and an alkoxy group as defined above), an alkenyl group as defined above (said alkenyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined above, an acyl group as defined above and an alkoxy group as defined above), an alkynyl group as defined above (said alkynyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined above, an acyl group as defined above and an alkoxy group as defined above), a hydroxy group, an alkoxy group as defined above, an amino group [which may be unsubstituted or substituted with one or two substituents, which may be the same or different selected from the group consisting of an alkyl group as defined above (said alkyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined above, an acyl group as defined above and an alkoxy group as defined above), an aryl group as defined above and an acyl group as defined above], a heterocyclic group as defined above a heterocyclic group as defined below [said heterocyclic group may be unsubstituted or substituted with at least one substituent selected from the group consisting of an alkyl group as defined above (said alkyl group being optionally substituted with at least one substituent selected from the group consisting of a halogen atom, an aryl group as defined above, an acyl group as defined above and an alkoxy group as defined above), an aryl group as defined above and an acyl group as defined above], an acyl group as defined above, a dienyl group as defined above and an aryl group as defined above.

Additionally, a compound of Formula Vl (an alpha ethoxy phenyl propionic acid as used in the dual PPARα/γ agonist NNC 61-0029 (J. Med. Chem. (2002)., 45, 789) have been used as the structural starting point for development of compounds of Formula VII, VIII, IX and X:

R:

^as0»^

G,17μtø

CLSGtJM 0.40μW

Insulin Secretagogues: This class of agents acts by stimulating the body to produce insulin. The most widely used of these agents are the sulphonylureas and the benzoic acid derivatives. The sulphonylureas have been widely used for many years. First generation sulphonylureas include tolbutamide, chlorpropamide and tolazamide, while second generation sulphonylureas include glyburide, glipizide and glimepiride. Benzoic acid derivatives are a more recent class of compounds used to stimulate insulin secretion, examples include repaflinide.

HGP Inhibitors: Such compounds (hepatic glucose production inhibitors) act by inhibiting the liver's production of glucose, probably through effects on AMP-kinase. Example of HGP inhibitors include the biguanides, e.g. metformin (which is also believed to have the further benefit of stimulating the process of transporting glucose into muscle).

Glucosidase Inhibitors: Such compounds act in the intestine to block the action of enzymes that are responsible for breaking down complex carbohydrates into simple sugars. The delayed breakdown of carbohydrates helps slow down their absorption into the bloodstream and, thus, slow down the increase in blood glucose levels after a meal. Typical examples are α-glucosidase inhibitors such as acarbose and miglitol. Glucosidase inhibitors are most commonly used in combination therapy with other agents, such as insulin sensitisers. Prandial Glucose Regulators (PGRs): Restoration of the insulin secretion pattern at mealtimes (prandial phase), without stimulating insulin secretion in the 'post- absorptive' phase, is the rationale for the development of 'prandial glucose regulators', drugs that are characterized by a very rapid onset and short duration of action in stimulating insulin secretion. Repaglinide, a carbamoylmethyl benzoic acid (CMBA) derivative is the best known example of a PGR.

The following experimental evidence illustrates the invention. Evidence

A parallel transcriptomics, proteomics and metabolomics study on human brain tissue has identified altered proteins, transcriptional and metabolite perturbations associated with mitochondrial and oxidative stress responses (Prabakaran et ai, 2004). ¹H-NMR spectroscopy in conjunction with computerised pattern recognition analysis revealed elevated glucose levels in the CSF of first-onset drug-naϊve schizophrenic patients, but not in the serum samples of the same patients, suggesting that the glucoregulatory changes are brain-specific (Holmes et al., 2006; the content of this reference is incorporated herein by reference); see also Figs. 2 and 3. Furthermore, cluster analysis of the transcriptome revealed that the genes relating to energy metabolism and oxidative stress differentiated -90% of schizophrenia patients from controls.

These abnormalities pertain to abnormal oxygen or glucose supply and/or growth factor (insulin/insulin-like growth factors) signalling resulting in global metabolic disturbances. Metabolic rates for glucose and oxygen consumption mirror each other in the brain; depletion of oxygen engenders an increase in anaerobic metabolism to lactate, a decrease in the efficiency of glucose conversion to ATP and thus an increased glucose demand to satisfy brain energy needs. Under hypoxic conditions, glycogen can be quickly mobilised in response to increased or inadequate glucose supply. Abnormal glucose profiles and a higher prevalence of type Il diabetes (15.8% versus 2-3% in general population) in schizophrenia patients, coupled with reduced glycolysis and glycogenesis and enhanced glycogenosis, suggest increased glucose demand and/or cellular hypoxia within the schizophrenia prefrontal cortex.

Experimental evidence now confirms that abnormal oxygen or glucose supply and/or growth factor (insulin/insulin-like growth factors) signalling mechanisms resulting in global metabolic disturbances in the schizophrenic brain.

The behavioural and biochemical effects of novel therapeutic approaches are investigated using animal models of psychotic disorders such as schizophrenia. Of the various animal models available, the rat has been selected as the most suitable animal model for in vivo and in vitro neurobiological and behavioural investigations.

The phencyclidine (PCP) animal model of schizophrenia is used for assessment of anti-psychotic therapies. PCP has been shown to induce a psychotic state in humans closely resembling schizophrenia, both with regards to negative and positive symptoms of the disease and has been shown to exacerbate symptoms in chronic stabilised schizophrenic patients (Krystal et a/., 1994). Animal studies have demonstrated that acute treatment with PCP gives rise to an array of symptoms that relate to schizophrenia symptoms including cognitive deficits (Adams & Moghaddam, 1998). Chronic intermittent exposure to PCP induces metabolic hypofunction in the rat brain, i.e. a reduction in the rates of glucose utilisation (e.g. Cochran et al., 2003). Interestingly, clozapine was able to reverse the cognitive deficits, whilst haloperidol was ineffective (Cochran et al., 2003). This observation aligns well with clinical investigations, where clozapine, but not haloperidol, treatment improves cognitive function (Serretti et al., 2004). Furthermore, phencyclidine has also been shown to alter concentrations of Neuropeptide Y and Peptide YY, the mRNA's of which were found to be significantly down-regulated in a microarray study of post-mortem schizophrenia brain (Prabakaran et al., 2004). Both peptides are closely linked to glucose metabolism and are targets for anti-obesity therapeutic treatments (Bays, 2004).

The phencyclidine (PCP) animal model of schizophrenia is used to test the effects of classical and novel anti-diabetics via nasal, intrathecal and intracerebral routes of delivery and compared with standard systemic clozapine treatment as an appropriate control. Clozapine is currently the most efficacious antipsychotic drug (Serretti et al., 2004). The effect of intranasal insulin serves as baseline comparator in this study for both insulin and non-insulin small molecule anti-diabetics.

Insulin (Novo Nordisk A/S), the GLP-1 agonists, exendin-1 (Bachem), acylated GLP-1 (NN2211)(Novo Nordisk A/S), the DPPIV inhibitor LAF-237 (Novartis), and PPAR agonists, thiazolidinediones, oxazolidinediones, are tested for their efficacy in the PCP animal models administered intranasally, intrathecal^ and intracerebrally. The effects of various added adjuvants is investigated as a means of improving bioavailability in the CSF and subsequent therapeutic efficacy. Commercially available insulin, GLP-1 agonists, DPPIV inhibitors, thiazolidinediones (troglitazone) and PPARαy. agonists are administered in order to assess the likely efficacy of these compounds as antipsychotic drugs.

Computer-aided drug design is used to generate new pharmacophore scaffold structures for in silico screening. A combinatorial approach to drug synthesis involving altering key lipophilic/hydrophilic properties of the drug is adopted to improve bioavailability and efficacy following nasal delivery.

DPPIV has been selected as a target for drug development for several reasons: first, DPPIV-mediated cleavage of the N-terminal His-Ala of GLP-1 results in biological inactivation in vivo and hence administration of specific DPPIV inhibitors greatly enhances insulin secretion. Secondly, experimental work has revealed the presence of a "disease-specific" 3,960Da cleavage product of VGF in the CSF of drug-naϊve patients with first onset paranoid schizophrenia (Huang et al., - in press). VGF is selectively expressed in neurons in the brain, particularly in the hypothalamus, and is thought to be cleaved by DPPIV. The 3,960Da schizophrenia peptide was mapped to amino acids 22-62 of the native VGF protein, immediately adjacent to the predicted secretory signal peptide. A further peak at 3,690Da could result from the cleavage of the VGF peptide with DPPIV between a Pro and GIy residue. Thirdly, high resolution 2.1A X-ray structures are available on the protein data bases (PDP ID 1 N1 M) and the configuration of the active site catalytic triad (S630, H740, D708) and the neighbouring E205-E206 motif is well established as necessary for dipeptide selection and interaction with inhibitors (Rosenblum & Kozarich, 2003; Aertgeerts et al., 2004).

Human DPPIV comprises a homodimer related in a twofold dyad axis in which each monomer contains an N-terminal eight-bladed β-propeller domain (residues 61 - 495) fused to a C-terminal α/β-hydrolase domain (residues 39-55 and 497-766). There are two paths to the active site located at the interface of the two domains, through the central pore (15A) of the β-propeller and through a -21 A side opening. Oligopeptide N-termini are recognised by the negatively charged side chains of E205 and E206 protruding from the β-propeller domain and directed at the active site triad of S630, H740 and D708. The best catalytic efficiencies for dipeptide cleavage by DPPIV were observed with peptides containing Pro or Ala at P1 binding at the hydrophobic pocket S1 lined by residues V656, Y631 , Y662, W659, Y666 and V711. The S2 pocket is also hydrophobic and constructed out of the side chains of residues R125, F357, Y547, P550, Y631 and Y666.

Relatively hydrophobic inhibitor structures are selected to facilitate passage across the nose-brain barriers, which might be quite different from those designed for oral administration. The known DPPIV inhibitor isoleucine thiazolidide is one useful starting point.

The interactions between putative structures and the EE constellation and the two hydrophobic pockets S1 and S2 is investigated to achieve these aims using sophisticated in silico design and library approaches. GLP-1 agonists are developed based on structural information on the GLP-1

Receptor and its interaction with truncated ligands (Al-Sabah & Donnelly, 2003). Exendin-4 shares approximately 50% sequence identity with GLP-1 , particularly in the N-terminal region, and is a potent GLP-1 R agonist. The substitution of Ala-2 in GLP-1 by GIy in exendin-4 is responsible for an increased DPPIV resistance of several orders of magnitude. The design of a specific synthetic peptoidal analogue of exendin-4 is based on the model proposed by Al-Sabah & Donnelly (2003), in which features of both the N- and C-termini of the peptide interact with receptor domains. By arranging key functionalities to be located at appropriate distances to allow these interactions to occur, an artificial exendin-4 molecule is designed to interact freely with the GLP-1 R molecule.

Bioavailability of compounds through nasal applications is assessed in animal models. This is achieved by quantitative HPLC analysis of brain tissue and CSF for the given compound. The degradability of the compound in the brain and toxicity associated with either short-term or long-term administration is also assessed. Furthermore, systemic effects of nasal drug application are monitored e.g. to detect any peripheral blood sugar changes. The ability of compounds to cross the blood-brain barrier following systemic administration and systemic effects/side-effects following intranasal applications are assessed. References

Adams & Moghaddam (1998) J Neurosci. 15;18(14):5545-54.

Aertgeerts et a/ (2004) Protein Science 13, 412-421.

Al-Sabah & Donnelly (2003) Br J Pharmacol 140, 339-346. Aziz & Anderson (2002) J Nutr 132, 990-995.

Bays (2004) Obesity Res. 12, 1197-1211.

Benedict et al (2004) Psychoneuroendocrinology 29, 1326- 1334.

Braceland et al (1945) Am J Psychr 159, 1018-1028.

Brambilla et al (1976) Diseases of the Nervous System 37, 98-103. Born et al (2002) Nat Neurosci 5, 514-516.

Cochran et al (2003) Neuropsychόpharmacology 28(2):265-75.

Craft ef a/ (1992) J Clin Expl Neuropsych 14, 253-267.

Craft et a/ (1993) Behav Neurosci 107, 926-940.

Craft et al (1994) Psychobiology 22, 95-105. Craft et al (1996) Neurobiol Aging 17, 123-130.

Craft et al (1999) Arch Gen Psychiatry 56, 1135-1140.

Day (1999) Diabetic Medicine 16, 179-192.

Figlewicz (2003) Am J Physiol Regul lntegr Comp Physiol 284, R882-R892.

Franzen & Nilsson (1968) Acta Psychiatrica Scand. 44, 24-26. Fucetola et al (1999) Psychiatry Res 88, 1-13.

Gold & Stone (1988) Neurobiol Aging 9, 709-717.

Green (1996) Am J Psychiatr 153, 321-330.

Hall ef a/ (1989) Neuropsychologia 27 , 1129-1138.

Holmes et al (2006) PIoS Med 22, 3(8). Holt et al (2004) Diabetic Medicine 21 , 515-523.

Huang ef a/ (2006).

Ilium (2000) EurJ Pharm Sc/ 11 , 1-18.

Ilium (2002) Drug Discov Today 7, 1184-1189.

Kaplan et al (2000) Λm J Clin Nutr 72, 825-836. Kern et al (2001 ) Neuroendocrinology 74, 270-280.

Krystal, et a/ (1994) y\rcA7 Gen Psychiatry 51 , 199-214.

Lieberman ef a/ (2005) N Engl J Med 353, 1286-1288.

Lewis (2000) Brain Res Brain Res Rev 31 , 270-276.

Livingstone & Rampes (2003) Practical Diabetes International 20, 327-331. Lorenz (1922) Arch Neurol Psychiatry 8, 184- 196.

McMartin et a/ (1987) J Pharm Sc/ 76, 535-540. Newcomer et a/ (1999) Schizophrenia Bull 25, 315-327.

Newcomer et al (2002) Archs. Gen. Psychiatr. 59, 337-345.

Parikh et al (2003) J Psychiatr Res 37, 43-51.

Paulsen et al (1995) J lntl Neuropsych Soc 1 , 88-99. Prabakaran et al (2004) MoI. Psych. 1-14.

Rasgon & Jarvik (2004) J. Gerontol. 59A, 178-183.

Rolin et al (2002) Am J Physiol Endocrinol Metab 283, E745-E752.

Rosenblum & Kozarich (2003) Curr Opin Chem Biol 7, 496-504.

Sakane et al (1991) Chem Pharm Bull (Tokyo) 39, 2456-2458. Saha et a/ (2005) PLoS Med 2(5), e141.

Saykin et al (1994) Archs Gen Psychiatry 51 , 124-131.

Schimmelbusch ef a/(1971) Brit. J. Psychiatr. 118, 429-436.

Schultz et a/ (1999) Am. J Psychiatr. 156, 640-642.

Serretti et al (2004) Curr Med Chem. 11(3):343-58. Stoff ers et al (2000) Diabetes 49, 741 -747.

Stone ef a/ (2003) Schizophrenia Res. 62, 93-103.

Vyas ef a/ (2005) Curr Drug Deliv 2, 165-175.

World Heath Organisation (1973) Report of the International Pilot Study of

Schizophrenia. Vo1 1, Geneva, Switzerland.

Claims

1. Use of an anti-diabetic agent in the manufacture of a medicament for the treatment of a disorder that is psychotic disorder or a condition present with cognitive decline or deficit.

2. Use according to claim 1 , wherein the disorder is selected from a schizophrenic disorder, a bipolar disorder, depression, anxiety, a stress-related disorder, an autistic spectrum disorder and attention-deficit hyperactivity disorder.

3. Use according to claim 1 or claim 2, wherein the medicament is adapted for administration to the CNS.

4. Use according to any preceding claim, wherein the medicament is adapted for intranasal, transdermal, sublingual, buccal, intrathecal, ocular or intracranial administration.

5. Use according to claim 4, wherein the medicament is formulated for nasal or intranasal administration.

6. Use according to any preceding claim, wherein the anti-diabetic agent is selected from the group consisting of: insulin; a GLP-1 agonist, a DPPIV inhibitor, insulin sensitisers, a dual PPAR agonist, an insulin secretagogue, an HGP inhibitor, a glucosidase inhibitor and a prandial glucose regulator (PGR).

7. Use according to claim 6, wherein the agent is insulin.

8. Use according to claim 6, wherein the agent is a GLP-1 agonist.

9. Use according to claim 8, wherein the GLP-1 agonist is selected exendin-4 or acylated GLP-1 (NN2211).

10. Use according to claim 6, wherein the agent is a DPP IV inhibitor selected from the group consisting of reversible product analogue inhibitors (such as pyrrolidines or thiazolidines), covalently modifying product analogue inhibitors (such as cyanopyrrolidines) and reversible non-peptidic heterocyclic inhibitors (such as xanthines and aminomethylpyrimidines)

11. Use according to claim 10, wherein the agent is P32/98.

12. Use according to claim 6, wherein the agent is a PPAR agonist or a PPAR dual agonist.

13. Use according to claim 12, wherein the PPAR agonist is a PPARy or PPARα/γ agonist.

14. Use according to claim 12, wherein the agent is a thiazolidinedione or oxazolidinedione agonist.

15. Use according to claim 12, wherein the agent is o-arylmandelic acid compound or a tetrazole compound.

16. Use according to claim 6, wherein the agent is a sulphonylurea or a benzoic acid derivative.

17. Use according to claim 16, wherein the agent is a sulphonylurea selected from tolbutamide, chlorpropamide, tolazamide, glyburide, glipizide and glimepiride.

18. Use according to claim 6, wherein the agent is a biguanide.

19. Use according to claim 18, wherein the biguanide is metformin.

20. Use according to claim 6, wherein the agent is an α-glucosidase inhibitor.

21. Use according to claim 20, wherein the α-glucosidase inhibitor is acarbose or miglitol.

22. Use according to any preceding claim, wherein the anti-diabetic agent comprises a drug linked to an oligomeric group that enhances avidity of the drug for a desired target in the CNS.

23. Use according to any preceding claim, wherein the medicament comprises an odorant.

24. Use according to any preceding claim, wherein the medicament is to be administered as a spray.

25. Use according to any preceding claim, wherein the medicament is to be administered with another anti-diabetic agent, and the anti-diabetic agents are provided for simultaneous, separate or sequential administration.

26. Use according to any preceding claim, wherein the medicament is to be administered with an anti-psychotic drug, and the agent and the drug are provided for simultaneous, separate or sequential administration.