Background of Invention Field of Invention [02] This invention relates to the use of aldose reductase inhibitors to treat psychiatric and neurological disorders and diseases.

Related Art [03] Abnormal glucose metabolism has long been suspected as an underlying pathophysiologic mechanism of mood disorders (Kooy F. H., Hyperglycemia in Mental Disorders, Brain, 42: 214-289 (1919); Goodwin and Jamison, Manic-depressive Illness, Oxford University Press, New York (1990)). More recently, glucose intolerance (Mueller, et al., intravenous Glucose Tolerance Test in Depression, Arch. Gen. Psychiatry, 21 (4): 470-7 (1969) ; Velde and Gordon, Manic-Depressive Illness, Diabetes Mellitus, and Lithium Carbonate, Arch. Gen. Psychiatry, 21 (4): 478-85 (1969)), insulin resistance (Mueller, et al., Insulin Tolerance Test in Depression, Arch. Gen. Psychiatry., 21 (5): 587-94 (1969)) and rates of type 2 diabetes mellitus more than twice that of the general population have been reported in manic-depressive and depressed patients (Lilliker S. L., Prevalence of Diabetes in a Manic-Depressive Population, Compr. Psychiatry, 21 (4): 270-5 (1980) ; Cassidy, et al., Elevated Frequency of Diabetes Mellitus in Hospitalized Manic- depressive Patients, Am. J ; Psychiatry, 156 (9): 1417-20 (1999)). A prospective study by Eaton et al (Eaton, et al., Depression and Risk for Onset of Type II Diabetes: A Prospective Population-Based Study, Diabetes Care, 19 (10): 1097-102 (1996)), which controlled for age, sex, race, and obesity, reported that individuals diagnosed with major-depressive disorder (no distinction made between bipolar and unipolar) have a 2.2 relative risk of developing type 2 diabetes.

Moreover, manic-depressive patients, when compared to other chronically ill psychiatric patients, have been reported to suffer the highest rates of diabetes, more than three times higher than that of schizophrenics (Lilliker, supra). The etiologic significance of this co- morbidity for the pathogenesis of mood disorders remains unknown.

[04] In addition, studies of diabetic patients report two to three-fold higher rates of major depression among diabetics (Gavard, et al., Prevalence of Depression in Adults With Diabetes: An Epidemiological Evaluation, Diabetes Care, 16 (8): 1167-78 (1993)). Studies of the temporal relationship of this co-morbidity in type 2 diabetics reveal that diagnosis of depression

typically precedes diabetes diagnosis, suggesting that the depression is not reactive to the stressors of diabetes (Lustman, et al., Depression in Adults With Diabetes: Results of 5-Year Follow-Up Study, Diabetes Care, 11 (8): 605-12 (1988)). The only consistently identified risk factor for depression in diabetics is peripheral neuropathy (Ellenberg, M.; Diabetic Neuropathy: Clinical Aspects, Metabolism, 25 (12): 1627-55 (1976); Viinamaki, et al., Mental Well-Being in People with Non-Insulin-DependentDiabetes, XctaPsychiatr. Scand., 92 (5): 392-7 (1995); Geringer, etal., Depression and Diabetic Neuropathy: A Complex Relationship, J. Geriatr. Psychiatry Neurol., 1 (1): 11- 5 (1988)). Based on this finding, investigators have speculated that the pathogenesis of depression in diabetics may involve a central neuropathy, a parallel neuropathy in the central nervous system (CNS) (Geringer, supra). In fact, there is evidence for a central neuropathy in both diabetics and mood disorder patients. High rates of T2-weighted MRI subcortical white matter hyperintensities (WMHs) have been reported in diabetics (Dejgaard, et al., Evidence for Diabetic Encephalopathy, Diabet. Med., 8 (2): 162-7 (1991); Pen-OS, et al., Brain Abnormalities Demonstrated by Magnetic Resonance Imaging in Adult IDDM Patients With and Without a History of Recurrent Severe Hypoglycemia, Diabetes Care, 20 (6): 1013-8 (1997)); bipolar disorder patients (Dupont, et al., Subcortical Signal Hyperintensities in Bipolar Patients Detected by MRI, Psychiatry Res., 21 (4): 357-8 (1987); Altshuler, et al., T2 Hyperintensities in Bipolar Disorder: Magnetic Resonance Imaging Comparison and Literature Meta-Analysis, Am. J Psychiatry, 152 (8): 1139-44 (1995)); and older unipolar patients (Coffey, et al., white Matter Hyperintensity on Magnetic Resonance Imaging: Clinical and Neuroanatomic Correlates in the Depressed Elderly, J Neuropsychiatry Clin. Neurosci, 1 (2): 135-44 (1989)).

[05] A recent review of structural neuroimaging studies in mood disorders concludes that there is strong evidence that increased rates of subcortical WMHs are present in bipolar and older unipolar patients, and hypothesizes that the WMHs represent lesions which interrupt fibers, resulting in disconnection among brain regions and subsequent dysregulation of mood (Soares J. C., and Mann J. J., The Anatomy of Mood Disorders--Review of Structural Neuroimaging Studies, Biol. Psychiatry, 41 (1) : 86-106 (1997)). The etiology of these lesions is unknown, and no postmortem studies have been reported. Theories of the etiology of these WMHs vary according to patient group. In both groups, there appears to be increasing prevalence with age (Aylward, et al., Basal Ganglia Volumes and White Matter Hyperintensities in Patients With Bipolar Disorder, Am. J Psychiatry, 151 (5): 687-93 (1994); Dupont, et al., Magnetic Resonance Imaging and Mood Disorders: Localization of White Matter and Other Subcortical Abnormalities, Arch. Gen.

Psychiatry, 52 (9): 747-55 (1995)). In the older unipolar, but not the bipolar patients, there is

some evidence to suggest a cerebrovascular etiology (Greenwald, et al., MRI Signal Hyperintensities in Geriatric Depression, Arty2., Psychiatry, 153 (9): 1212-5 (1996)). However, Hickie et al (Hickie, et al., Subcortical Hyperintensities on Magnetic Resonance Imaging: Clinical Correlates and Prognostic Significance in Patients With Severe Depression, Biol. Psychiatry, 37 (3): 151- 60 (1995)) in a study of 39 older (mean age of 64 years) depressed (32 unipolar and seven bipolar) inpatients report that multiple regression analysis of potential clinical predictors of WMHs including cerebrovascular risk factors such as hypertension and history of previous cerebrovascular disease, revealed that only patient age and family history of affective disorder predicted the occurrence of MRI T2-weighted WMHs. In bipolar patients, in whom WMHs have been reported at all ages and as early as adolescence (Botteron, et al., Preliminary Study of Magnetic Resonance Imaging Characteristics in 8-to 16-Year-Olds With Mania, J Am. Acad.

Child Adolesc. Psychiatry, 34 (6): 742-9 (1995)), there has been no association with atherosclerotic disease or hypertension. (McDonald, et al., Hyperintense Lesions on Magnetic Resonance Images in Bipolar Disorder, Biol. Psychiatry, 45 (8): 965-71 (1999)). Recently, Kato et al (Kato, et al., Decreased Brain Intracellular pH Measured by 31P-MRS in Bipolar Disorder: A Confirmation in Drug-Free Patients and Correlation with White Matter Hyperintensity, Eur. Arch. Psychiatry Clin.

Neurosci., 248 (6): 301-6 (1998)) report that WMHs in seven euthymic, medication-free, bipolar patients correlate with regions of reduced intracellular pH as detected by 31p MR spectroscopy, providing the first evidence that the WMHs represent actual cellular pathology of white matter. There is also evidence to suggest that WMHs are associated with more severe and treatment refractory mood disorder. Dupont et al (Dupont, et al., Psychiatry Res., 21 (4) : 357-8 (1987) ; Dupont, et al., Subcortical Abnormalities Detected in Bipolar Affective Disorder Using Magnetic Resonance Imaging: Clinical and Neuropsychological Significance, Arch. Gen. Psychiatry, 47 (1) : 55-9 (1990)) report a positive correlation with number of previous hospitalizations in bipolar patients, and Hickie et al (Hickie, supra) report a negative correlation with treatment response to both pharmacotherapy and electroconvulsive therapy in older unipolar patients.

[06] Although cerebrovascular risk factors, such as hypertension and atherosclerosis, contribute to WMHs in diabetics, diabetes has been determined to be a risk factor for WMHs independent of the contribution of hypertension and atherosclerosis (Schmidt, et al., Magnetic Resonance Imaging Signal Hyperintensities in the Deep and Subcortical White Matter: A Comparative Study Between Stroke Patients and Normal Volunteers, Arch. Neurol., 49 (8): 825-7 (1992)). Moreover, just as peripheral neuropathy is a risk factor for depression in diabetics, peripheral neuropathy is

also a risk factor for WMHs in diabetics. WMHs have been reported in 69% of diabetics with peripheral neuropathy compared to 12% in age-matched normal controls (Dejgaard, supra).

[07] When increased polyol pathway activity was first reported to occur in diabetic animals, over 30 years ago, concentrations of sorbitol were noted to be elevated in both the peripheral (sciatic nerve) and central (spinal cord) nervous systems (Gabbay, et al., Sorbitol Pathway: Presence in Nerve and Cord with Substrate Accumulation in Diabetes, Science, 151 (707): 209-10 (1966)). Through the polyol pathway, glucose is converted to sorbitol by aldose reductase using NADPH as a cofactor. Nervous tissue is particularly vulnerable to increased polyol pathway activity, because it does not require insulin for transport of glucose into the cell (Greene, D. A., and Winegrad, A. I., Effects of Acute Experimental Diabetes on Composite Energy Metabolism in Peripheral Nerve Axons and Schwann Cells, Diabetes, 30 (11): 967-74 (1981)).

Therefore, during hyperglycemia, glucose concentration equilibrates across the cell membrane resulting in high intracellular concentrations that mirror concentrations in the extracellular compartment. High intracellular glucose concentrations result in increased intracellular conversion of glucose to sorbitol through the polyol pathway. High intracellular concentrations of sorbitol have been correlated with declining numbers of myelinated nerve fibers in diabetics with peripheral neuropathy (Dyck, et al., Nerve Glucose, Fructose, Sorbitol, Myo- inositol, and Fiber Degeneration and Regeneration in Diabetic Neuropathy, N. Engl. R Med., 319 (9): 542- 8 1988)). The precise mechanism of nerve damage is thought to be multifactorial and to include both direct nervous tissue damage and indirect ischemic damage secondary to microvascular changes in the perineurium (small vessel disease). Because of sorbitol's limited ability to cross cell membranes, it accumulates intracellularly and acts as an osmolyte, causing osmotic stress (Griffey, et al., Diabetic Neuropathy: Structural Analysis of Nerve Hydration by Magnetic Resonance Spectroscopy, JAMA, 260 (19): 2872-8 1988)). As well, oxidative stress and nerve ischemia can occur with increased polyol pathway activity, because of the depletion of NADPH and NAD+ which also serve as cofactors, respectively, for glutathione reductase, a free radical scavenging enzyme, and for endoneurial nitric oxide synthase, a vasodilatory enzyme important for microvascular function (Low, et al., The Roles of Oxidative Stress and Antioxidant Treatment in Experimental Diabetic Neuropathy, Diabetes, 46 Suppl. 2: S38-42 (1997)).

Furthermore, elevated sorbitol concentration has been associated with depletion of myoinositol, resulting in a myoinositol-related defect in nerve sodium-potassium adenosine triphosphatase (ATPase) with subsequent slowing of nerve conduction in diabetic animals (Greene, et al., Sorbitol, Phosphoinositides, and Sodium-Potassium-ATPase in the Pathogenesis of Diabetic

Complications, N. Engl. J Med., 316 (10): 599-606 (1987)). In both diabetic rats and diabetic humans, electrophysiological indicators of nerve conduction and biopsied nerve tissue have shown improvement with administration of drugs that inhibit aldose reductase (Sima, et al., Regeneration and Repair of Myelinated Fibers in Sural-Nerve Biopsy Specimens from Patients with Diabetic NeuropathyTreatedwith Sorbinil, N. Engl. J : Med., 319 (9): 548-55 (1988); Sima, et al., Overt Diabetic Neuropathy: Repair of Axo-Glial Dysjunction and Axonal Atrophy by Aldose Reductase Inhibition and its Correlation to Improvement in Nerve Conduction Velocity, Diabet. Med., 10 (2): 115-21 (1993)).

[08] In 1984, it was reported that multiple sclerosis patients have elevated levels of sorbitol and fructose in their cerebrospinal fluid, however, the relevance of the elevated levels are not known, nor is it suggested that a prevention of the accumulation of sorbitol and/or fructose would alleviate the symptoms of multiple sclerosis (Smith, S. L., and Novotny, M., Elevation of Certain Polyols in the Cerebrospinal Fluid of Patients With Multiple Sclerosis,. J. of Chromatography, 336: 351-355 (1984)).

Brief Description of the Invention [09] It is an object of this invention to use aldose reductase inhibitors to treat psychiatric disorders or diseases and/or neurological diseases or disorders. It is a further object of this invention that aldose reductase inhibitors can be used to treat psychiatric disorders or disease and/or neurological diseases or disorders in animals or humans. Administration of aldose reductase inhibitors to a human or animal having a psychiatric disorder or disease and/or neurological diseases or disorders will prevent the accumulation of sorbitol and thus treat the disease or disorder or lessen the symptoms of the disease or disorder. These diseases or disorders includes, but are not limited to, bipolar disorder, major depression, schizoaffective disorder, schizophrenia, dementia of elderly, affective psychoses, episodic Axis II psychotic conditions, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer disease.

[10] It is an object of this invention to use aldose reductase inhibitors to prevent the build- up or accumulation of sorbitol in the brain and central nervous system and peripheral nervous system (especially for patients with amyotrophic lateral sclerosis). It is a further object of this invention that aldose reductase inhibitors can prevent the build-up of sorbitol in animals or human having neurological diseases or disorders and psychiatric diseases or disorders.

Prevention of the build-up or accumulation of sorbitol in the brain and central nervous system and peripheral nervous system of animals or humans having neurological diseases or disorders and psychiatric diseases or disorders will help treat those diseases or disorders and/or alleviate the symptoms of those diseases or disorders and psychiatric diseases or

disorders. These diseases or disorders includes, but are not limited to, bipolar disorder, major depression, schizoaffective disorder, schizophrenia, dementia of elderly, affective psychoses, episodic Axis II psychotic conditions, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer disease.

[11] It is another object of this invention to use aldose reductase inhibitors to prevent the onset of psychiatric disorders or disease and/or neurological diseases or disorder in animals and humans. It is a further object of this invention that one administers aldose reductase inhibitors to animals and humans having a predisposition to psychiatric disorders or disease and/or neurological diseases or disorder. These diseases or disorders includes, but are not limited to, bipolar disorder, major depression, schizoaffective disorder, schizophrenia, dementia of elderly, affective psychoses, episodic Axis II psychotic conditions, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer disease.

[12] It is an object of this invention to administer compounds which inhibit or prevent the accumulation of sorbitol in the brain and/or central nervous system of an animal (including mammals and humans) to prevent or treat various psychiatric disorders or disease and/or neurological diseases or disorders in the animal. The psychiatric disorders or disease and/or neurological diseases or disorder include, but are not limited to, bipolar disorder, major depression, schizoaffective disorder, schizophrenia, dementia of elderly, affective psychoses, episodic Axis II psychotic conditions, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer disease. Compounds which prevents or inhibits sorbitol accumulation can be aldose reductase inhibitors.

[13] Examples of aldose reductase inhibitors useful in this invention include, but are not limited to, alrestatin, sorbinil, N-4- (benzoylamino) phenylsulfonyl glycine, zenarestat, tolrestat, fidarestat, ponalrestat, epalrestat, GP-1447, ONO-2235, CT-112, WAY-121,509, and 3- (arylmethyl)-2, 4,5-trioxoimidazolidine-1-acetic acid.

Detailed Description of the Invention [14] This invention involves the usage of aldose reductase inhibitors to treat psychiatric disorders or neurological diseases in humans and animals.

[15] Numerous aldose reductase inhibitors exist. A partial listing of these compounds include alrestatin, sorbinil, N-4- (benzoylamino) phenylsulfonyl glycine, zenarestat, tolrestat, fidarestat, ponalrestat, epalrestat, GP-1447, ONO-2235, CT-112, WAY-121,509, IDD 598, and 3- (arylmethyl)-2, 4,5-trioxoimidazolidine-1-acetic acid. Other aldose reductase inhibitors are well-known in the art field and are included in this invention.

[16] Aldose reductase inhibitors can be administered by any method. It is preferable to administer aldose reductase inhibitors orally, and via the following modes of injections: intravenous, intramuscular, intraspinal, intrameningeal, intracranial, and intrathecal. It is more preferable to administer aldose reductase inhibitors orally.

[17] As used herein, the term"pharmaceutically acceptable carrier"means a chemical composition with which the active ingredient may be combined and which, following the combination, can be used to administer the active ingredient to a subject.

[18] As used herein, the term"physiologically acceptable"ester or salt means an ester or salt form of the active ingredient which is compatible with any other ingredients of the pharmaceutical composition, which is not deleterious to the subject to which the composition is to be administered.

[19] The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single-or multi-dose unit.

[20] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, and other mammals.

[21] Pharmaceutical compositions that are useful in the methods of the invention may be prepared, packaged, or sold in formulations suitable for parenteral, topical, pulmonary, intranasal, buccal, ophthalmic, intrathecal, intraspinal, intrameningeal, intracranial, or another route of administration.

[22] A pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a"unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of

the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

[23] Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations.

Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i. e. powder or granular) form for reconstitution with a suitable vehicle (e. g. sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

[24] Pharmaceutical compositions of the invention formulated for pulmonary delivery may also provide the active ingredient in the form of droplets of a solution or suspension. Such formulations may be prepared, packaged, or sold as aqueous or dilute alcoholic solutions or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration preferably have an average diameter in the range from about 0.1 to about 200 nanometers. The formulations described herein as being useful for pulmonary delivery are also useful for intranasal delivery of a pharmaceutical composition of the invention.

[25] As used herein,"parenteral administration"of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical

wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal, intraspinal, intrameningeal, intracranial injections, and kidney dialytic infusion techniques.

[26] For central nervous system (CNS) disorders an amount of the compound sufficient to inhibit the conversion of glucose to sorbitol CNS is necessary. CNS disorders, for this invention, include bipolar disorder, major depression, schizoaffective disorder, schizophrenia, dementia of elderly, affective psychoses, episodic Axis II psychotic conditions, multiple sclerosis, and Alzheimer disease. (ALS affects the peripheral nervous system.) The amount of aldose reductase inhibitor to be administered depends on the particular compound used.

One can determine the amount of aldose reductase inhibitor to use by monitoring several indicia which can be accomplished with ease. These indicia include, but are not limited to, the amount of the compound in the CSF and the amount of sorbitol in the CSF. The amount of compound in the CSF depends, in part, on the drug's ability to cross the blood-brain- barrier and enter the CNS (if the drug is not directly administered into the CSF or brain). As an example, it is preferable to administer fidarestat (SNK 860) orally in the amount of between 1 mg/day and 40 mg/day, however the dosage administered orally can range from 500 gg/day to 1000 mg/day. From animal studies, it is estimated that the concentration of fidarestat in the CNS is 20-times less than the concentration of fidarestat in the periphery.

Therefore, a preferable dosage of fidarestat to achieve the desired CNS concentration is in the range of 20 mg/liter/day to 800 mg/liter/day but can range from 1 mg/liter/day to 20 g/liter/day. Should the ability of fidarestat to cross the blood-brain barrier increase or should the compound be administered to the CSF, then the dosage administered will be less than the dosage administered orally or intramuscularly.

[27] For patients with ALS, the preferred dosage of fidarestat is less than the preferred dosage for CNS disorders because ALS is primarily a periperal nervous system disorder. For ALS, a preferred dosage range is 1 mg and 40 mg per day but can range from 500 jig to 1000 mg per day.

[28] Aldose reductase inhibitors can be used to treat psychiatric disorders in humans and in animals. The particular psychiatric disorders include, but are not limited to, bipolar disorder, major depression, schizoaffective disorder, schizophrenia, dementia of elderly, affective psychoses (such as mania and psychotic depression), and episodic Axis II psychotic conditions.

[29] Aldose reductase inhibitors may also be useful in treating neurodevelopmental disorders, such as but not limited to, autism, mental retardation, and subclinical or latent psychosis. Furthermore, aldose reductase inhibitors may be used to treat multiple sclerosis, amyotrophic lateral sclerosis (ALS), and other neurodegenerative diseases. Diabetes may be present in the patients or animals having these psychiatric disorders and diseases, neurodevelopmental disorders and diseases, and neurodenerative disorders and diseases, and other conditions.

[30] The glucose metabolite concentrations in cerebral spinal fluid are determined for multiple sclerosis patients with progressive multiple sclerosis (MS Prog) (n = 8) and for multiple sclerosis patients with relapsing or remitting forms of multiple sclerosis (MS RR) (n = 9). The control patients (n = 16) are individuals who have had spinal taps for the investigation of conditions which do not affect polyol metabolism (e. g., headaches). The mean age for the patients are 42.3 ( 12) years for MS Prog, 39.6 ( 8) years for MS RR; and 38.8 ( 12) years for control patients. Three-fourths of the patients are female, and all are white. Of these patients, the cerebral spinal fluid levels of sorbitol and myioinositol are highly elevated in the MS Prog group as compared to the control and only slightly elevated in the MS RR group compared to the control group. Fructose levels are highly elevated in both types of multiple sclerosis patients compared to control. See Table 1 for the results.

Table 1

Group Glucose Lactate Sorbitol Fructose Myoinositol (jiM) (mg/dl) (mM) (RM) (AM) Mea=SD MeanSD MeanSD Mean+SDa Mean+SD Control 54.17 1. 39_0. 23 14.8+2.7 18774 15236 MS RR 61.315 1. 580. 36 18. 04. 5 405132 158+33 MS Prog 58.310 1. 600. 48 27. 36. 4 305199 235195 ameans significantly different by one-way ANOVA, p<0.001. bMS Prog mean significantly different from Neurocontrol and MS RR means by Least Significant Difference test, p<0.001.

Example 1 [31] In a placebo-controlled, double-blind study lasting 6 months, patients with any of the following disorders are recruited: bipolar disorder, major depression, schizoaffective disorder, and schizophrenia, with or without diabetes comorbidity. This study could use fidarestat as either a sole or an adjunctive treatment for the psychiatric disorder.

[32] Fifty patients are randomized to placebo, 20 mg per day of fidarestat, or 40 mg per day of fidarestat. Patients take the medication and placebo orally. All patients have blood sorbitol and cerebral spinal fluid (CSF) sorbitol levels measured. Patients also have an MRI to assess white matter hyperintensities. Interviews are conducted to determine psychiatric disease diagnosis and rating scales are administered to determine level of symptoms (e. g., for depression: Hamilton Depression Scale; for bipolar disorder: HAM-D or Young Mania Scale ; for, all disorders: Brief Psychiatric Rating Scale (BPRS)).

[33] Rating scales are administered biweekly for 6 months. Sorbitol levels in blood are determined biweekly. Sorbitol levels in the CSF are assessed at the beginning and end of treatment. Patients undergo another MRI at the end of six months for comparison with first MRI for assessment of effect on white matter disease.

[34] At the end of six months, all patients are assessed for an improvement of clinical symptoms, decreased MRI evidence of brain white matter hyperintensities, and decreased sorbitol levels in the CSF and blood.

[35] Compared to placebo-treated subjects, psychiatric subjects treated with fidarestat should show a greater improvement or stabilization of their disorders as indicated by the following: Depressed subjects treated with an aldose reductase inhibitor (ARI) will have a greater reduction in HDRS score, on average, from a score of 25 to 10 points compared to placebo-treated subjects. Manic subjects treated with an aldose reductase inhibitor (ARI) will have a greater reduction in YMRS score, on average, from a score of 40 to 10 points compared to placebo-treated subjects. All psychiatric patients including schizophrenic, schizoaffective, depressed, manic and other subjects treated with an aldose reductase inhibitor (ARI) will have a greater reduction in BPRS score, on average, from a score of 40 to 10 points compared to placebo-treated subjects.

[36] Volume of MRI white matter hyperintensities in psychiatric disorder subjects will show a greater decrease, on average, from 10%--20% of total white matter to 5%--10 % compared to placebo-treated subjects who would have no reduction or a modest (1% or 2%) increase. This finding demonstrate that aldose reductase inhibition improves an MRI indicator of CNS white matter disease.

[37] In the patients in this study, the CSF sorbitol concentrations prior to treatment should range from approximately 20 llmoles/liter to 100, umoles/liter. Following treatment, the CSF sorbitol concentrations should range from approximately >1 Rmoles/liter to 30 umoles/liter.

This reduction in CSF sorbitol concentrations demonstrates the effective inhibition of aldose reductase in the CNS.

Example 2 [38] In a placebo-controlled, double-blind study lasting 6 months, patients with any of the following disorders are recruited: multiple sclerosis (MS), amyotrophic lateral sclerosis, and Alzheimer disease, with or without diabetes comorbidity.

[39] Fifty patients are randomized to placebo, 20 mg per day of fidarestat, or 40 mg per day of fidarestat. Patients take the medication and placebo orally. All patients have blood sorbitol and cerebral spinal fluid (CSF) sorbitol levels measured. Patients also have an MRI to assess white matter hyperintensities.

[40] Assessment of the patients'neurological condition is conducted biweekly. For Alzheimer's disease, the assessments include Clinical Global Impression (CGI), Mini-Mental State Exam (MMSE), the ADAS-Cog scale, and the Neuropsychiatiric Inventory (NPI). For MS patients, the assessments include Kurtzke's Expanded Disability Status Scale (EDSS), the SF-36-Short form 36, Ashworth Spasticity Scale, Mini-Mental State Exam (MMSE), and the Neuropsychiatiric Inventory (NPI). For ALS patients, the assessments include the SF-36 - Short form 36, quantitative myometry, forced vital capacity measurement, ALS Functional Rating Scale, and the Ashworth Spasticity Scale. Sorbitol levels in the CSF are assessed at the beginning and end of treatment. Patients undergo another MRI at the end of six months for comparison with first MRI for assessment of effect on white matter disease.

[41] At the end of six months, all patients are assessed for an improvement of clinical symptoms, decreased MRI evidence of brain white matter hyperintensities, and decreased sorbitol levels in the CSF and blood. Compared to the placebo-treated subjects, the neurologic subjects treated with fidarestat should show a greater improvement or stabilization of their disorders as indicated by the following: MS subjects treated with an aldose reductase inhibitor (ARI) will have a greater increase in Kurtzke's Expanded Disability Status Scale (EDSS), on average, from a score of 3 points to 4 points, a greater increase in MMSE, on average, from a score of 24 points to 26 points, a greater decrease in Ashworth Spasticity Scale score, on average, from a score of 4 points to 2 points, and a greater increase in the SF- 36 score, on average, from a score of 40 points to 60 points, compared to placebo-treated subjects. Alzheimer subjects treated with an aldose reductase inhibitor (ARI) will have a greater reduction in NPI score, on average, from a score of 30 points to 20 points, a greater

increase in MMSE, on average, from a score of 20 points to 22 points, and a greater decrease in CGI score, on average, from a score of 4 points to 2 points compared to placebo-treated subjects. ALS subjects treated with an aldose reductase inhibitor (ARI) will have a greater reduction in the Ashworth Spasticity Scale score, on average, from a score of 4 points to 2 points, a greater increase in the ALS Functional Rating Scale, on average, from a score of 20 points to 30 points, a greater increase in the SF-36 score, on average, from 40 points to 60 points, and a greater percentage of subjects with improvements in forced vital capacity and maximal voluntary isometric muscular contraction (MVIC) of the knee and elbow joints compared to placebo-treated subjects.

[42] Volume of MRI white matter hyperintensities in neurological disorder subjects will show a greater decrease on average from 10%--20% of total white matter to 5% to 10 % compared to placebo-treated subjects who would have no reduction or a modest (1% or 2%) increase. This finding demonstrates that aldose reductase inhibition improves an MRI indicator of CNS white matter disease.

[43] The CSF sorbitol concentrations prior to treatment range from approximately 20 Rmoles/liter to 100 Fmoles/liter. Following treatment, concentrations range from approximately >1 umoles/liter to 30 Fmoles/liter. This reduction in CSF sorbitol concentrations demonstrates the effective inhibition of aldose reductase in the CNS.

[44) The examples provided herein are for illustrative purposes only and are in no way intended to limit the scope of the present invention. While the invention has been described in detail, and with reference to specific embodiments thereof, it will be apparent to one with ordinary skill in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.