Clozapine is one drug which carries a high risk (GJ Killian et al, Lancet 1999; 354: 1841-5. L La Grenade et al, N Engl J Med 2001; 345: 224-5).

Clozapine can also cause depression of white cell counts and in the worst cases complete loss of normal white blood cell production (agranulocytosis).

The present invention relates to the co-administration of selenium together with a drug for the treatment or prevention of psychiatric or neurological disorders and particularly with clozapine. The invention provides pharmaceutical formulations comprising a drug for the treatment or prevention of psychiatric or neurological disorders together with any biologically assimilable form of selenium, such that when the drug is administered the daily dose of selenium is between 10 Ag and 2000 Ag per day.

Preferably, the daily dose of selenium provided by the formulations of the present invention is between 50 Ag

and 500 yg/day and very preferably between 150 and 300 Ug/day.

The selenium may be provided in the form of selenium yeast, selenomethionine, selenocysteine or any appropriate selenite or selenate compound. This may form a component of the formulation. Alternatively the selenium may be chemically linked to the drug to form a selenium-drug derivative.

The drug of the formulations of the present invention is one used for the prevention or treatment of psychiatric or neurological disorders. The drug may be one approved by a regulatory authority for such a treatment, including the US Food and Drug Administration (FDA) or the European Medicines Evaluation Agency (EMEA). The preferred invention is not to combine selenium with other multi-vitamin preparations, which have not been approved for administration to patients with psychiatric or neurological disorders. Preferably, the drug is one used for the treatment or prevention of psychiatric disorders including schizophrenia and bipolar disorder.

The drug clozapine is particularly suited for the formulations of the present invention.

The formulations are preferably orally administrable.

In a second aspect of the invention, the selenium and the drug may be formulated separately but provided in the same pack with instructions for co-administration.

The present invention provides a pack containing the selenium and the drug packaged for co-administration.

In a third aspect of the invention there is provided a method for the treatment or prevention of any neurological or psychiatric disease by the co- administration of a drug conventionally used to treat that disease together with selenium in any biologically assimilable form in a daily dose of between 10 Ag and 2000 Ag selenium per day. The treatment may be by separate administration of the drug and the selenium, or by administration of a formulation of the first aspect of the invention.

The invention further provides use of a formulation of the first aspect of the invention in the manufacture of a medicament for the treatment or prevention of any neurological or psychiatric disease.

The treatments are of psychiatric or neurological disorders. Preferably, the invention is used to treat psychiatric disorders including but not limited to schizophrenia, bipolar disorder, depression, anxiety disorders and personality disorders. Alternatively, the invention is for the treatment or prevention of neurological disorders including but not limited to epilepsies, Parkinson's disease, dementias of both Alzheimer and vascular types, Huntington's disease, spinocerebellar ataxias, Friedreich's ataxia, myotonic. dystrophy, amyotrophic lateral sclerosis and multiple sclerosis.

The present invention also provides a method for the reduction of side effects caused by administration of a drug for the treatment of a psychiatric or neurological disorder to a patient by the co-administration, separately or in a formulation according to the first aspect of the invention, of the drug together with

selenium in any biologically assimilable form to provide a daily dose of between 10 Ag and 2000 Ag selenium per day.

In most cases it is likely that the preferred range of selenium to used will be in the range of 50 to 500 yg/day and very preferably in the range of 150 to 300 yg/day.

The present invention is described in particular with reference to the treatment of cardiovascular illness in patients who are also being treated for psychiatric and neurological disorders. The cause of the risk of developing this illness is unknown and multiple factors may be involved. One pilot study has reported that schizophrenic patients on clozapine, a drug conventionally used to treat schizophrenia, have low selenium levels (LA Linday et al, J Clin Psychopharmacol 1995; 15: 353-60). This looked at only a few patients, however, did not analyse selenium in schizophrenic patients on other drugs, and did not look at selenium levels in patients with other disorders.

For the present invention, a large study has been carried out in normal individuals, in patients with various mood disorders including depression and bipolar disorder, in schizophrenic patients on drugs other than clozapine, and in schizophrenic patients on clozapine.

The results are shown in Table 1 below. Here the selenium levels are expressed in ymol/litre and are shown as means plus or minus the Standard Error of the Mean (SEM) Table 1 Healthy Mood Schizophrenia Schizophrenia controls disorders clozapine other drugs N 56 36 57 42 Mean age 43. 140. 636. 137. 3 Plasma Se 1. 49 0.04 1. 39 0. 05 1. 28 0.04 1. 47 0.06 Red cell Se 1. 80 0.08 1. 70 0.07 1. 47 0. 07 1. 70 0.07 This shows that all of the groups of patients, irrespective of what drugs they were on, exhibited low selenium levels, but that the levels were exceptionally low in the schizophrenic patients on clozapine.

Selenium is a constituent of many enzymes, particularly ones involved in antioxidant defences (MP Rayman, Lancet 2000; 232-240). Selenium deficiency leads to a particular risk of cardiovascular disease, especially myocarditis and cardiomyopathy. Selenium deficiency also increases susceptibility to the serious cardiac complications of viral infections (MA Beck et al, Nature Medicine 1995; 1: 433-6).

The present invention is based on the inventor's suggestion that selenium deficiency is a major cause of the cardiovascular and perhaps other problems which are associated with the ingestion of drugs for psychiatric and neurological disorders, and especially clozapine where selenium will also be helpful in preventing the depression of white cell counts and agranulocytosis.

In order to reduce the risks of drug administration, it is now proposed that all drugs for neurological and psychiatric disorders should be formulated with

sufficient selenium to prevent and correct any selenium deficiency. Though it is not clear why drugs so commonly are associated with selenium deficiency, it is now suggested that some of them increase selenium excretion or impair selenium absorption into the body.

It may therefore be necessary to incorporate levels of selenium into the drug formulation to provide a daily intake of selenium either around the normal daily requirement of selenium or, in appropriate cases, daily intakes several times higher than that.

Various official bodies have made recommendations about the usual daily selenium requirement (M Rayman 2000, Lancet 356: 233-241). These range from a low of about 50 g/day to a high of around 100 Sg/day. However, these figures do not take into account the possibility that drugs or illnesses may interfere with selenium absorption or excretion and the present invention therefore proposes that the broad range of selenium supplementation needed by those taking therapeutic drugs may range from a low of 10 pg/day in those whose selenium intakes are adequate or near adequate to a high of 2000 yg/day in those who have particular problems with selenium metabolism or absorption. In most cases it is likely that the preferred range of supplemental selenium to be added to the drug will be in the range of 50 to 500 Ag/day and very preferably in the range of 150 to 300 yg/day.

This is illustrated by a further experimental study on giving selenium to patients with schizophrenia who were taking clozapine or other psychiatric drugs (see table 2) Table 2-SELENIUM TREATMENT Lengt, Yi, ; lent g g ZCAION. zuge 9 Male'25'Since Schizophrenia 02/09/02 1. 2 1. 4 02/09/02 Clozapine 1998 (200mcg) 450mg nocte 07/10/02 . 1 07/10/02 2. 1 Female 26 Since Schizophrenia 02/09/02 1. 2 1. 9 12/09/02 Epilim 1000/d ; 1992 (200meg) 4mg/d ; 07/10/02 2. 3 2. 4 Zoloft 200mg/d ; Marine 3g/d ; Vitamin B Female 22 2 years Schizophrenia 02/09/02 1. 2 1. 5 02/09/02 Clozapine + (200mcg) 600mg/d ; 07/10/02 2. 2 2. 0 Epilim 2000mg/d ; Logynon ED 1/d Male 41 25 Schizophrenia 02/09/02 1. 1 1. 3 02/09/02 Clozapine years Mild Autism (200mcg) 800mg/d ; 07/10/02 2. 3 2. 1 Losec 20mg/d ; Clonazepam 3mg/d ; Benzotropine 4mg/d ; + laxatives Female 22 3 years Schizophrenia 03/06/02 1. 3 1. 0 05/06/02 Risperidone (lOOmcg) 8mg/d ; Levlen 7/06/02 1. 0 1. 0 ED 1/d ; 11/07/02 Quetiapine 1. 2 1. 3 400mg/d ; Vitamin E lg/d ; FGF Iron 1/d Male 22 4 years Schizophrenia 02/09/02 0. 8 1. 3 19/09/02 Clozapine (200mcg) 300mg/d ; 14/10/02 i9 i Epilim 1500mg/d Stelazine 5mg/d ; Maxepa 4g/d ; Ranitidine 300mg/d ; Benzhexol 5mg/d ; Maxalon 20mg/d ; Lithium 500mg/d Male 28 Since Schizophrenia 02/09/02 1. 5 2. 4 02/09/02 Clozapine May (200mcg) 300mg nocte 2001 07/10/02 2. 1 2. 8 Length A4e of te Plaima , ITlzess ,, v ge GT. VEN,,., ," Female 37 8 years Schizophrenia Oz/o9/o2 1. 1 1. 5 02/09/02 Clozapine (200mcg) 400mg/d ; 07/10/02 2. 5 2. 4 Citalopram 60 ; Zuclopenthixol 300mg I. M. 2/52 ; Temazepam lOmg/d ; Lithium 900mg/d ; Benzotropine 2mg/d Male 38 12 Schizophrenia 02/09/02 1. 2 1. 6 02/09/02Clozapine years (200mcg) 700mg/d ; 07/10/02 2. 4 2. 3 Epilim 2g/d Nine patients were studied. Prior to treatment all patients had red cell and plasma selenium levels in the lower part of the range for psychiatric patients. Eight of the patients were given 200yg of selenium per day in the form of selenium yeast and one was given 100yg per day. At the end of the supplementation period, all the eight patients who were given 200yg per day showed plasma and red cell selenium levels in the upper part of the range for normal individuals. However, the patient given 100 Ag per day showed no change in plasma selenium and only a small rise in red cell selenium.

This indicates that for many patients 10gag per day is unlikely to be sufficient whereas 200pg per day is likely to be sufficient giving rise to a preferred range of daily doses from 150pg to 300yg per day.

The selenium may be provided in any form which may be assimilated by the body. Many selenium supplements are prepared by growing yeast or possibly other micro- organisms on selenium-containing medium and such yeast or other micro-organism derived sources would be appropriate. Selenium may also be cheated or otherwise linked to a range of other compounds, and in

particular amino acids. Selenomethionine and selenocysteine are common naturally occurring compounds which are widely used as selenium supplements.

Inorganic salts of selenite and also selenate may be used. Any assimilable form of selenium may be employed.

The selenium may be incorporated into the actual drug delivery system whether that be tablets, liquids or emulsions, hard or soft gelatin capsules, powders, drinks, foods or any other appropriate system which may be used by those skilled in the art to deliver either a drug or a selenium product. Usually the selenium will actually be incorporated into the drug formulation or may be chemically linked to the drug to form a selenium-drug derivative. Sometimes it may be appropriate to provide the selenium in a separate formulation but linked to the drug in a combination package.

Example Formulations 1. A tablet formulation of any drug for a neurological or psychiaric disorder formulated together with a selenium compound which delivers a daily amount of selenium between 10 Ag and 2000 Ag. The selenium may be in any biologically assimilable form including yeast selenium, selenomethionine, selenocysteine, sodium selenite or sodium selenate.

2. As in example 1 where the formulation is a hard or soft gelatin capsule 3. As in example 1 where the formulation is a liquid or an emulsion with or without flavouring.

4. As in example 1 where the formulation is in any other form appropriate for oral administration including a powder or a liquid.

5. As in examples 1-4 where the drug is clozapine or one of its derivatives.

6. As in examples 1-4 where the drug is any drug for the treatment of schizophrenia including but not limited to chlorpromazine, haloperidol, risperidone, olanzapine, quetiapine, zotepine, amisulpiride, ziprasidone, sertindole, ethyl eicosapentaenoate or aripiprazole.

7. As in examples 1-4 where the drug is any drug for the treatment of depression including but not limited to amitriptyline, lofepramine, dothiepin, doxepin, trimipramine, imipramine, clomipramine, protriptyline, nortriptyline, venlafaxine, fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram, reboxetine, mirtazepine, nefazodone, trazodone, moclobemide, viloxazine, maprotiline, phenelzine, tranylcypromine or ethyl-eicosapentaenoate.

8. As in examples 1-4 where the drug is any drug for the treatment of bipolar disorder, including but not limited to lithium salts, valproic acid and its derivatives and carbamazepine.

9. As in examples 1-4 where the drug is any drug for the treatment of anxiety including but not limited to any benzodiazepines, any beta-blockers and buspirone.

10. As in examples 1-4 where the drug is any drug for the treatment of epilepsy including but not limited to carbamazepine, lamotrigine, sodium valproate, phenytoin, benzodiazepines, barbiturates, topiramate, gabapentin or vigabatrin.

11. As in examples 1-4 where the drug is any drug for the treatment of Parkinson's disease including but not limited to levodopa, benserazide, carbidopa, selegiline, tolcapone, bromocriptine, ropinirole, apomorphine, pergolide, other dopamine receptor agonists, amantadine or anticholinergic drugs.

12. As in examples 1-4 where the drug is any drug for the treatment of Huntington's disease, Friedreich's ataxia, myotonic dystrophy, amyotrophic lateral sclerosis, multiple sclerosis or any other neurodegenerative disease including but not limited to ethyl-eicosapentaenoate, riluzole, lofepramine and cyclo-oxygenase 2 inhibitors.

13. As in examples 1-4 where the drug is any drug for the treatment of any form of dementia including but not limited to donepezil, rivastigmine, or galantamine or any cholergic drug.