(12) United States Patent
`Peet et al.
`
`USOO6384077B1
`(10) Patent No.:
`US 6,384,077 B1
`(45) Date of Patent:
`May 7, 2002
`
`(54) HIGHLY PURIFIED EPA FOR TREATMENT
`OF SCHIZOPHRENIA AND RELATED
`DSORDERS
`
`(75) Inventors: Malcolm Peet, Sheffield (GB); Krishna
`S Vaddadi, Melbourne (AU)
`(73) Assignee: Laxdale Limited, Stirling (GB)
`(*) Notice:
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/492,741
`(22) Filed:
`Jan. 27, 2000
`(30)
`Foreign Application Priority Data
`Jan. 27, 1999
`(GB) ............................................. 990 1809
`(51) Int. Cl. ................................................ A61K 31/20
`(52) U.S. Cl. ....................................................... 514/560
`(58) Field of Search .......................................... 514/560
`(56)
`References Cited
`U.S. PATENT DOCUMENTS
`
`5,252,333 A 10/1993 Horrobin .................... 424/422
`5,840,944 A 11/1998 Furihata et al. ............. 554/175
`FOREIGN PATENT DOCUMENTS
`
`GB
`WO
`
`214.8713 A 6/1985
`WO98/16216
`4/1998
`
`OTHER PUBLICATIONS
`Malcolm Peet et al., Phospholipid Spectrum Disorder in
`Psychiatry pp. 1-19, 1999.
`Brian E. Leonard, Fundamentals of Psychopharmacology,
`pp. 186–187, 1997.
`Diagnostic and Statistical Manual of Mental Disorders, 4"
`Ed., published by the American Psychiatric Assoc., pp. 285,
`1995.
`Martin A. Samuels, M. D. et al, Office Practice of Neurol
`ogy, Chapter 122, Huntington's Disease, pp. 654-655, 1996.
`S. Leucht et al, Schizophrenia Research, vol. 35, “Efficacy
`and extrapyramidal side-effects . . .'', pp. 51-68, 1999.
`Nina Willumsen et al, Biochimica et Biophysica Acta. Vol.
`1369, “On the effect of 2-deuterium-... ', pp. 193-203,
`1998.
`
`E. Mayatepek et al, The Lancet, vol. 352, “Leukotriene
`C4-synthesis deficiency ... ', pp. 1514-1517, Nov. 7, 1998.
`Atsushi Yamashita et al., J. Biochem., vol. 122, No. 1,
`“Acyl-transferases and Transacylases ... ', pp. 1-16, 1997.
`Yang Cao et al., Genomics, Vol. 49, "Cloning, Expression,
`and Chromosomal Locatlization ... ', pp. 327-331, 1998.
`Monica Piccini et al, Genomics, vol. 47, "FACL4, a New
`Gene Encoding Long-Chain Acyl-CoA. ... ', pp. 350-358,
`1998.
`Michael J. Finnen et al, Biochemical Society Trans., “Puri
`fication and characterisation ... ', pp. 19, 1991.
`Andrew L. Stoll et al, Arch. Gen. Psychiatry, vol. 56,
`“Omega 3 Fatty Acids in Bipolar Disorder”, pp. 407-412,
`May 1999.
`B. Puri et al., Archives of General Psychiatry, No. 55,
`“Sustained remission of positive and . . . ', pp. 188-189,
`1998.
`Stephen T. Warren, Science, vol. 271, “The Expanding
`World of Trinucleotide Repeats", pp. 1374–1375, Mar. 8,
`1996.
`Victor O. Ona et al, NATURE, vol. 399, “Inhibition of
`caspase-1 slows disease progression . . . ', pp. 263-267,
`May 20, 1999.
`Philippe Dijan et al., Proc. Natl. Acad. Sci., vol. 93, “Codon
`repeats in genes associated . . . ', pp. 417-421, Jan. 1996.
`M. Flint Beal, MD, Annals of Neurology, vol. 38, No. 3,
`“Aging, Energy, and Oxidative Stress in ... ', pp. 357-366,
`Sep.1995.
`
`Primary Examiner William R. A. Jarvis
`(74) Attorney, Agent, or Firm-Jacobson Holman, PLLC
`(57)
`ABSTRACT
`A pharmaceutical preparation comprising EPA in an appro
`priately assimilable form where of all the fatty acids present
`in the preparation at least 90%, and preferably at least 95%,
`is in the form of EPA and where less than 5%, and preferably
`less than 3%, is in the form of DHA is provided for the
`treatment of a psychiatric or central nervous disorder. The
`preparation may be administered with conventional drugs to
`treat psychiatric or central nervous disorders to improve
`their efficacy or reduce their side effects.
`
`21 Claims, 3 Drawing Sheets
`
`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1040, p. 1 of 14
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`

`

`U.S. Patent
`
`May 7, 2002
`
`Sheet 1 of 3
`
`US 6,384,077 B1
`
`Figure 1. The synthesis of eicosapentaenoic acid from alpha-linolenic acid
`
`18:3n-3
`
`Alpha-linolenic acid
`
`Delta-6-desaturation
`
`18:4n-3
`
`Stearidonic acid
`
`Elongation
`
`20:4n-3
`
`Eicosatetraenoic acid, n-3
`
`20:5n-3
`
`Eicosapentaenoic acid
`
`Hikma Pharmaceuticals
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`IPR2022-00215
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`Hikma Pharmaceuticals
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`U.S. Patent
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`US 6,384,077 B1
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`NOI LOTICISN\/?IL TV/NS) IS CIICHITOHc|SOHCH
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`
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`VOO-\/-ITTH
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`
`
`s?onpoud uo?ep?xO
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`US 6,384,077 B1
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`1
`HIGHLY PURIFED EPA FOR TREATMENT
`OF SCHIZOPHRENIA AND RELATED
`DISORDERS
`BACKGROUND OF THE INVENTION
`Even though many new drugs have been discovered over
`the past twenty years, psychiatric disorders are still rela
`tively poorly treated. With most psychiatric illnesses, drug
`treatments do not treat all patients Successfully. This is true
`of Schizophrenia, Schizoaffective and Schizotypal disorders,
`bipolar disorder (manic-depression), unipolar depression,
`dementias, panic attacks, anxiety, sleep disorders, attention,
`hyperactivity and conduct disorders, autism, personality
`disorders, and all other psychiatric conditions. For example,
`in depression, Standard drugs achieve a 50% reduction in
`Standard depression Scores in about two thirds of patients:
`the others do not respond. In Schizophrenia, the average
`improvements are only of the order of 20–30% (S Leucht et
`al, Schizophrenia Research 1999;35:51-68) although indi
`vidual patients may do much better than this.
`The Same is true of neurological disorders like Alzhe
`imer's disease and other dementias, Parkinson's disease,
`multiple Sclerosis, Stroke, epilepsy and Huntington's dis
`ease. Again, many patients fail to respond to existing
`treatments, or respond only to a limited degree. In none of
`these conditions do existing drugs reliably produce a com
`25
`plete remission of Symptoms. There is therefore a great need
`for new treatments, particularly ones which have novel
`mechanisms of action.
`In PCT filing WO98/16216 attention was drawn to the
`value of a particular fatty acid, eicosapentaenoic acid (EPA),
`and its derivatives, in the treatment of Schizophrenia, depres
`Sion and dementias. EPA is a highly unsaturated fatty acid
`which can be derived from the dietary essential fatty acid,
`O-linolenic acid by a series of three reactions (FIG. 1). EPA
`is a fatty acid containing 20 carbon atoms and 5 double
`bonds, all in the cis-configuration. The double bonds are
`35
`located at the 5, 8, 11, 14 and 17 positions and the full
`chemical name is therefore all cis (or all Z) 5, 8, 11, 14,
`17-eicosapentaenoic acid (or Sometimes icosapentaenoic
`acid). The abbreviation which is always used is EPA. EPA is
`one of the highly unsaturated fatty acids, the main types of
`which are shown in FIG. 2. The reactions which convert
`alpha-linolenic acid to EPA are slow in humans and only a
`very Small proportion of dietary C-linolenic acid is con
`verted to EPA. EPA is also found in marine micro-organisms
`and, via the food chain, makes up between 3% and 30% of
`45
`natural marine oils derived from oily fish and marine mam
`mals. EPA is found linked to many different chemical
`Structures. It can be found in the form of phospholipids, tri,
`di- and monoglycerides, amides, esters of many different
`types, Salts and other compounds. In each case the EPA
`50
`moiety can normally be split from the complex molecule to
`give the free acid form which can then be linked again to
`other complex molecules.
`As described in PCT filing WO 98/16216 it was unex
`pectedly found that an oil enriched in EPA was of value in
`treating Schizophrenia, while an oil enriched in the closely
`related fatty acid, docosahexaenoic acid (DHA), was not.
`This was Surprising because DHA is found in large amounts
`in human brain whereas EPA is found only in trace quanti
`ties. It was therefore anticipated that DHA would be effec
`60
`tive but EPA would not. In fact the opposite was found. WO
`98/16216 disclosed the use of EPA and its derivatives for the
`treatment of psychiatric disorders.
`SUMMARY OF THE INVENTION
`The present invention provides a pharmaceutical prepa
`ration comprising EPA in an appropriately assimilable form
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`where of all the fatty acids present in the preparation at least
`90%, and preferably at least 95%, is in the form of EPA and
`where less than 5%, and preferably less than 3%, is in the
`form of docosahexaenoic acid. Such preparations are for the
`treatment of any disorder except peripheral vascular disease
`and hyper-triglyceridaemia.
`Preferably, among the other fatty acids present there are
`less than 5%, and preferably less than 3%, of each of AA or
`DPA-n-3, individually. The same preferably applies for any
`other fatty acids which might compete with the EPA.
`It is preferred that the aggregate DHA, AA and/or DPA
`n-3 content is less than 10%, of the total fatty acids present,
`and preferably less than 5%.
`The EPA may be in the form of ethyl-EPA, lithium EPA,
`mono-, di- or triglyceride EPA or any other ester or Salt of
`EPA, or the free acid form of EPA. The EPA may also be in
`the form of a 2-substituted derivative or other derivative
`which slows down its rate of oxidation but does not other
`wise change its biological action on psychiatric or brain
`disorders to any substantial degree (N. Willumsen et al.,
`Biochimica Biophysica Acta, 1998, 1369: 193–203).
`Such pharmaceutical preparations may be used for the
`treatment of a psychiatric or central nervous System
`disorder, including: Schizophrenia, Schizoaffective disorder
`or a Schizotypal disorder; depression or manic-depression
`(bipolar disorder); anxiety or panic disorder or Social
`phobia, or a Sleep disorder or an attention deficit, conduct,
`hyperactivity or personality disorder; autism; Alzheimer's
`disease, vascular dementia or another dementia, including
`multi-infarct dementia, Lewy body disease and diseases
`attributable to prion disorders; Parkinson's disease, or other
`motor System disorder; multiple Sclerosis, Stroke; epilepsy;
`and Huntington's disease or any other neuro-degenerative
`disorder.
`The present invention further provides formulations for
`use in psychiatric and neurological disorders in which a drug
`which acts primarily on neurotransmitter metabolism or
`receptorS is prepared for co-administration with a pharma
`ceutical preparation according to the first aspect of the
`invention, as well as pharmaceutical formulations compris
`ing a preparation according to the first aspect of the inven
`tion together with a drug which acts primarily on neurotrans
`mitter metabolism or receptors. The conventional drug may
`administered in conventional dosage, and the EPA formu
`lations according to the first aspect of the invention admin
`istered to the patient Separately. The conventional drug may
`be combined with the EPA preparations of the first aspect of
`the invention in a combination formulation, or the two may
`be provided in Separate individual formulations but in a
`combination pack.
`The EPA-containing preparations of the present invention
`may be administered with any drug known to have an effect
`on the treatment of psychiatric or central nervous System
`disorders to improve the efficacy of the drug or reduce its
`side effects.
`Suitable drugs for co-administration with the EPA prepa
`rations of the first aspect of the invention are clozapine, and
`any one of the class of typical or atypical neuroleptics,
`including chlorpromazine, haloperidol, risperidone,
`Olanzapine, Sertindole, Ziprasidone, Zote pine or
`amisulpiride. Others are mentioned below.
`The present invention still further provides a method of
`treating or preventing the Side effects of a drug used in
`treating psychiatric or neurological disorders by administra
`tion of the drug and a pharmaceutical preparation according
`to the first aspect of the present invention.
`
`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1040, p. 5 of 14
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`BRIEF DESCRIPTION OF THE DRAWINGS
`This invention is further understood by reference to the
`drawings wherein:
`FIG. 1 is a Schematic showing the Synthesis of eicosap
`entaenoic acid from alpha-linolenic acid.
`FIG. 2 is a Schematic showing the metabolism of essential
`fatty acids.
`FIG. 3 is a Schematic showing phospholipid signal trans
`duction.
`
`4
`Acyltransferases and transacylases involved in fatty acid
`remodelling of phospholipids and metabolism of bioactive
`lipids in mammalian cells. J Biochem 122:1-16, 1997). This
`sequence thus removes from the nerve cell the HUFAS and
`the LyPLS and brings to an end the events associated with
`Signal transduction, So preparing the neuron for the next
`stimulus (FIG. 3).
`There is now a Substantial amount of evidence which
`demonstrates that in the three major psychotic mental ill
`neSSes there is increased activity of one or more of the
`phospholipase group of enzymes and particularly in one or
`more of the PLA group. These three illnesses are
`Schizophrenia, bipolar disorder and major depression: the
`three disorders are often found together in the same families,
`and often have overlapping ranges of Symptoms. It has long
`been thought that at least part of their biochemical basis is
`common to all three disorders and it is possible that the
`PLA abnormality constitutes that common factor. In
`Schizophrenia, there are increasing circulating levels of
`PLA in the blood. In bipolar disorder, lithium, which is the
`main established treatment, has been shown to inhibit the
`activity of PLA. In major depression, there is depletion of
`HUFAS of the n-3 series from membranes, coupled with
`activation of inflammatory responses which occurs with
`enhanced activity of PLA. Each of those illnesses, however,
`involves more than one biochemical abnormality: while a
`PLA or related phospholipase abnormality may be common
`to all three, the other abnormalities are probably Specific to
`each disease.
`In Schizophrenia, it has recently been discovered that
`there is a Second abnormality in the fatty acid cycle. This is
`a deficit in function of FACL-4, the enzyme which links
`HUFAS to coenzyme A in human brain (Y Cao et al,
`Cloning, expression and chromosomal localization of
`human long-chain fatty acid-CoA ligase 4 (FACL4) Genom
`ics 1998; 49:327–330). It is known that there is a defect in
`the incorporation of HUFAS into phospholipids in schizo
`phrenia but the precise enzyme has not been known.
`However, FACL-4 is found in brain, is specific for HUFAS,
`and when absent produces both brain abnormalities and also
`minor physical abnormalities Such as a high arched palate
`which are typical of patients with schizophrenia (M Piccini
`et al., FACL-4, a new gene encoding long-chain acyl-CoA
`Synthetase 4, is deleted in a family with Alport Syndrome,
`elliptocytosis and mental retardation. Genomics
`1998:47:350–358). It is the combined presence of both the
`enzyme abnormalities which produces the disease.
`The second or other abnormalities in bipolar disorder and
`in major depression are not yet known. Another
`phospholipase, PLC, which acts at the Sn3 position to
`liberate inositol phosphates and diacylglycerol may be
`involved in bipolar disorder. Both of these molecules, like
`LyPL and HUFAS, are involved in cell signalling: overac
`tivation of both PLC and PLA is likely to be related to
`bipolar disorder.
`In the neurodegenerative conditions there appears to be an
`uncontrolled activation of membrane degrading enzymes
`like phospholipases, coupled with increased formation of
`free radicals associated with the oxidation of HUFAS and the
`membrane damage produced by LyPL. This type of
`phenomenon, with membrane damage associated with
`exceSS phospholipase activity, has been well described by
`many investigators in Alzheimer's disease and other
`dementias, in multiple Sclerosis, in Stroke and other brain
`disorders caused by ischaemia or injury, in Parkinson's
`disease, in epilepsy and in Huntington's disease. In attention
`deficit disorder, also known as hyperactivity, there are
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`DETAILED DESCRIPTION OF THE
`INVENTION
`It is important in treatment of psychiatric disorders to use
`pure or nearly pure EPA and EPA derivatives. It is a
`Surprising conclusion that DHA and related fatty acids may
`not only be ineffective but may actually reduce the efficacy
`of EPA and its derivatives.
`Phospholipids are the main components of nerve cell
`membranes. In nerve cells the middle carbon atom of
`phospholipids, known as Sn2, is usually attached to a highly
`unsaturated fatty acid (HUFA) such as DHA, arachidonic
`acid (AA), and sometimes EPA. HUFAS are fatty acids
`containing 18–26 carbon atoms and three or more double
`bonds. When nerve cells are activated, for example by
`dopamine or Serotonin, the activity of a group of enzymes
`collectively known as phospholipase A (PLA) is fre
`quently increased. PLA releases the HUFA from the Sn2
`position, giving a free molecule of HUFA and a molecule of
`what is known as a lysophospholipid (LyPL) (a phospholipid
`without a fatty acid attached to the Sn2 position) (FIG. 3).
`Both of these molecules can be highly active cell Signalling
`agents themselves, and can change cell function in a number
`of different ways. In addition, the HUFA can be converted to
`prostaglandins, leukotrienes, hydroxy acids and a whole
`range of Short-lived molecules which regulate neuronal
`function. For example, one of these molecules derived from
`arachidonic acid, leukotriene C4, Seems to be absolutely
`required for normal nerve cell growth and development (E
`Mayatepek and B Flock, Leukotriene C4-synthesis defi
`ciency: a new inborn error of metabolism linked to a fatal
`developmental syndrome Lancet 1998; 352: 1514–7).
`If cell function is to be normal, it is important that this
`activation should be temporary and should be terminated by
`45
`removing the free HUFA and the LyPL. Otherwise mem
`brane damage may result because the LyPL can be destruc
`tive. Furthermore the free HUFAS are easily oxidised to
`highly active free radicals which can do great damage. There
`is an emerging consensus that Such membrane damage is a
`fundamental pathological basis for many neurodegenerative
`disorders, including Alzheimer's disease and other
`dementias, Parkinson's disease, Stroke, Huntington's
`disease, all types of ischaemic damage, and multiple Scle
`rosis. A range of initiating causative factors may all cause
`damage by the same common route. Phospholipid break
`down to LyPLS and free HUFAS may also be important in
`epilepsy.
`The Signal transduction processes involving HUFAS and
`LyPLS are terminated in most cases by a two Sequence
`reaction. First, the HUFA is linked to coenzyme Aby a group
`of enzymes known as fatty acid coenzyme A ligases
`(FACLS). These enzymes are also known as acyl-CoA
`synthetases. The HUFA-coenzyme A derivative is then
`linked to the LyPL by a group of enzymes known as acyl
`CoA: lysophospholipid acyltransferases (ACLATs) which
`liberate coenzyme A in the process (A Yamashita et al.,
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`deficits in the blood of the highly unsaturated fatty acids
`which can be acted upon by phospholipases.
`In all of these Situations, therefore, there is Some evidence
`of increased phospholipase activity and Signal transduction
`activity which may not be terminated in a normal way. Thus
`the phospholipases, FACLS and acyl-transferases present
`new targets for drug action. Our observation that EPA
`enriched materials are beneficial in psychiatric disorders
`may therefore be explained in Several ways:
`EPA is known to inhibit phospholipase A (MJ Finnen &
`CR Lovell, Biochem Soc Transactions, 1991;19:915) and so
`will help to down regulate the initial activation process.
`Interestingly, in this assay System, the related fatty acid
`docosahexaenoic acid (DHA) had no effect.
`EPA has an unusually high affinity for the human brain
`enzyme FACL-4 (YCao et al., 1998 see above). Usually with
`enzymes which act on HUFAS, the activities with HUFAS
`like EPA, DHA and AA are similar, or very frequently, DHA
`and AA are more active than EPA. With FACL-4, however,
`activity for AA was more than twice as great as for DHA,
`whereas that for EPA was 50% greater than for AA (Y Cao
`et al., 1998). This means that EPA will more readily than
`other HUFAS enter the cycle, form an EPA-CoA derivative,
`link to LyPL and so terminate the activity of free LyPL. Thus
`EPA will, more effectively than other HUFAS, stop the
`activation once it has started.
`Because EPA will compete with AA for incorporation into
`the Sn2 position of phospholipids, EPA will also reduce the
`amount of AA incorporated into that position. This is likely
`to be particularly important in depression, where AA levels
`are relatively or absolutely abnormally high.
`EPA itself is a HUFA which can be converted to desirable
`compounds like prostaglandin I (PGI) and prostaglandin
`E. (PGE) which have a range of anti-inflammatory and
`antithrombotic actions which may be particularly useful in
`neurodegenerative disorders and in depression. The com
`pounds derived from EPA appear to be less potentially
`harmful than the equivalent compounds derived from AA.
`Replacement of AA by EPA is therefore likely to be of
`particular value in all the neurodegenerative disorders
`described above, where at least part of the damage is
`attributable to overactive phospholipases which release AA
`which can then be converted to pro-inflammatory com
`pounds.
`45
`The purification of EPA is difficult and complex. Because
`its five double bonds must all be in the right positions in the
`carbon chain and must all be in the cis configuration, EPA is
`difficult to synthesize. In nature EPA is almost always found
`mixed with other fatty acids in the forms of triglycerides and
`phospholipids. The principles of purification of EPA are well
`known to those skilled in the art and include low temperature
`crystallisation, urea fractionation, lithium crystallisation,
`fractional distillation, high pressure liquid chromatography,
`Supercritical carbon dioxide chromatography and various
`other forms of chromatography using Silica gels and other
`column packings. The application of these known tech
`niques has been difficult to apply in practice on a large Scale
`and only recently has pure EPA (more than 90% pure and
`preferably more than 95% pure) become available for testing
`in psychiatric and CNS disorders. In one version of the
`purification process, natural fish oil triglycerides rich in EPA
`are Saponified and the fatty acids converted to the ethyl ester
`form. A preparation enriched in ethyl EPA is then prepared
`by molecular distillation with collection of the appropriate
`fraction. This fraction is then converted to a preparation
`containing over 80% of ethyl EPA by urea precipitation. The
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`final preparation of more than 96% pure ethyl EPA is then
`achieved by either Silica gel chromatography or high pres
`Sure liquid chromatography.
`Conventionally, most studies on the uses of EPA and
`related fatty acids have used materials partially enriched in
`EPA but also containing substantial amounts of other fatty
`acids, especially docosahexaenoic acid (DHA) which is
`found alongside EPA in most natural oils. The fatty acids
`have usually been in the triglyceride or ethyl ester forms,
`and occasionally in the free acid and phospholipid forms.
`Docosapentaenoic acid (DPA n-3) is also a common com
`ponent of Such materials. The new understanding of possible
`mechanisms of action of EPA which we have developed has,
`however, led to the realisation that the purer is the EPA the
`better is likely to be the activity. This is not just a question
`of dose, although that is indeed a valuable aspect of the
`application of pure EPA. From the point of view of a patient,
`particularly a mentally disturbed patient, it is obviously
`better to give, Say, 1 g of EPA as a 95% pure preparation
`than, Say, 5 g of a 19% pure preparation providing the same
`total amount of EPA. The patient is much more likely to
`comply with the lower volumes required with the highly
`purified compound.
`More importantly, other fatty acids such as AA, DPAn-3,
`and DHA, which are relatively similar in structure to EPA,
`but do not share the same spectrum of biological activity,
`compete with EPA for binding to the active sites of all the
`relevant enzymes. Thus these other fatty acids will compete
`with EPA for occupation of these active sites and reduce its
`activity. The purer the preparation of EPA the more likely is
`it to occupy the relevant active binding sites, and the more
`likely is it to be able to have desirable biological effects.
`Our attention was unexpectedly drawn to the importance
`of highly purified EPA by our experience with a patient, a
`depressed women aged 35 years. She had had a long history
`of depression with Hamilton Depression Rating Scale Scores
`ranging from 15 to 25. Trials of several different
`antidepressants, including traditional tricyclic compounds
`and newer Selective Serotonin reuptake inhibitors had failed
`to have an impact. Because of evidence of the importance of
`EPA in depression she was given a three months trial of 4
`g/day of an EPA enriched fish oil containing 25% of EPA,
`together with 8% of DHA and 10% of other highly unsat
`urated fatty acids. At the start of this trial she had a Hamilton
`Score in the 20–22 range and at the end a Hamilton Score in
`the 16-18 range, a Small but not very important improve
`ment. She continued the EPA-rich oil for a further two
`months without any further change. A 96% pure preparation
`of ethyl-EPA with less than 3% DHA then became available
`to me and it was Suggested that the woman should Switch
`from taking 4 g/day of the 25% EPA preparation to 1 g/day
`of the 96% preparation. We expected is that this would be
`more convenient but did not expect any clinical improve
`ment because the EPA daily dose remained unchanged.
`However, Surprisingly, after about 3–4 weeks she began to
`experience a major improvement with Hamilton Scores
`falling below 6 for the first time for several years. As a result
`of this, and of thinking about the evidence relating to the
`binding of EPA to FACL-4 and presumably to other proteins,
`we came to the conclusion that it was important for clinical
`efficacy to administer EPA in a highly purified form for
`maximum clinical effectiveness. Surprisingly, the same
`daily dose of EPA in a purified form seems considerably
`more effective than that dose when mixed with other fatty
`acids which may compete with EPA for binding to the
`relevant Sites of action.
`This initial experience has now been confirmed by many
`other case reports in a range of psychiatric disorders. Some
`examples of the observations made include the following:
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`Schizophrenia: A patient with a ten-year history had been
`well controlled by taking 16x0.5 g capsules a day of fish oil
`containing 24% of EPA and 8% of DHA. This provided
`around 1.9 g/day of EPA and 0.6 g/day of DHA. He was not
`taking other antipsychotic drugs. However, he did not like
`taking the high doses of fish oils and tried to reduce the dose.
`However, when he did this the symptoms returned and it was
`concluded that he had to take around 2 g/day of EPA to
`remain well. When the purified ethyl-EPA became available,
`he was Switched to 4x0.5 g capsules, also providing around
`2 g/day. This controlled his symptoms very well. He there
`fore dropped the dose to 1 g/day. Unlike the previous
`situation with the mixed fish oil providing 1.9 g/day of EPA
`and 0.6 g/day of DHA, reducing the ethyl-EPA dose to
`1g/day did not lead to a recurrence of Symptoms. 1 g/day in
`pure form therefore appeared as effective and possibly more
`effective than 1.9 g per day of EPA when mixed with DHA
`and other fatty acids.
`Bipolar disorder: Bipolar disorder is a condition in which
`either a depressive or a manic State is episodic, or in which
`depressive or manic States alternate. The Standard treatments
`are lithium or valproate derivatives, or the antipsychotic
`neuroleptic drugs which are particularly used to control the
`manic States. Standard antidepressants are Sometimes used
`but they have to be applied with caution because there is a
`risk that they may precipitate a manic State.
`Very high doses (9-10 g/day) of mixed EPA and DHA
`have been reported to be helpful in managing bipolar
`patients, improving depression and reducing the risk of
`relapse into either a depressive or a manic episode (A Stoll
`et al., Omega-3 fatty acids in bipolar disorder. Archives of
`General Psychiatry, 1999; 56: 407-412). Prior to the avail
`ability of the pure ethyl-EPA, five patients with bipolar
`disorder, whose condition was only partially controlled by
`lithium with intermittent neuroleptics to control the manic
`episodes, were given 10–20 g/day of a fish oil containing
`18% of EPA and 12% of DHA. This provided 1.8-3.6 g of
`EPA and 1.2-2.4 g of DHA per day. On this treatment the
`patients were leSS depressed, and leSS prone to mood Swings,
`as indicated by following their clinical course for over a
`year. They were, however, far from completely normal.
`When the pure ethyl-EPA became available, they were
`Switched from the fish oil to the pure EPA at a dose of 2
`g/day in the form of four 0.5g Soft gelatin capsules. In each
`case their clinical condition improved considerably. Their
`depressions became Substantially better and they showed
`less tendency to mood Swing. In particular they all noted an
`improvement in Something which is difficult to measure by
`conventional psychiatric rating Scales. This is a Sense of
`inner tension or dysphoria, a State which is associated with
`the illness, but which may be exaggerated or changed by
`antipsychotic drugs to a State of confused tension, Some
`times described as a Sense of the brain being replaced by
`cotton wool, and a difficulty of thinking clearly in a Straight
`line. Remarkably, the patients reported that this Sense of
`dysphoria, tension and “cotton-Wool thinking” was greatly
`reduced or disappeared altogether. They had not noticed this
`effect which being treated with the higher dose of EPA in the
`form of the EPA/DHA mix in fish oil. Thus again the purified
`EPA had a greater and qualitatively different effect from the
`mixed EPA and DHA, supporting the idea that DHA actually
`reduces the therapeutic effect of EPA, and that highly
`purified EPA is therapeutically more effective.
`Attention deficit hyperactivity disorder (ADHD): ADHD
`and closely related conditions like attention deficit disorder
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`and conduct disorders are commonly found in children.
`Occasionally they may be successfully treated by behaviour
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`modification and other psychological techniqueS or by care
`ful attention to diet. However, in most cases, paradoxical
`treatment with one of the Stimulant drugs related in their
`action to amphetamine is required. Methylphenidate and
`dextroamphetamine are the commonest used. A Seven year
`old boy with serious ADHD since infancy was driving his
`parents to distraction. Psychological measures and diet had
`completely failed, and his condition was only partially
`controlled by methylphenidate. The parents were concerned
`about the long term consequences of Stimulant drugs. The
`boy was therefore tried on two capsules of pure ethyl-EPA
`per day. There was little change for the first two weeks but
`then a substantial improvement in behaviour developed. The
`boy became less tense and irritable, leSS hyperactive, more
`open to reasoned discussion and enormously leSS disruptive
`both at home and school. Even when his methylphenidate
`was stopped, his behaviour remained improved.
`Dementia: A 75 year old woman developed dementia,
`probably of Alzheimer type but possibly with multi-infarct
`contributions because of associated cardiovascular disease.
`AS often occurs She also became withdrawn and depressed
`but, unfortunately, this State was interrupted by irrational
`and Violent outbursts, usually directed at members of her
`family, but also Sometimes against complete Strangers. She
`was tried on two cholinergic drugs: although these produced
`a Small improvement in her cognitive State they did nothing
`for her depression, irritability and anger. She was tried on a
`dose of 4x 0.5g capsules of pure ethyl-EPA, two given in the
`morning and two in the evening. Within four weeks she had
`ex