Defence Medical Report

by Dr. Heather Ashton

Introduction and references to source materials

Psychotropic Drugs
Use of Psychotropic Drugs
Adverse Effects of Psychotropic Drugs
Description of some abnormal mental states which can be caused by psychotropic drugs
Psychotropic Drugs Prescribed for Mr. Koupparis (1982-1987)
Medical History of Mr. Koupparis with respect to psychotropic drugs and mental state.
Mr. Koupparis' mental state in relation to his use of psychotropic drugs
Undisclosed or Missing Section
Conclusion

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Medical Report on Mr. Panos Koupparis

Dr. C. H. Ashton

Department of Pharmacological Sciences
University of Newcastle upon Tyne

I am Reader in Clinical Psychopharmacology at the University of Newcastle upon Tyne and Consultant Physician in Clinical Pharmacology. My major research, clinical and teaching interest for the past 25 years has been in the field of psychotropic drugs (drugs that effect the mind) in man.

In preparing this report I have had access to the following material:

Letters from Mr. Koupparis.
"Opening Note" prepared by the Prosecution giving outline of the case.
Copy letter and report sent to the President of Cyprus.
Copy of client's own account of his taking of prescribed drugs.
Client's own account of "events preceding arrest of P. Koupparis".
Copy of prescriptions of Dr. Sophocleous.
Copy of prescriptions of Dr. Evdoka.
List of drugs apparently prescribed by Dr. Evdoka.
Copy statement of Dr. Antonopoulos.
Copy statement of Mr. Georgiades.
Prison medical records (copies).
Statement of Dr. Alan Frazer, Police Surgeon.
Report of Cheryl Ashworth in 1981.
Statement of Dr. Zeider.

I have seen additional material which the defence will not put in evidence.
I ignore this for the purposes of this opinion.

I am asked to advise on the effect on Mr. Koupparis of drugs prescribed for him by doctors in Cyprus.

Before discussing this in detail, it may be helpful to summarise the general features of these drugs, with emphasis on particular aspects applicable to this case.

I. Psychotropic Drugs

The drugs which were prescribed for Mr. Koupparis were nearly all psychotropic drugs (e.g. drugs which affect the mind, due to pharmacological actions in the brain). These include:

Tranquillisers (anxiolytics, tranquillosedatives, hypnotics, minor tranquillisers)
These drugs are used for alleviation of anxiety and insomnia. The drugs in this class which were prescribed for Mr. Koupparis were all BENZODIAZEPINES. There are many different preparations of these drugs, but they all have essentially the same pharmacological effects.
Antidepressants
These drugs are used for the treatment of depressive illnesses. There are two classes, both of which were prescribed for Mr. Koupparis:
1. TRICYCLIC ANTIDEPRESSANTS
2. MONOAMINE OXIDASE INHIBITORS
These two classes have essentially the same therapeutic effects. Their pharmacological actions in the brain are similar, although achieved through slightly different mechanisms. Some patients may respond better to one of the classes of drugs.
Antipsychotics (Neuroleptics, major tranquillisers)
These drugs are mainly used for the control of severe psychotic states such as schizophrenia and mania.
Lithium carbonate
This is a drug used as a "mood stabiliser" in various excited states including mania. It is also used long term to prevent relapse of depression. It is extremely toxic and requires careful and regular monitoring of blood concentrations with appropriate dose adjustments.

II. Use of Psychotropic Drugs

Some general principles can be applied to the use and clinical effects of all psychotropic drugs. All doctors, especially psychiatrists, would be expected to be familiar with these principles.

The effects of all psychotropic drugs depend on the personality characteristics and state of mind of the patient.
Examples:
1. Although in general tranquillisers have a calming effect, they can cause excitement and aggression and even increased anxiety in people with certain types of personality.
2. Although antidepressants usually produce a normalisation of depressed mood, they can precipitate mania in susceptible subjects.
3. Although antipsychotics usually normalise the mental state in a psychosis they can cause delirium, mood changes and paranoid delusions in some subjects. Such "Paradoxical" drug reactions are difficult to predict, but doctors should monitor patients and watch for early signs of deviant responses - especially in patients with unusual personality characteristics.
All the drugs within one group, (e.g. tranquillisers, antidepressants, antipsychotics) have similar effects.
For this reason there is no justification for regularly prescribing more than one drug from the same group simultaneously.
The use of combinations of drugs from different groups is generally inadvisable.
This is because some drug actions may be additive and others antagonistic, and the total effects unpredictable. Such combinations are occasionally used in special circumstances, but in this case particularly close supervision is necessary.
All drugs have adverse effects
1. Adverse effects are in general more likely with high dosage; the risk increases with increasing dosage.
2. When two or more drugs of the same group are prescribed together, their adverse effects are additive.
3. If drugs from different groups have adverse effects in common, these too are additive.
4. In order to minimise adverse effects, it is prudent to prescribe the lowest possible dose which controls the patient's symptoms and to adhere to the limits of maximum recommended dosage (available from manufacturer's drug data sheets and, in Britain, from the British National Formulary).
5. In the case of many drugs (especially antidepressants) increasing dosage above recommended levels does not add to the therapeutic effect. In fact at high doses the therapeutic effect may decline while adverse effects increase.
(Reference: Asberg, M. et al. (1971) Relationship between plasma level and therapeutic effect of nortriptyline. British Medical Journal, 3, 331-4).

III. Adverse Effects of Psychotropic Drugs

Adverse effects that are relevant to the present case are listed below. Description of mental states marked * are given in the next section.

BENZODIAZEPINES
References
The many adverse effects of benzodiazepines are reviewed in: Adverse Drug Reaction Bulletin (1986) 51, 201-4; Journal of the Medical Defence Union (1987) 3, 6-8; Drug Newsletter (1985) 31, 125-8. Copies of these publications are enclosed.
All benzodiazepines, especially when used chronically, can lead (inter alia) to the following effects:
These may occur if the drugs are stopped, if the dose is reduced, or sometimes during continued use (due to the development of tolerance and/or exposure to extra stress). Such symptoms include:
References - Ashton, H. (1984) Benzodiazepines: an unfinished story.
British Medical Journal, 288, 1135-40; Ashton, H. (1987)
Benzodiazepine Withdrawal: outcome in 50 patients. British Journal of Addiction. 82, 665-671.
(Copies enclosed).
Halcion (triazolam)
A rather specific adverse reaction is reported to occur with this potent and short-acting benzodiazepine when used in excessive dosage. The reaction includes intolerable psychological changes including severe anxiety, depersonalisation, feelings of unreality, *paranoia, restlessness, depression and deterioration of existing depression, suicidal tendencies, loss of weight and many other symptoms.
It is recommended that the dose of triazolam should not exceed 0.25 mg (Drug and Therapeutics Bulletin, 1979).
References: van der Kroef, C. (1979) The Lancet, Sept. 8. p. 526; Drug and Therapeutics Bulletin, Sept. 1979 p.76 (enclosed).
Antidepressants
1. TRICYCLIC ANTIDEPRESSANTS
  Adverse effects include:
  
  excessive sedation (some preparations)
  excessive stimulation (some preparations)
  agitation, restlessness, acute anxiety
  precipitation of mania*, especially in patients with manic-depressive disorders.
  precipitation of psychosis*, especially in schizophrenic patients.
  toxic confusional psychosis*, delirious states*
  withdrawal syndrome (on stopping or reducing dosage) acute anxiety, irritability, restlessness, insomnia, nightmares.
2. MONOAMINE OXIDASE INHIBITORS
  agitation
  
  tremor
  precipitation of mania*, confusion, psychosis*
  interactions with certain foods
  withdrawal reactions
Antipsychotic Drugs
Anticholinergic drugs (e.g. Akineton) may be required to combat muscle spasms and abnormal movements caused by antipsychotics. These drugs can produce confusional states*, agitation, disorientation, and these effects may be additive with those of the antipsychotic drugs.
Lithium carbonate

References

Textbook of Adverse Drug Reactions ed. D.M. Davies (1985) Oxford University Press.
Brain Systems, Disorders and Psychotropic Drugs H. Ashton (1987) Oxford University Press.
Oxford Textbook of Psychiatry Gelder M, Gath D. and Mayou R. (1983) Oxford University Press.
Psychopharmacology: From Theory to Practice ed. J.D. Barchas, P.A. Berger, D. Ciaranello; G.R. Elliott (1977) Oxford University Press.

IV. Description of some abnormal mental states which can be caused by psychotropic drugs

Mania (Reference: Oxford Textbook of Psychiatry by Gelder M, Gath D, and Mayou R, Oxford University Press, 1983).
The central features of mania are elevation of mood, increased activity and self-important ideas. Some patients may experience euphoria but others become irritable and angry. Mood often varies during the day, and there may be brief periods of depression.
Quotes from pp. 191-193 (emphasis added)
1. "Expansive ideas are common. The patient believes that his ideas are original, his opinions important, and his work of outstanding quality".
2. Some patients "make reckless decisions to give up good jobs, or embark on plans for harebrained and risky business ventures".
3. "Sometimes these expansive theme are accompanied by grandiose delusions. The patient may believe that he is a religious prophet or destined to advise statesmen about great issues. At times the delusions are persecutory, the patient believing that people are conspiring against him because of his special importance".
4. "Insight is invariably impaired. The patient may see no reason why his grandiose plans should be restrained or his extravagant expenditure curtailed".
5. "Most patients can exert some control over their symptoms for a short time" and "can talk with an appearance of calmness and reasonableness".
  Drugs which can cause, aggravate or precipitate mania include antidepressants, including TRICYCLIC ANTIDEPRESSANTS and MONOAMINE OXIDASE INHIBITORS. (Above reference and Textbook of Adverse Drug Reactions, 1985).
Psychotic states: Schizophrenia with delusions and paranoia
(Reference: Oxford Textbook of Psychiatry, cited above)
Quotes from pp. 273,274: paranoid symptoms with delusions of persecution (emphasis added)
1. "The subject believes that someone, or some organisation, or some force or power is trying to harm him in some way; to damage his reputation, cause him bodily injury, to drive him mad and bring about his death".
2. "The symptoms may take many forms from the direct belief that people are hunting him down, to complex and bizarre plots with every kind of science fiction elaboration".
3. Delusions of grandeur: The patient "thinks he is chosen by some power, or by destiny, for a special mission or purpose. He thinks that he is particularly good at helping [people].... that he has invented machines ... or solved mathematical problems beyond most people's comprehension".
  Drugs which can cause, aggravate or precipitate the above psychotic states include TRICYCLIC ANTIDEPRESSANTS, MONOAMINE OXIDASE INHIBITORS, and BENZODIAZEPINE withdrawal.
  (References as above).
Toxic confusional psychoses (delirious states)
(Reference: Textbook of Adverse Drug Reactions, ed. D.M. Davies, Oxford University Press, 1985).
Statements and Quotations from pp. 552 (emphasis added)
1. The cardinal symptom is fluctuating level of consciousness but clouding of consciousness may be minimal.
2. There may be pronounced mood changes including perplexity, great anxiety, fear, hostility and depression.
3. Paranoid delusions may develop. "In some patients when clouding of consciousness is mild, delusional ideas may be constant and well elaborated and can lead to the erroneous diagnosis of a primary schizophrenic illness".
  Drugs which can cause toxic confusional psychoses include BENZODIAZEPINES in high dose and in withdrawal, ANTIPSYCHOTIC DRUGS, anticholinergic drugs commonly used with antipsychotic drugs (the effects of these two drugs may summate), MONOAMINE OXIDASE INHIBITORS and TRICYCLIC ANTIDEPRESSANTS - "possibly more commonly than is usually believed". (Above reference, P-555).
Anxiety
Depression
These states may be cause[d], aggravated or precipitated by BENZODIAZEPINES and ANTIPSYCHOTIC DRUGS, TRICYCLIC ANTIDEPRESSANTS, MONOAMINE OXIDASE INHIBITORS, and anticholinergic drugs.

V. Psychotropic Drugs Prescribed (singly or together) for Mr. Koupparis, or obtained over the counter from Pharmacies (1982-1987)

Tranquillisers (all BENZODIAZEPINES)

Ativan (lorazepam)
Mogadon (nitrazepam)
Normison (temazepam)
Lexanotil (bromazepam)
Rohypnol (flunitrazepam)
Valium (diazepam)
Xanax (alprazolam)
Halcion (triazolam)
Noctamid (lormetazepam)
Antidepressants

Parstelin (tranylcypromine + trifluoperazine)
MONOAMINE OXIDASE INHIBITOR + Antipsychotic
Anafranil (clomipramine) TRICYCLIC
Ludiomil (maprotiline) similar to tricyclic
Vivalan (viloxazine) similar to tricyclic
Antipsychotics

Largactil (chlorpromazine)
Redeptin (fluspirilone) (injection)
Stelazine (trifluoperazine)
Melleril (thioridazine)
Clopixol (zupenthixol decanoate) (injection)
Navane (thiothixine)
Akineton (an anticholinergic drug used to counteract side effects of antipsychotic drugs.)
Lithium
Priadel (lithium carbonate)

This list may not be exhaustive as the doctors and pharmacists records are incomplete.

In view of the large number of drugs taken, and the fact that all drugs have adverse effects, Mr, Koupparis would have been vulnerable to a very large number of adverse effects. Factors which would increase the risk of experiencing such effects are:

individual vulnerability or susceptibility.
excessive or large doses of drugs.
combinations of drugs used together
(see Section III).

VI. Medical History of Mr. Koupparis with respect to psychotropic drugs and mental state.

Mental state in 1981
There is clear evidence that Mr. Koupparis was considered to be mentally normal in June, 1981. At that time he was referred to a consultant psychiatrist (Dr. A. W. Beard) because of a complaint of muscle jerks occurring at the onset of sleep. Dr. Beard reported in his letter (7.5.81) to the GP, Dr. Zeider: "I could find no evidence of a neurotic personality disorder, nor of any stress in his life situation". Mr. Koupparis was also examined in June 1981 by a clinical psychologist (Cheryl Ashworth), who administered a number of tests. Her psychological report states the "Mr. Koupparis presented as a polite, confident and relaxed young man". With regard to the psychological tests: "Mr. Koupparis' scores showed no evidence of symptoms or traits of generalised anxiety or 'neuroticism' on either Crown Crisp Eperiential Index or the Eysenck Personality Questionnaire (E.P.Q.). He obtained a high score on the extroversion dimension of the E.P.Q. His profile on the Edwards' Personal Preference Schedule described a high need for achievement and autonomy, a very strong liking for change and challenge, and qualities of endurance and self-confidence, while at the same time liking to be friendly and warm, and to show very little aggression towards others".
Note: The E.P.Q. is a well recognised and widely used psychological test which, in addition to testing personality traits of extroversion and neuroticism (anxiety) has a scale for psychoticism, which tends to give high scores for individuals prone to psychiatric disorders. Nothing remarkable in Mr. Koupparis, scores on this scale was noted by the psychologist. In her report, she only remarked that he scored highly for extroversion, a perfectly normal finding denoting a highly sociable and outgoing personality type.
These tests are not designed to measure any depressive tendencies. Nevertheless Mr. Koupparis was clearly neither depressed or manic in 1981, and did not strike the two specialists as being vulnerable in this direction.
(References: Eysenck, H.J. and Eysenck, S.B.G. (1975) Eysenck Personality Questionnaire. Hodder and Stoughton, Essex; Eysenck, H.J. and Eysenck, S.B.G. (1976) Psychoticism as a dimension of personality. Hodder and Stoughton, London).
The complaint for which Mr. Koupparis was referred to Dr. Beard was probably a case of hypnagogic hallucinations, a condition in which the subject experiences, usually just after dropping off to sleep, a sudden violent muscle jerking, often accompanied by an auditory hallucination of a loud bang or explosion. The condition has also been termed "exploding head syndrome". Most normal people have experienced these symptoms occasionally, but the condition may also be associated with migraine, epilepsy and narcolepsy. The isolated condition is reported to be benign and not associated with neurotic or other mental disorders. I have personally observed the condition in patients undergoing benzodiazepine withdrawal and it has also been noted during the use of other benzodiazepines. It probably reflects a heightened state of central nervous system activity which may be triggered by diverse factors.
(References:
Start of psychotropic medication: 1981
The first mention of Mr. Koupparis' use of psychotropic medication is the above referral in which the psychologist noted that he had found that the nocturnal muscle jerks were alleviated by the benzodiazepine, lorazepam (Ativan) but that he did not want to rely on the medication for the rest of his life. However, Dr. Beard suggested that Mr. Koupparis should try another benzodiazepine, nitrazepam (Mogadon) for the condition, and this period seems to mark the start of his regular use of psychotropic medications.
1982-1984
As recommended by Dr. Beard, Mr. Koupparis was prescribed nitrazepam (Mogadon) during 1982 by his general practitioner, Dr. Zeider. He apparently took this regularly, but the dose is not stated. In 1983, Mr. Koupparis went to Cyprus where he was given another benzodiazepine, temazepam (Normison) by the local pharmacist as an alternative to nitrazepam. He took temazepam in (normal) doses of 1-2 capsules (10-20 mg) nightly for about 9 months. In 1984, on a return visit to England, he ran out of capsules and apparently suffered withdrawal symptoms which were severe enough to stop him from working and included depression.
Comment. Withdrawal symptoms, which can be severe, are not uncommon on sudden cessation of regular therapeutic doses of benzodiazepines, and have been widely reported in the literature. These symptoms can be incapacitating and can include depression (see p.6,7). Mr. Koupparis had been taking regular benzodiazepines for 3 years (lorazepam, nitrazepam, temazepam) and a withdrawal reaction on sudden cessation was highly likely. Such a reaction would have left him in a highly emotional state, and very vulnerable to stress.
1985
In 1985 Mr. Koupparis became depressed and in June 1985 he consulted a psychiatrist in Cyprus, Dr. Sophocleous.
The note taken by Ms. Postgate from Dr. Sophocleous' notes is appended at 'A'. According to Mr. Koupparis' account it is not an entirely accurate version of what Dr. Sophocleous prescribed. it does, however, confirm that the doctor did prescribe a number of the drugs which Mr. Koupparis describes.
Mr. Koupparis questions whether he was injected with Redeptin and suggests it was in fact insulin. I comment on this later. Mr. Koupparis does not recollect Mutabon D. Mr. Koupparis says he did not take Priadel or Clopixol. He says, however, that he was additionally prescribed Noctamid and Normison which are both benzodiazepine[s].
On Dr. Sophocleous' notes there appear various references indicating the patient's condition such as "O.K". "Better". If indeed Mr. Koupparis' condition was as indicated the type and quantity of drugs presented would seem either unnecessary or at least excessive. Some of the drugs presented were anti-psychotic. Psychosis can arise from mental illness such as manic depression or schizophrenia or can be drug induced. On the material on the face of his notes I cannot say what the diagnosis was or whether it was correct. Judging solely from the pattern of prescription, I would not put great faith in Dr. Sophocleous' treatment and this view might affect the reliability of his diagnosis. I understand that Mr. Koupparis does not accept that at this stage he was in a psychotic state and points to the fact that he was carrying on various businesses over this period in a normal manner. I suggest later that his state on referral to Dr. Sophocleous may well have been due to benzodiazepine withdrawal.
I will comment on the various drugs Dr. Sophocleous may have prescribed:
Lexotanil (lexotan, bromazepam) is a benzodiazepine. The dose prescribed of this drug was 3 mg x 2 + 12 mg nocte, a total daily dose of 18 mg. The maximum recommended dose of bromazepam (British National Formally, 1988) is 18 mg, but Mr. Koupparis appears to have been taking other benzodiazepines at the same time. Mr. Koupparis states that he was also prescribed the benzodiazepines Noctamid, (lormetazepam) and Normison, (temazepam) by Dr. Sophocleous. However, Dr. Sophocleous did not keep clear records of his prescriptions in his medical notes.
It is likely that Mr. Koupparis was prescribed excessive doses of various benzodiazepines.
Parstelin is a mixed preparation containing in each tablet 10 mg tranylcypromine (a monoamine oxidase inhibitor; see antidepressants, P.7,8) and 1 mg trifluoperazine (a phenothiazine; see antipsychotics, p.8). The prescription was for 4 tablets daily - i.e. 40 mg tranlcypromine and 4 mg trifluorperazine. The recommended dose of tranylcypromine (British National Formulary) is 10-30 mg initially; maintenance dose 10 mg daily. Thus the dose of this drug was also excessive.
Priadel (lithium carbonate) 400 mg nocte. This is a highly toxic drug which requires close monitoring of its effects including regular estimations of blood concentration. The recommended dosage is 250- 2000 mg daily, adjusted according to plasma concentrations. Adverse effects include toxic psychoses. There is no record of whether this drug was taken or adequately monitored. Mr. Koupparis states his blood was never tested.
Stelazine (trifluoperazine) (an antipsychotic)
Melleril (thioridazine) (an antipsychotic)
Redeptin (fluspirilone) (an antipsychotic)
There seems no medical justification for using these three drugs together (see p.4) and their combined dosage is excessive and likely to give rise to adverse effects. Mr. Koupparis states that he was also given Akineton Retard which is an antidote used to control muscle spasm induced as a side-effect of antipsychotic drugs. Muscle disturbances are an adverse effect of antipsychotics, especially when given in high doses.
At about this time Mr. Koupparis also received a series of injections from Dr. Sophocleous. The nature of these is not clear. Mr. Koupparis believes the treatment to have been insulin injections and Dr. Sophocleous' notes (seen by Ms Debbie Postgate) contain an entry 5.12.85 "12 Ins", which he altered in her presence to "B12 1M". Mr. Koupparis described the administration of those injections: he was told to lie still and wait 3/4 hour after the injection, experienced palpitations and was then given a lot of sweet food and drinks. This would be consistent with insulin. An entry in the notes for 9.12 85 is "1.M. Redeptin 2 ml" (4 mg). An entry on 16.12.85 is "7 days Redeptin 2 ml" and "18 days Clopixol 100 mg"; also: "Clopixol 100 mg nocte". "Clopixol 100" is also recorded on 28.11 85, and Melleril 200 mg nocte on 9.12.85 and Melleril 100 mg nocte 7 days on 16.12.85.
The meaning of these entries is not clear but it would appear that Mr. Koupparis was subjected to gross overdoses of antipsychotic drugs. Insulin injections are an obsolete treatment for schizophrenia; they cause a sharp fall in blood sugar which induces a confused and sometimes comatose state requiring close supervision. Redeptin (fluspirilene) is used by injection for schizophrenia (see above for recommended dose) and Clopixol (zupenthixol decanoate) is another drug used by injection for schizophrenia in recommended doses as follows (British National Formulary): test dose 100 mg, then after 7-28 days 100-200 mg or more, followed by 200-400 mg at intervals of 2-4 weeks. Maximum 600 mg weekly.
There is no justification for using these treatments as recorded. Insulin treatment for psychosis is obsolete. The use of Redeptin and Clopixol in the doses recorded. and together with another antipsychotic (Melleril) represents a gross overdosage, likely to leave the patient in a confused and oversedated state.
Mr. Koupparis states (Pharmacology 29.12.88) that following this period of injections he continued to receive Melleril (thioridazine), Largactil (chlorpromazine) (i.e. two antipsychotics) and three benzodiazepines, Valium (diazepam), Normison (temazepam) and Rohypnol (flunitrazepam). He reports that he "slept virtually round the clock" and was "totally unable to work", a not surprising effect of a combination of several antipsychotic drugs and several benzodiazepines.

1986

Dr. Sophocleous' medical records have an entry dated 13.1.86. "No panics, no anxiety". However, Dr. Sophocleous changed the treatment back to the antidepressant Parstelin 4 tablets daily (an excessive dose (see p.19), and the benzodiazepines Lexotanil, 12 mg daily, Rohypnol, 2-4 mg nocte; his medical records also note prescribing Valium (diazepam) on 13.1.86. Thus Mr. Koupparis was also receiving excessive doses of benzodiazepines. Mr. Koupparis states that he also continued to receive Stelazine (antipsychotic), Largactil (antipsychotic) and Akineton (antipsychotic antidote).

Mr. Koupparis records that he continued to sleep most of the day but also developed agoraphobia and photosensitivity, which may have been adverse effects of benzodiazepines and/or antipsychotics.

Mr. Koupparis consulted another psychiatrist, Dr. Evdokas, whom he first saw on 12.8.86.

Ms. Postgate's list taken from Dr. Evdokas' notes is appended at 'B'. At 'C' are appended prescriptions found in Cyprus. There is already exhibited, ex 17, a certificate from a pharmacist in March, 1987. Mr. Koupparis again questions the accuracy of Dr. Evdokas' notes. I would question whether Mr. Koupparis lack of memory of a particular prescription is necessarily reliable given his state. That said Mr. Koupparis disputes prescriptions for Fluanxol, Lexotanil and Rohypnol and Stelazine though prescriptions for Fluanxol were found. He was prescribed Akiniton retard which deals with side effects of antipsychotic drugs and would tend to indicate that something like Fluanxol was administered. In any event in doctors notes show it was only administered for one week. Mr. Koupparis states Navane was not prescribed though a prescription for Navane was found. The remaining drugs he accepts he was prescribed and in addition was prescribed Valium. He states that [he] continued to take Halcion through to the period he came to England. It does appear on the list of drugs which the pharmacist certified in March 1987 in order they could pass through English customs. It also appeared at 'D' Ms Postgate's notes of Dr. Evdokas' comments on his prescriptions. He does indicate there stopping various drugs at various times but does not say he stopped Halcion.

At the time when he first consulted Dr. Evdokas, Mr. Koupparis states (Pharmacology, 29.12.88) that he was taking 30-50 mg Valium (diazepam), 3-6 mg Rohypnol (flunitrazepam) and 10-40 mg Normison (temazepam) daily. This is a grossly excessive dose of benzodiazepines and indicates a high degree of tolerance and dependence. Additionally he says he was taking Parstelin, Largactil and Akineton retard. Mr. Koupparis states that Dr. Evdokas was "quite alarmed at the range and extent of the drugs that he was taking" and that Dr. Evdokas advised him to stop all his medication and to return in two weeks for a new treatment. Mr. Koupparis obeyed these instructions but, not surprisingly, developed an acute withdrawal reaction. He states that he "turned into a wild animal ... had panic attacks, anxiety attacks, flushes, hot and cold sweats, runaway palpitations, hyperventilation, trembling, oscillating ..., involuntary muscle jerks and spasms... agoraphobia, xenophobia, and all sorts of strange ideas and behaviour" (Mr. Koupparis' letter 20.11.88). These symptoms are typical of a benzodiazepine withdrawal reaction (p.6) and would occur either on cessation of the drugs or on sudden reduction of dosage. In fact Dr. Evdokas records that on 12.8.86 he prescribed a new mixture of drugs which were repeated, with some variations, on 8 occasions up to 2.1.87. The drugs prescribed included the following:

Fluanxol (flupenthixol)	3 mg daily	(antipsychotic)
Lexanotil (bromazepam)	6 mg nocte	(benzodiazepine)
Rohypnol (flunitrazepam)	?	(benzodiazepine)
Stelazine (trifluoperazine)	10 mg nocte	(antipsychotic)
Largactil (chlorpromazine)	50 mg nocte	(antipsychotic)
Halcion (triazolam)	0.5 mg nocte	(benzodiazepine)
Ludiomil (maprotiline)	75 mg	(antidepressant)
Navane (thiothixine)	10 mg	(antipsychotic)
Anafranil (clomipramine)	75-100 mg nocte	(antidepressant)
Xanax (alprazolam)	1-1.5 mg daily	(benzodiazepine)
Vivalan (viloxazine)	250 mg daily	(antidepressant)

At any one time during this period it appears that Mr. Koupparis. was taking several of these drugs together, often 2 antidepressants (Anafranil and Vivalan or Anafranil and Ludiomil), 2 antipsychotics (Navane and Largactil) and 2 or more benzodiazepines (Xanax and Halcion) as well as "fairly massive doses of Valium which I used to suppress the horrific panic attacks I was getting for months afterwards" [after August, 1986]. (Pharmacology 29.12.88.) The combined effect of excessive psychotropic drug dosage as well as withdrawal effects due to changes in dosage would have been highly likely to result in a variety of abnormal mental states, including acute anxiety, psychosis, depression, mania, paranoia and mental confusion.

Mr. Koupparis records (Pharmacology, 29.12.88): "I became a chronic agoraphobic totally unable to leave the house. I suffered anxiety attacks and disorientation. I hid from the world in my darkened bedroom and I began to develop irrational ideas. I also experienced a few months of vivid dreams which occurred while I was awake and well as asleep ... . I stopped bathing, shaving and even refused to take off my track suit for months at a time. I was irritable and short tempered. but by the end of that year I began to stabilise and make positive progress; the agoraphobia eased, the attacks subsided and I became brighter, stayed awake longer and surprisingly I was very happy. In fact, I think my original depression had ended a year or more earlier but I had been too drugged to notice".

Note By the end of 1986 Dr. Evdokas had stopped the antipsychotic drugs that Mr. Koupparis has been taking, and he was then taking two antidepressant drugs Anafranil (clomipramine) 75 mg/day and Ludiomil (maprotiline) 50 mg/day. The combined dosage of these drugs could well have precipitated a manic or psychotic state, known adverse effects of these drugs (se P-7). The return of Mr. Koupparis' happiness, combined with irrational ideas may have been the start of a drug induced manic psychosis, a state that became more evident early in 1987 (see below).

1987

In January, 1987, Mr. Koupparis states that "from time to time I would lose track of reality ... . I appeared to be suffering from bouts of amnesia after taking my Halcion pills at night where I would get very talkative ... by now my ideas were bordering on the absurd and my behaviour had become highly eccentric ...". (see adverse effects of antidepressants, and Halcion (triazolam) psychosis p.7). He began to develop delusions and, for example he told his wife that he was "a NATO spy charged with keeping an eye on her sister's boss who was a soviet illegal under the cover of a German businessman".

His wife became worried and suggested to Dr. Evdokas that he should consult a specialist in London. According to Mr. Koupparis Dr. Evdokas readily agreed to this but suggested that he cut down on his drugs (especially the 40-50 mg Valium) before he went.

It seems certain that from about this time Mr. Koupparis was in a very disturbed psychological state, with mania and delusions, and that he was still taking large doses of a mixture of psychotropic drugs. The pharmacist's prescription in Cyprus dated 24.3.87 includes the following drugs.

Vivalan (viloxazine)	3 tabs at morning	(antidepressant)
Anafranil (clomipramine)	75 mg	(antidepressant)
Anafranil	75 mg
Halcion (triazolam)	0.5 mg at night	(benzodiazepine)
Xanax (alprazolam)	0.5 mg	(benzodiazepine)
Ludiomil (maprotiline)	50 mg	(antidepressant)
Valium (diazepam)	10 mg daily	(benzodiazepine)

Mr. Koupparis says he was receiving all of these.

This prescription includes 3 antidepressant drugs, each in full doses, and 3 benzodiazepines also in large doses. To take all these drugs together would be grossly excessive, and likely to produce adverse effects.

In March 1987, Mr. Koupparis came to London in a wildly deluded state. He records (Pharmacology 29.12.88.) that he was "well on my way to 'cloud cuckoo land' and within two weeks I was in London firmly believing that the whole world has gone mad and that I was the only sane person left. My psychosis had begun and I was compelled by my rampant delusions to bring my thriller fiction to life in a hilariously tragic fiasco culminating in my arrest. During this period I became very erratic in taking my drugs and for some very obscure reasons I took random and massive overdoses of Vivalan and Halcion, I drank heavily ... and accepted unknown drugs ... including copious amounts of cannabis ... ".

Note Vivalan, Halcion and cannabis can all precipitate or aggravate manic or schizophreniform psychotic states (see p.).

It was in this condition that Mr. Koupparis committed his bizarre offence - for which he was arrested in May 1987. He was clearly in a psychotic state and was taking large doses of a number of drugs any of which alone or in combination would have been likely to aggravate or precipitate such a state. There is evidence that over a period there was some improvement in Mr. Koupparis condition after he was taken into custody. Dr. Frazer's report of May 1987 indicates he was highly disturbed on admission. The notes of his stay in F wing at Brixton, which is the hospital wing, and on his discharge from that wing indicate that when the drug regime was withdrawn in the course of time his condition improved.

VII. Mr. Koupparis' mental state in relation to his use of psychotropic drugs

In 1981 Mr. Koupparis was considered mentally well with no abnormal tendencies when examined intensively by a psychologist who administered several psychological tests. In particular, he had no neurotic or psychotic traits and showed no sign of depression.
His first use of psychotropic drugs appears to be in 1981 when he took Ativan (lorazepam) and then Mogadon (nitrazepam), prescribed for a benign sleep condition, not associated with psychological disturbance. The Mogadon was changed to Normison (temazepam) when Mr. Koupparis went to Cyprus in 1983 and regular use of benzodiazepines continued for 3 years between 1981 and 1984.
In 1984 Mr. Koupparis suddenly stopped temazepam because he ran out of capsules on a visit to England. He suffered a severe withdrawal reaction which was incapacitating enough to stop him working and also included mental depression. Such a withdrawal reaction on sudden cessation of regular benzodiazepines is well documented in the medical literature. It can occur in normal people and is not uncommon. The withdrawal symptoms may include depression which may be severe enough to precipitate suicide. Benzodiazepine withdrawal also leaves the subject extremely susceptible to stress.
In my opinion the onset of Mr. Koupparis' depression was precipitated by his benzodiazepine withdrawal reaction in 1984.
In 1985 Mr. Koupparis' depression became worse. It may have been aggravated by stress of and possibly by his resumption of large doses of benzodiazepines on his return to Cyprus. An adverse effect of chronic benzodiazepine use is depression, aggravation of depression and even provocation of suicide (p.5).
When Mr. Koupparis attended the psychiatrist Dr. Sophocleous he probably had a mixed anxiety and depression which in my opinion was caused or aggravated by his drugs (benzodiazepines) as well as marital stresses.
In June 1985 Mr. Koupparis was prescribed by Dr. Sophocleous excessive doses of further benzodiazepines as well as an excessive dose of an antidepressant drug, the monoamine oxidase inhibitor Parstelin. Adverse reactions to Parstelin include precipitation of mania, confusion and psychosis, and in my opinion the start of Mr. Koupparis" psychotic state is largely attributable to excessive doses of this drug.
Dr. Sophocleous then prescribed antipsychotic drugs for Mr. Koupparis (1985-1986). These included no less than 3 antipsychotic drugs (Stelazine, Melleril and Redeptin) followed by injections of Redeptin, Clopixol (another antipsychotic) and possibly insulin. These prescriptions represented a gross overdosage of antipsychotic drugs. Combined with benzodiazepines, also prescribed, they would be likely to lead to mental confusion and oversedation and it is not surprising that Mr. Koupparis reports that during this period he "slept virtually round the clock".
Not surprisingly, Mr. Koupparis' anxiety and depression returned under these conditions and he was again prescribed excessive doses of the antidepressant Parstelin by Dr. Sophocleous early in 1986, along with further benzodiazepines. As previously stated, psychotic states can be precipitated by Parstelin, and in my opinion Mr. Koupparis' earlier psychotic state while taking Parstelin (see (2)) was aggravated or reinstated by further Parstelin.
Dr. Evdokas stopped or reduced the drugs Mr. Koupparis was taking, especially the benzodiazepines. Mr. Koupparis again underwent an acute benzodiazepine withdrawal reaction with all the classical signs of such a reaction - including severe anxiety and an acute psychosis "with all sorts of strange ideas and behaviour". The acute psychosis on this occasion was in my opinion definitely aggravated by benzodiazepine withdrawal.
Another course of various drugs was prescribed by Dr. Evdokas. is included several antidepressants (Ludiomil, Anafranil, Vivalan), several antipsychotics (Fluanxol, Stelazine, Navane, Largactil), and several high dose potent benzodiazepines (Lexotanil, Rohypnol, Halcion, Xanax). The antipsychotics were then phased out but Mr Koupparis continued taking at least two antidepressants simultaneously and several benzodiazepines. Mr. Koupparis then entered a manic phase, beginning at the end of 1986 and continuing into 1987. This state was in my opinion aggravated, or precipitated by the high doses of antidepressants, which are known to precipitate mania (see P.7,8). In addition the potent benzodiazepine Halcion (triazolam) taken in doses of 0.5 mg or more can cause paranoid reactions (Mr. Koupparis was prescribed 0.5 mg). (see p-7).
References:
By the time Mr. Koupparis came to London and began to perpetrate his offence in the Spring of 1987, his mind was in a state of gross perturbation which was in my opinion largely due to the combination of prescribed drugs (at least 3 antidepressants and at least 3 benzodiazepines) that he was taking. His judgement was likely to have been clouded so that he became erratic in the use of drugs and took "random and massive overdoses of Vivalan [antidepressant] and Halcion [benzodiazepine]". Thus, in my opinion, Mr. Koupparis' offence was committed while he was suffering from a drug-induced psychosis. The fact that he was able to operate in a relatively rational manner (given his delusions) was probably attributable to his unusually high intelligence (noted by Dr. Dolores Mouyiasi) and his prior knowledge and experience of scientific matters and computers.

VIII. Undisclosed or Missing Section

IX. Conclusion

Mr. Koupparis' mental state was entirely normal in 1981 as evidenced by the reports of a consultant psychiatrist and a psychologist who found no psychotic or neurotic traits. His mental deterioration began after he was prescribed psychotropic drugs and consisted of:

anxiety and depression on sudden cessation of benzodiazepines in 1984,
Further mental symptoms after prescription of excessive doses of Parstelin (an antidepressant monoamine oxidase inhibitor) in 1985,
mental confusion, oversedation and return of depression after excessive doses of antipsychotics in 1985-6,
Possible psychosis after further excessive doses of Parstelin in 1986,
acute benzodiazepine withdrawal reaction with further psychotic symptoms when dosage of benzodiazepines reduced in August 1986,
further psychosis and mania associated with excessive doses of antidepressants and potent benzodiazepines including Halcion and Xanax in early 1987,
further psychosis associated with increased and erratic doses of antidepressants (Vivalan), benzodiazepines (Halcion) and the addition of cannabis in the Spring of 1987.

The combined high doses of drugs prescribed and taken by Mr. Koupparis over the years amounted to a brain-washing procedure which would be likely to cause substantial loss of control of brain functions including judgement, grasp of reality and emotional reactions. The drugs would be likely to cause these effects in a normal person and still more in a person prone to a manic-depressive disorder.

The prescribed drugs would, furthermore, blur the judgement of the individual concerning the taking of other drugs, such as unprescribed doses of benzodiazepines. In addition, the drugs could have the effect of fixing the mind on unreal or paranoid ideas. An individual, especially one with high intelligence, experience and expertise could remain capable of carrying out bizarre actions, focused by a "tunnel vision" of fantasy induced by the drugs. Such an individual could well retain a clear memory of his feelings and actions after recovery. In my personal experience (and also evidenced in many other documentations) individuals who have experienced psychotic states, drug induced or -not, are often able to recount such experiences in great detail after recovery.

Since Mr. Koupparis was prescribed antipsychotic drugs over a sustained period I will consider whether he might have been suffering from manic depression. I would point out that there was no evidence of such a disorder before the use of psychotropic drugs, and that it is likely that the drugs precipitated this disorder. For example, Mr. Koupparis did not appear to have suffered from depression before his first withdrawal from benzodiazepines in 1984; and there is no evidence of psychosis before he took excessive doses of Parstelin in 1985. Even if Mr. Koupparis was prone to manic-depression, this condition would have been greatly aggravated by the excessive doses of, and periods of withdrawal from, the medley of psychotropic drugs prescribed. All of these drugs can produce psychotic states.

The fact that Mr. Koupparis' mental state has improved progressively in prison, where he has stopped his-psychotropic drugs but received no further treatment, suggests that his mental condition was largely if not entirely due to his intake of mind-altering drugs. Such drugs may make a person believe in different delusions sometimes conflicting over a period of time.

Finally, it is my opinion that on the balance of probabilities, Mr. Koupparis would not have committed the offence with which he is charged if he had not been exposed to psychotropic medication.

Of importance in following this conclusion are the following observations:

Mr. Koupparis' (documented) friendly, polite, confident and relaxed personality in 1981, before exposure to psychotropic drugs.
Mr. Koupparis' (documented) progressive recovery towards mental normality after cessation of psychotropic drugs in prison from May 1987 onwards.
The known effects of all the psychotropic drugs to which Mr. Koupparis was exposed (with documented evidence) between 1981 and 1987, in excessive dosages and inappropriate combinations, with periods of sudden withdrawal or reductions of dosage.

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