Dr Yolande Lucire
PhD MBBS DPM
FORENSIC & MEDICO-LEGAL PSYCHIATRY
AKATHISIA CLINIC
Level 5, Edgecliff Centre
203-233 New South Head Road
EDGECLIFF NSW 2027
PO Box 474, Edgecliff NSW 2027.
All appointments: (02) 9327 1499
Fax:
(02) 9327 2288
Enquiries Dr. Yola Lucire: 9327-2288 / 0411 158 246
Website: http://www.lucire.com.au
Email: lucire@ozemail.com.au
Provider No. 0012 809B
11 October 2012
Re:
Simon Roberts
D.O.B:
08.12.1978 (29 years)
Continuing Treatment Order Application for Mental Health Review
Tribunal
This is the second report that I have written for the Mental Health Review Tribunal
about Simon. It is intended as a polemic.
Observations
Very little had changed since my first report on Simon, until very recently when he
stopped turning up for enforced Clopixol (zuclopenthixol) injection.
He cannot metabolise the drug, so he gets terrible side effects when it builds to toxic
levels in his body. It is worse soon after the injections.
This practice (multiplied many times) causes failure to recover, suicide, homicide and
‘the crisis in mental health,’ increases in demand for beds, and 43 homicides and
937 suicides committed by patients under Mental health care in NSW between 2002
and 2008.i
I had seen Simon quite a few times around that time, early 2008 and I saw no
evidence of psychosis. However I saw plenty of evidence of drug side effects. It was
at this time that I did a genetic test, and found he was an Intermediate Metaboliser at
2D6*4.ii
See footnote for explanation of metabolizer types.iii
Summary of information
Simon has a defective gene, 2D6*1*4. He is an Intermediate Metaboliser at
cytochrome P450 2D6.
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Simon Roberts, CTO Application, September 2012
The following drugs are metabolised by CYP45 2D6:
These drugs will sooner or later accumulate and cause side effects as listed in each
drugs’ Product Information.
Acetaminophen (aka paracetamol), Ajmaline, Alprenolol, Amiflamine, Amitriptyline,
Amphetamine, Amprenavir, Aprindine, Aripiprazole, Atomoxetine, Benztropine,
Bisoprolol, Brofaramine, Bufuralol, Bunitrolol, Butylamphetamine, Captopril,
Carteolol, Carvedilol, Cevimeline, Chlorpromazine, Chlorpheniramine, Chlorpyrifos,
Cinnarizine, Citalopram, Clomipramine, Clozapine, Codeine, Debrisoquine,
Delavirdine,
Desipramine,
Dexfenfluramine,
Dextroamphetamine,
Dextromethorphan, Diazinon, Dihydrocodeine, Diltiazem, Diprafenone, Dolasetron,
Donepezil, Doxepin, Encainide, Ethylmorphine, Ezlopitant, Flecainide, Flunarizine,
Fluoxetine, Fluperlapine, Fluphenazine, Fluvoxamine, Galantamine, Guanoxan,
Haloperidol, Hydrocodone, Ibogaine, Iloperidone, Imipramine, Indoramin, Lidocaine,
Loratidine,
Maprotline,
Mequitazine,
Methadone,
Methamphetamine,
Methoxyphenamine, Metoclopramide, Metoprolol, Mexiletine, Mianserin, Minaprine,
Mirtazapine, Nefazodone, Nifedipine, Nisoldipine, Norcodeine, Nortriptyline,
olanzapine, Ondansetron, Oxycodone, Parathion, Paroxetine, Perhexiline,
Perphenazine, Phenacetin, Phenformin, Procainamide, Promethazine, Propafenone,
Propranolol, Quanoxan, Quetiapine, Ranitidine, Remoxipride, Risperidone,
Sertraline, Sparteine, Tacrine, Tamoxifen, Tamsulosin, Thioridazine, Timolol,
Tolterodine, Tradodone, Tramadol, Trimipramine, Tropisetron, Venlafaxine,
Verapamil, Zotepine, and Clopixol (zuclopenthixol).
This means that if Simon is to have a psychiatric drug at all, it must be as a single
drug, and it must be at a significantly lower dose than a standard dose. Standard
refers to the lowest single dose manufactured.
This treatment regime never happens for Simon. Instead, he is given huge doses,
and often, polypharmacy. After so many years on the drugs, epigenetic factors set in
and the enzymes become even less efficient.
Until 2008 he used cannabis. One cannot use cannabis with psychiatric drugs if one
has a genetic mutation, because it inhibits the enzyme CYP 3A4, that picks up after
the other enzymes, if the others are saturated, inhibited or defective.
Simon has never had a hospital admission that has not been precipitated by either
being on illicit drugs, or being on psychiatric drugs and having side effects. He has
numerous side effects.
This is the most crucial diagnosis to be made in psychiatry as the correct treatment
for mental illness is catastrophic for the toxic psychosis, and may cause it. Toxic
states are well described in the ICD 10iv, Psychotropic drugs are par excellence
psychoactive substances, and any Product Information (PI) contains many of these
categories, but it seems random which ones are included in which PI. For example
Efexor (venlafaxine) PI lists homicidal ideation as a side effect, but only in USA PI. I
have seen and reported homicidal ideation in patients taking all antidepressants and
antipsychotics, old and new. Risperdal PI does not include akathisia, but its
2
Simon Roberts, CTO Application, September 2012
manifestations, which are balkanised. Indeed akathisia has many faces, many
manifestations.v
It has taken me quite some time to realise that my junior colleagues have not been
taught that is essential to differentiate toxic states from mental illness. I have charted
the difference between toxic psychosis and mental illness in the table below.
TOXIC PSYCHOSES
THE FUNCTIONAL PSYCHOSES
Akathisia, restlessness, obsessive
preoccupation with death, dying, and suicide,
Inexplicable impulse to kill people one most
loves, violence, behavioural dyscontrol,
confusion/ambulant delirium, manic shift,
Weird violent dreams, insomnia,
Sick, vomiting, racing heart, loss of
coordination, cognitive impairment memory
problems.
Confabulations, shifting false reports,
misinterpretation, serotonin toxicity or
neuroleptic malignant syndrome.
Toxin or medication in use or recently used
Clear sensorium, absent confusion.
Absent physical / neurological disease.
Absent substance/medication use.
Specific voices 3rd party or conversation.
Fixed delusions, correctly defined.
Mania or depression.
Absent causation.
Akathisia, restlessness, obsessive
preoccupation with death, dying and suicide.
Inexplicable impulse to kill people one most
loves, violence, behavioural dyscontrol,
confusion/ambulant delirium, manic shift.
Weird violent dreams, insomnia.
Sick, vomiting, racing heart, loss of
coordination, cognitive impairment memory
problems.
Confabulations, shifting false reports,
misinterpretation, serotonin toxicity or
neuroleptic malignant syndrome.
Absent causation by substance of medication.
Clear Sensorium, absent confusion.
Absent physical / neurological disease.
Absent substance/medication use.
rd
Specific voices 3 party or conversation.
Fixed delusions, correctly defined.
Mania or depression.
3
Simon Roberts, CTO Application, September 2012
ICD F10 - F19 MENTAL AND BEHAVIOURAL
DISORDERS
DUE TO PSYCHOACTIVE SUBSTANCE USE
PROMINENT: CONFUSION, LACK OF
CORDINATION MEMORY/COGNTION IMPAIRED
ALL “FUNCTIONAL PSYCHOSES” CARRY THE
EXCLUSION
“NOT CAUSED BY SUBSTANCE OR
MEDICATION”
ABSENT: CONFUSION, LACK OF CORDINATION,
OTHERWISE CLEAR THINKING
333.99 Neuroleptic and SSRI- Induced
Akathisia
292.81 Substance - Induced Delirium
292.84 Substance – Induced Mood Disorder
292.83 Substance- Induced Persisting Amnesic
Disorder/Dementia
292.11 Substance - Induced psychotic disorder,
with delusions/hallucinations
995.2 Adverse Effects of Medication NOS
295 Schizophrenia
295.40 Schizophreniform Disorder
297.1 Delusional Disorder
298.8 Brief Psychotic Disorder
296 Manic Episode
296 Major Depressive Episode
Simon tells me that eight weeks ago, he stopped receiving Clopixol (zuclopenthixol).
He told me that he had become, in his words, “manic and delirious” on the
flupenthixol.
Previously, Simon was associated with a domain called extraterrestrialempathy.com,
and all sorts of things were discussed on that. He had weird beliefs at the time that
he was on the Clopixol (zuclopenthixol), and he knew they were weird. He knew the
Clopixol (zuclopenthixol) was causing the weird beliefs. He knew his mood was
elevated and manic, but could not control the mood but was able to control
behaviours. Disturbance of mood, up or down, is a side effect of most psychiatric
drugs for some people. At times, Simon was also depressed.
Simon informed his psychiatrist, who refused to believe that Clopixol decanoate
(whose PI I had provided for Simon) was the same drug, indeed a trade name, for
zuclopenthixol decanoate and metabolised by CYP450 2D6, as is Haldol.
He says that since he has been off the Clopixol (zuclopenthixol) for eight weeks, and
his abnormal thinking has disappeared.
While on Clopixol (zuclopenthixol) Simon had severe akathisia. He was angry,
agitated, couldn’t sit down and relax, and was restless, pacing.vi
During the first week after the injections it was particularly bad.
For the first two or three days he would scream at Nicky, his partner, and also his
parents.
He sometimes felt he might be unable to control it, but he knew he had it, and that it
would pass. He was worried about the effect this had on his relationship.
4
Simon Roberts, CTO Application, September 2012
This experience would settle towards the end of the first week after the injection, but
the delirium and paranoia continued.
Simon has experienced this pattern on every drug he has had.
Akathisia is the worst and most repressed side effect in psychiatry. Its mechanism is
not understood. It is also a side effect of many non-psychiatric drugs.
Akathisia causes an inner sense of agitation or torment, deep grinding pain in the
body and overwhelming restlessness; literally, ‘I cannot sit down,’ interspersed with
bouts of exhaustion.
There is no relief for it.vii
Epidemic akathisia is the reason that psychiatric patients have become aggressive
and suicidal. Epidemic akathisia caused by new generation drugs is why psychiatric
wards are now locked. The condition is largely undiagnosed by Australian doctors
and psychiatrists, and its non-recognition is one of the main reasons mental health
care is failing.
You need to examine patients for it, and look for subjective restlessness, violent
thoughts regarding self (suicidal ideation) and others (homicidal ideation),
behavioural dyscontrol and toxic hallucinosis.
While on the Clopixol, Simon slept only four hours a night. He says that he didn’t turn
up for his last injection, and now all his side effects are now gone. His sleep pattern
is normal and he is sleeping all night.
He says he is now placid, only eight weeks after his last injection.
In 2008, Simon recalls the side effects of the medication were particularly severe,
including vomiting. He had suicidal impulses, but knew how to control them. He was
helped by his understanding of the side effects of the drug on someone with his
genotype.
He would run out the door, intending to throw himself under a train, and then he
would think about what I had told him.
I had warned him about suicidal impulses on psychiatric drugs, associated with
akathisia, and he said that kept him from harming himself.
He said,
In a way you saved my life.
Many people have said that to me. But for three years I was not permitted by the
Medical Board to even explain these things to patients, or to talk to them about the
side effects of the drugs they were on.
Simon had weird, bad dreams of alien abduction and disturbing sexual content,
which are typical of akathisia. The symptom is called ‘paroniria,’ and it can happen
on all psychiatric drugs.
Simon doesn’t have violent thinking any more, or hostility.
5
Simon Roberts, CTO Application, September 2012
On zuclopenthixol, the fatigue was terrible. He would crash, but then he couldn’t
sleep.
He had toxic hallucinations, best described as ‘apparitions.’ He saw flashes of light,
and objects in his peripheral vision were unclear.
He felt he was being poisoned, and indeed knew he was being poisoned, because
he knew that the drug zuclopenthixol was accumulating in his body because of his
defective metabolising gene. Simon says that his doctors dismissed his beliefs.
He reports that his memory was appalling, and he could not function normally. He
says he cannot recall much of the last twelve years.
Reviewing his file, I note an episode of malignant hyperpyrexia with tachycardia on
clozapine around September 2000. He said he was using cannabis and
amphetamines as well. He said he got diagnosed with schizophrenia and bipolar,
and was given all the drugs associated with treatment of those disorders. They gave
him lithium, for depression, for six months. Simon got so sick he was transferred to
Macquarie Hospital, where, he told me, he remained for nearly a year. He says he
has not been so sick since.
I told him about his genotype, and explained to him why amphetamines make him
psychotic and why cannabis and amphetamines are such a bad combination for
someone with a defective gene.
Simon said,
I don’t take (illicit) drugs since you did the CYP450 test and explained to
me why I was getting sick.
Summary of opinion
Simon told me there has been little involvement from mental health workers in the
last twelve months, except the insistence that he continue his CTO. He gets no care,
no monitoring of his huge weight gain for possible metabolic syndrome, only
enforced medication, which is counterproductive.
Simon told me his weight increased dramatically from 80 kg to 180 kg. He is at risk
for metabolic syndrome, which is associated with early death. This has not been
monitored. Simon now weighs 130 kg, and he hopes his weight continues to fall. He
said he had some blood tests recently, and his liver function was said to be normal. I
have not seen those tests.
Simon has had a job for a few weeks, which he is declaring to Centrelink. He feels
that he is unlikely to be able to remain in this job if he continues to be forcibly
medicated with drugs that make him aggressive, disordered and cognitively
impaired. Drug levels accumulate in poor and intermediate metabolisers, and
intermediate metabolisers are more at risk than poor metabolisers, as the latter are
usually allowed to stop taking them, (but not always and often not in Australia, where
drugs that patients say are making them feel worse, even suicidal, are enforced by
Mental Health Review Tribunals) even though non-compliance with treatment is
characteristic of akathisia.
6
Simon Roberts, CTO Application, September 2012
There is no evidence of mental illness, only of neurotoxicity, which should be
diagnosed as ‘Psychoactive Substance Induced Disorder’ in the International
Classification of Diseases, which is Australia’s official diagnostic tool for
epidemiology, health management and clinical purposes.
Simon has never required any kind of treatment or admission while not on
substances, illicit or psychiatric. He has always had terrible side effects from drugs.
He told me that he spent three months at Concord Hospital after I last saw him. He
was declared to be unresponsive to all drugs.
Comment: By now, epigenetic factors may have set in. The drugs themselves
change the metabolising genes, and the patients’ metabolism deteriorates further.
There were several things I learnt in the first week of my psychiatry training, back in
1965. Most important was:
Do not replace a schizophrenic illness with a neuroleptic psychosis.
This is the most important diagnosis one needs to make correctly in psychiatry, as
the treatment for one is catastrophic for the other.
Psychiatry now recognises the ‘roll-back phenomenon’ as acute Akathisia at DSM
333.99 with suicidality.
It was stated in my undergraduate textbook, ‘Clinical Psychiatry,’ (by Mayer-Gross,
Slater, and Roth, London, 1960, p. 231), that (old) antidepressants induce suicide in
some people.
“With beginning convalescence (following initiation of treatment with
tricyclic antidepressants), the risk of suicide once more becomes serious
as retardation fades.”
However the rising numbers of suicides and homicides under mental health care, in
the cases I have been involved with, have all been caused by the addition of further
drugs metabolised by CYP450, given to people who are already reacting adversely
either to illicit substances or to antidepressants. I now have about 140 gene-tested
cases.
Simon’s condition has never, for one minute, met the criteria for schizophrenia.viii
Schizophrenia carries an exclusion clause:
E. Substance/general medical condition exclusion: The disturbance is not
due to the direct physiological effects of a substance (e.g., a drug of
abuse, a medication) or a general medical condition.
Schizophrenia cannot be diagnosed after medication is given and it takes time to
make a diagnosis. There are 167 drugs that cause hallucinations and they must all
be excluded. False beliefs abound in normal people.ix
For example, Zyprexa PI includes schizophreniform disorder, delusions and
hallucinations as it listed side effects and all other drug PI should too.
7
Simon Roberts, CTO Application, September 2012
Simon’s so-called, ‘mental-illness’ has always been induced by either illicit
substances or medicines, or their sudden withdrawal. There is nobody treating him
now who has seen him as I have, when he is not on medication.
Simon does not have schizophrenia or schizophreniform disorder, and never did. He
experienced substance-induced or substance withdrawal bipolar disorders on every
occasion. He has no delusions or hallucinations when he is not taking illicit
substances or medications.
Simon, at least on medication, fits criteria for schizotypal personality disorder and
this explains his fringe beliefs and strange speech patterns.
Yours sincerely,
Dr. Yolande Lucire
Forensic Psychiatrist
10218—PSYCHIATRIC DRUGS
Mr Daryl Maguire to the Deputy Premier, and Minister for Health—
i
1. Has the Minister and her predecessors been warned by
individuals that suicides committed by patients and clients under
mental health care could be caused by psychiatric drugs:
1. that affect persons who have a genetically determined
inability to metabolise them;
2. that such persons should be recognised by their adverse
medication responses?
2. How many persons have committed suicide whilst under mental
health care in the years 2003 to 2008?
3. How many have committed homicide?
4. Do these figures represent a deterioration or improvement in the
numbers of suicides under mental health care:
1. before 1990;
2. before 2002?
Answer—
I am advised:
1. NSW Health advises me that there has been correspondence to
previous Health Ministers in relation to this issue. I have also
received such correspondence. The Chief Psychiatrist in
8
Simon Roberts, CTO Application, September 2012
consultation with the NSW Mental Health Clinical Advisory
Council is currently considering these issues.
2. According to the Mental Health Client Incident Information
System, there were 937 notifications of suspected suicides of
persons under mental health care that were reported to the NSW
Health Department between 1 Jan 2003 and 31 Dec 2008.
3. According to the Mental Health Client Incident Information
System, there were 43 notifications of suspected homicides by
persons under mental health care that were reported to the NSW
Health Department between 1 Jan 2003 and 31 Dec 2008.
4. It is not possible to compare the data over this time period due to
the fact that different methodology was used to collate this data.
Question asked on 13 May 2010 (session 54-1) and published in Questions &
Answers Paper No. 197
<http://bulletin/prod/la/lapaper.nsf/V3QnBySN/541~197/$file/197-QA-S.pdf> .
10219—SUICIDES CAUSED BY ANTIDEPRESSANTS
Mr Daryl Maguire to the Deputy Premier, and Minister for Health—
1. How many suicides have been investigated by toxicologists or
geneticists, as recommended in The Pharmacogenetics Journal
to which a NSW psychiatrist has contributed?
2. Has NSW Health had genetic evaluations for "ability to
metabolise drugs" as is done by medical examiners and
coroners in the USA and UK to distinguish between suicide
caused by mental illness and suicide caused by psychiatric
drugs?
3. Can the Minister provide advice from the Department of Health
on the issue of antidepressant-induced akathisia suicide and
homicide?
4. Is the Minister aware:
1. of the claim antidepressant drugs increase suicide;
2. this is the subject of public health advisories in all
countries other than Australia and NSW?
5. Is the Minister aware that antidepressants caused about 1 in 500
users to commit suicide in clinical trials presented to the US FDA
for the purposes of licensing and follow-up studies?
Answer—
I am advised:
1. Any deaths and suicides of people under the care of public
mental health services are investigated by the NSW Coroner.
9
Simon Roberts, CTO Application, September 2012
Questions relating to the Coronial process should be directed to
the NSW Attorney General.
2. NSW Health has not funded any research into 'genetic
evaluations for ability to metabolise drugs'.
3. to (5) The Chief Psychiatrist in consultation with the NSW Mental
Health Clinical Advisory Council is currently considering these
issues.
4. I invite the Member to submit any studies or material he may
have on these issues for further consideration.
Question asked on 13 May 2010 (session 54-1) and published in Questions &
Answers Paper No. 197
<http://bulletin/prod/la/lapaper.nsf/V3QnBySN/541~197/$file/197-QA-S.pdf> .
10220—DEATHS DUE TO ZYPREXA AND RISPERDAL
Mr Daryl Maguire to the Deputy Premier, and Minister for Health—
1. Is the Minister aware that in Zyprexa and Risperdal clinical trials
presented to the US FDA to get these drugs licensed, it was
revealed that:
1. 1 in 208 (20) Zyprexa (olanzapine) subjects died;
2. 1 in 250 (12) risperidone clinical trial subjects died;
3. most of the deaths (21) were suicides?
2. Is the Minister aware of damages being paid to States and
individuals consequent on litigation for fraudulent promotion of
medication?
3. Is the Minister aware that by 2003, 288 deaths had been
reported to the TGA of persons taking new "Atypical" drugs?
4. What warnings have been issued to patients and prescribers re
the above drugs?
5. (a) Have these deaths been thoroughly investigated by coroners
as they are in the USA, as described in the editorial provided to
which an Australian (NSW) psychiatrist has contributed?
6. (b) Has an inquiry been made into what medications they were
taking or had recently taken?
Answer—
I am advised:
(1) and (2) Agreement for drugs to be included for Australian use rests
10
Simon Roberts, CTO Application, September 2012
with the Commonwealth Government. The Therapeutic Goods
Administration (TGA) regularly evaluates prescription medicines for
quality and safety and to ensure that the product is effective for its
intended use. NSW Health ensures that any warnings issued by the
TGA are included in relevant clinical guidelines.
(3) The TGA's Office of Medicines Safety Monitoring receives reports of
suspected adverse reactions to prescribed medicines, vaccines, overthe-counter medicines and complementary medicines.
(4) The TGA provides advice on suspected adverse reactions to
prescription medicines to the public and prescribers as required.
Information is available to patients and prescribers in the Approved
Product Information leaflets on medicines approved in Australia.
(5) Questions concerning the Coronial Process should be directed to
the NSW Attorney General
Question asked on 13 May 2010 (session 54-1) and published in
Questions & Answers Paper No. 197
<http://bulletin/prod/la/lapaper.nsf/V3QnBySN/541~197/$file/197-QAS.pdf> .
Answer received on 17 June 2010 and printed in Questions & Answers
Paper No. 211 <
ii
Psychopharmacology (Berl). 2002 Jun;162(1):67-73. Epub 2002 Apr 20.
Maintenance therapy with zuclopenthixol decanoate: associations between plasma
concentrations, neurological side effects and CYP2D6 genotype.
Jaanson P, Marandi T, Kiivet RA, Vasar V, Vään S, Svensson JO, Dahl ML.
Source
Department of Psychiatry, University of Tartu, 31 Raja St., 50417 Tartu, Estonia.
Peeter.Jaanson@kliinikum.ee
Abstract
RATIONALE:
Several antipsychotic drugs are metabolised by the polymorphic cytochrome P(450) CYP2D6. The
impact of the polymorphism on the plasma levels and the occurrence of side effects have not been
clearly established.
OBJECTIVE:
To investigate the impact of the CYP2D6 polymorphism on the steady-state plasma concentrations of
zuclopenthixol and the occurrence of extrapyramidal side effects (EPS) and tardive dyskinesia (TD)
during treatment with zuclopenthixol-decanoate.
METHODS:
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Simon Roberts, CTO Application, September 2012
Fifty-two clinically stable schizophrenic outpatients on monotherapy with zuclopenthixol-decanoate
(100-400 mg/4 weeks) were genotyped for the CYP2D6 variants CYP2D6*3 and CYP2D6*4. Steadystate plasma levels of zuclopenthixol were analysed using high-performance liquid chromatography.
Assessments of EPS, TD and psychopathology were performed twice with an 8-week interval using
the extrapyramidal symptoms rating scale, the abnormal involuntary movement scale and the brief
psychiatric ratig scale.
RESULTS:
Thirty-five patients were homozygous extensive metabolisers (EMs), 13 were heterozygous EMs and
4 were poor metabolisers (PMs). While there were no significant genotype-related differences in the
doses of zuclopenthixol decanoate, PMs as well as heterozygous EMs had significantly higher steadystate plasma levels of zuclopenthixol than homozygous EMs (median 9.5 nmol/l; 8.2 nmol/l and 5.9
nmol/l, respectively, P<0.05). The median dose-corrected plasma concentrations were 0.029, 0.038
and 0.048 nmol.l(-1).mg(-1) in homozygous EMs, heterozygous EMs and PMs, respectively, with
statistically significant differences between homozygous EMs and heterozygous EMs ( P=0.014) and
homozygous EMs and PMs ( P=0.03). Patients with neurological side effects were significantly older
than patients without ( P=0.02 in case of parkinsonism and P=0.04 in case of TD). Mutant CYP2D6*3
and *4 alleles tended to occur more frequently in patients with neurological side effects. An odds ratio
(OR) of 2.3 (95% confidence interval 0.7-6.9) for development of parkinsonism and an OR of 1.7 (95%
confidence interval 0.5-4.9) for TD was calculated in an individual with at least one mutated allele.
However, the ORs were not statistically significant.
CONCLUSIONS:
The higher zuclopenthixol steady-state plasma concentrations in heterozygous EM and PM
schizophrenic patients receiving monotherapy with zuclopenthixol-decanoate than in homozygous
EMs indicates a significant role of CYP2D6 in the systemic elimination of zuclopenthixol. The
tendencies for patients carrying at least one mutated CYP2D6 gene to have an increased risk of
parkinsonism and TD are in accordance with previous studies. Age was a significant risk factor for
neurological side effects.
iii Characterization of Metabolic Types CYP450 enzyme-mediated drug metabolism displays wide
interindividual variability. Several key polymorphisms may be associated with variability in the function
of enzyme metabolism as compared to the normal gene structure. Most variants result in synthesis of
enzymes that are diminished or devoid of catalytic activity. Alternatively‚ duplication gene variants
result in increased metabolic activity (see Table 1).
Extensive Metabolizers (EM) These individuals possess the normal genotype— referred to as “wild
type” by molecular biologists— which is free of inactivating polymorphisms‚ deletions‚ or duplications.
In Caucasian populations‚ EM is the most common genotype. Current drug dosing recommendations
typically assume that the patient is an extensive metabolizer.
Poor Metabolizers (PM) These individuals are homozygous for an inactivating polymorphism or
compound heterozygous for 2 different inactivating polymorphisms. The severity of functional enzyme
deficiencies varies among those with a PM genotype, though most lack a functional enzyme.
Especially important for PM individuals is that they often do not receive any therapeutic benefit from
drugs that are activated by CYP450 metabolism. Additionally‚ deficient enzyme function may result in
an inability to clear certain medications‚ which may lead to toxicity and serious to sometimes
lifethreatening side effects.
Intermediate Metabolizers (IM) These individuals have 1 normal allele and 1 allele with an
inactivating polymorphism. Individuals with an IM genotype demonstrate a wide range of levels of
enzyme activity. Some produce sufficient functional enzyme‚ while others do not. This group of
metabolizers is particularly susceptible to abolishment of the residual functional CYP450 enzyme in
response to inhibition by other drugs or metabolites. Thus‚ individuals with an IM genotype can
develop a poor metabolizer phenotype in response to a “second hit” by the effects of drug inhibition or
environmental factors.
Ultrarapid Metabolizers (UM) These individuals have a duplication of a functional gene‚ resulting in
ultrarapid metabolism. Presently‚ UM metabolizer genotypes have only been found for the CYP2D6
enzyme. Duplications from 3 to 13 copies of the CYP2D6 gene have been reported and the rate of
12
Simon Roberts, CTO Application, September 2012
metabolism is often directly correlated to the number of copies present.6 Individuals with a UM
genotype may metabolize medications too quickly. Most often the drug is so rapidly cleared it does not
reach therapeutic levels‚ and the therapeutic response is dramatically minimized or totally eliminated.
This results in UM patients almost always being nonresponders to CYP2D6-metabolized
antidepressant medications. Alternately‚ if a drug becomes effective only when it is metabolized‚ the
UM patient may produce the metabolite more quickly than anticipated‚ resulting in toxicity and side
effects.
iv World Health Organization
F10 - F19
Mental and behavioural disorders due to psychoactive substance use
Overview of this block
F10. – Mental and behavioural disorders due to use of alcohol
F11. – Mental and behavioural disorders due to use of opioids
F12. – Mental and behavioural disorders due to use of cannabinoids
F13. – Mental and behavioural disorders due to use of sedative hypnotics
F14. – Mental and behavioural disorders due to use of cocaine
F15. – Mental and behavioural disorders due to use of other stimulants, including caffeine
F16. – Mental and behavioural disorders due to use of hallucinogens
F17. – Mental and behavioural disorders due to use of tobacco
F18. – Mental and behavioural disorders due to use of volatile solvents
F19. – Mental and behavioural disorders due to multiple drug use and use of other
psychoactive substances
Four and five character codes may be used to specify the clinical conditions, as follows:
F1x.0 Acute intoxication
.00 Uncomplicated
.01 With trauma or other bodily injury
.02 With other medical complications
.03 With delirium
.04 With perceptual distortions
.05 With coma
.06 With convulsions
.07 Pathological intoxication
F1x.1 Harmful use
F1x.2 Dependence syndrome
.20 Currently abstinent
.21 Currently abstinent, but in a protected environment
.22 Currently on a clinically supervised maintenance or replacement regime [controlled
dependence]
.23 Currently abstinent, but receiving treatment with aversive or blocking drugs
.24 Currently using the substance [active dependence]
.25 Continuous use
.26 Episodic use [dipsomania]
F1x.3 Withdrawal state
.30 Uncomplicated
.31 With convulsions
F1x.4 Withdrawal state with delirium
The ICD-10 Classification of Mental and Behavioural
Disorders: Clinical descriptions and diagnostic guidelines
2
.40 Without convulsions
13
Simon Roberts, CTO Application, September 2012
.41 With convulsions
F1x.5 Psychotic disorder
.50 Schizophrenia-like
.51 Predominantly delusional
.52 Predominantly hallucinatory
.53 Predominantly polymorphic
.54 Predominantly depressive symptoms
.55 Predominantly manic symptoms
.56 Mixed
F1x.6 Amnesic syndrome
F1x.7 Residual and late-onset psychotic disorder
.70 Flashbacks
.71 Personality or behaviour disorder
.72 Residual affective behaviour
.73 Dementia
.74 Other persisting cognitive behaviour
.75 Late-onset psychotic disorder
F1x.8 Other mental and behavioural disorders
F1x.9 Unspecified mental and behavioural disorder
Introduction
This block contains a wide variety of disorders that differ in severity (from uncomplicated
intoxication and harmful use to obvious psychotic disorders and dementia), but that are all
attributable to the use of one or more psychoactive substances (which may or may not have
been medically prescribed).
The substance involved is indicated by means of the second and third characters (i.e. the first
two digits after the letter F), and the fourth and fifth characters specify the clinical states. To
save space, all the psychoactive substances are listed first, followed by the four-character
codes; these should be used, as required, for each substance specified, but it should be noted
that not all four-character codes are applicable to all substances.
Diagnostic guidelines
Identification of the psychoactive substance used may be made on the basis of self-report
data, objective analysis of specimens of urine, blood, etc, or other evidence (presence of drug
samples in the patient’s possession, clinical signs and symptoms, or reports from informed
third parties). It is always advisable to seek corroboration from more than one source of
evidence relating to substance use.
Objective analyses provide the most compelling evidence of present or recent use, though
these data have limitations with regard to past use and current levels of use.
Many drug users take more than one type of drug, but the diagnosis of the disorder should be
classified, whenever possible, according to the most important single substance (or class of
substances) used. This may usually be done with regard to the particular drug, or type of drug,
causing the presenting disorder. When in doubt, code the drug or type of drug most frequently
misused, particularly in those cases involving continuous or daily use.
Only in cases in which patterns of psychoactive substance taking are chaotic and
indiscriminate, or in which the contributions of different drugs are inextricably mixed, should
code F19. – be used (disorders resulting from multiple drug use).
Misuse of other than psychoactive substances, such as laxatives or aspirin, should be coded
by means of F55. – (abuse of non-dependence-producing substances), with a fourth character
to specify the type of substance involved. Cases in which mental disorders (particularly
delirium in the elderly) are due to psychoactive substances, but without the presence of one of
the disorders in this block (e.g. harmful use or dependence syndrome), should be coded in
14
Simon Roberts, CTO Application, September 2012
F00 – F09. Where a state of delirium is superimposed upon such a disorder in this block, it
should be coded by means of F1x.3 or F1X.4.
The level of alcohol involvement can be indicated by means of a supplementary code from
Chapter XX of ICD-10: Y90. – (evidence of alcohol involvement determined by blood
alcohol content) or Y91. – (evidence of alcohol involvement determined by level of
intoxication).
F1x.0 Acute intoxication
A transient condition following the administration of alcohol or other psychoactive
substance, resulting in disturbances in level of consciousness, cognition, perception,
affect or behaviour, or other psychophysiological functions and responses.
This should be a main diagnosis only in cases where intoxication occurs without more
persistent alcohol- or drug-related problems being concomitantly present. Where
there are such problems, precedence should be given to diagnoses of harmful use
(F1x.1), dependence syndrome (F1x.2), or psychotic disorder (F1x.5).
Diagnostic guidelines
Acute intoxication is usually closely related to dose levels (see ICD-10, Chapter XX).
Exceptions to this may occur in individuals with certain underlying organic
conditions (e.g. renal or hepatic insufficiency) in whom small doses of a substance
may produce a disproportionately severe intoxicating effect. Disinhibition due to
social context should also be taken into account (e.g. behavioural disinhibition at
parties or carnivals). Acute intoxication is a transient phenomenon. Intensity of
intoxication lessens with time, and effects eventually disappear in the absence of
further use of the substance. Recovery is therefore complete except where tissue
damage or another complication has arisen.
Symptoms of intoxication need not always reflect primary actions of the substance:
for instance, depressant drugs may lead to symptoms of agitation or hyperactivity, and
stimulant drugs may lead to socially withdrawn and introverted behaviour. Effects of
substances such as cannabis and hallucinogens may be particularly unpredictable.
Moreover, many psychoactive substances are capable of producing different types of
effect at different levels. For example, alcohol may have apparently stimulant effects
on behaviour at lower dose levels, lead to agitation and aggression with increasing
dose levels, and produce clear sedation at very high levels.
Includes: acute drunkenness in alcoholism, “bad trips” (due to hallucinogenic drugs) &
drunkenness NOS
4
Differential diagnosis. Consider acute head injury and hypoglycaemia. Consider also
the possibilities of intoxication as the result of mixed substance use.
The following five-character codes may be used to indicate whether the acute
intoxication was associated with any complications:
F1x.00 Uncomplicated
Symptoms of varying severity, usually dose-dependent, particularly at high dose
levels.
F1x.01 With trauma or other bodily injury
F1x.02 With other medical complications
Complications such as haematemesis, inhalation of vomitus.
F1x.03 With delirium
F1x.04 With perceptual distortions
F1x.05 With coma
F1x.06 With convulsions
F1x.07 Pathological intoxication
15
Simon Roberts, CTO Application, September 2012
Applies only to alcohol. Sudden onset of aggression and often violent behaviour that
is not typical of the individual when sober, very soon after drinking amounts of
alcohol that would not produce intoxication in most people.
F1x.1 Harmful use
A pattern of psychoactive substance use that is causing damage to health. The
damage may be physical (as in cases of hepatitis from the self-administration of
injected drugs) or mental (e.g. episodes of depressive disorder secondary to heavy
consumption of alcohol).
Diagnostic guidelines
The diagnosis requires that actual damage should have been caused to the mental or
physical health of the user.
Harmful patterns of use are often criticized by others and frequently associated with
adverse social consequences of various kinds. The fact that a pattern of use or a
particular substance is disapproved of by another person or by the culture, or may
have led to socially negative consequences such as arrest or marital arguments is not
in itself evidence of harmful use.
Acute intoxication (see F1x.0), or “hangover” is not itself sufficient evidence of the
damage to health required for coding harmful use.
Harmful use should not be diagnosed if dependence syndrome (F1x.2), a psychotic
disorder (F1x.5), or another specific form of drug- or alcohol-related disorder is
present.
F1x.2 Dependence syndrome
5
A cluster of physiological, behavioural, and cognitive phenomena in which the use of
a substance or a class of substances takes on a much higher priority for a given
individual than other behaviours that once had greater value. A central descriptive
characteristic of the dependence syndrome is the desire (often strong, sometimes
overpowering) to take psychoactive drugs (which may or may not have been
medically prescribed), alcohol, or tobacco. There may be evidence that return to
substance use after a period of abstinence leads to a more rapid reappearance of other
features of the syndrome than occurs with nondependent individuals.
Diagnostic guidelines
A definite diagnosis of dependence should usually be made only if three or more of
the following have been present together at some time during the previous year:
(a) a strong desire or sense of compulsion to take the substance;
(b) difficulties in controlling substance-taking behaviour in terms of its onset,
termination, or levels of use;
(c) a physiological withdrawal state (see F1x.3 and F1x.4) when substance use has
ceased or been reduced, as evidenced by: the characteristic withdrawal syndrome
for the substance; or use of the same (or a closely related) substance with the
intention of relieving or avoiding withdrawal symptoms;
(d) evidence of tolerance, such that increased doses of the psychoactive substances
are required in order to achieve effects originally produced by lower doses (clear
examples of this are found in alcohol- and opiate-dependent individuals who may
take daily doses sufficient to incapacitate or kill nontolerant users);
(e) progressive neglect of alternative pleasures or interests because of psychoactive
substance use, increased amount of time necessary to obtain or take the substance
or to recover from its effects;
(f) persisting with substance use despite clear evidence of overtly harmful
consequences, such as harm to the liver through excessive drinking, depressive
16
Simon Roberts, CTO Application, September 2012
mood states consequent to periods of heavy substance use, or drug-related
impairment of cognitive functioning; efforts should be made to determine that the
user was actually, or could be expected to be, aware of the nature and extent of
the harm.
Narrowing of the personal repertoire of patterns of psychoactive substance use has
also been described as a characteristic feature (e.g. a tendency to drink alcoholic
drinks in the same way on weekdays and weekends, regardless of social constraints
that determine appropriate drinking behaviour).
It is an essential characteristic of the dependence syndrome that either psychoactive
substance taking or a desire to take a particular substance should be present; the
subjective awareness of compulsion to use drugs is most commonly seen during
attempts to stop or control substance use. This diagnostic requirement would exclude,
for instance, surgical patients given opioid drugs for the relief of pain, who may show
signs of an opioid withdrawal state when drugs are not given but who have no desire
to continue taking drugs.
The dependence syndrome may be present for a specific substance (e.g. tobacco or
diazepam), for a class of substances (e.g. opioid drugs), or for a wider range of
different substances (as for those individuals who feel a sense of compulsion
regularly to use whatever drugs are available and who show distress, agitation, and/or
physical signs of a withdrawal state upon abstinence).
6
Includes: chronic alcoholism
Dipsomania
Drug addiction
The diagnosis of the dependence syndrome may be further specified by the following
five-character codes:
F1x.20 Currently abstinent
F1x.21 Currently abstinent, but in a protected environment
(e.g. in hospital, in a therapeutic community, in prison, etc.)
F1x.22 Currently on a clinically supervised maintenance or replacement
regime [controlled dependence]
(e.g. with methadone; nicotine gum or nicotine patch)
F1x.23 Currently abstinent, but receiving treatment with aversive or blocking
drugs
(e.g. naltrexone or disulfiram)
F1x.24 Currently using the substance [active dependence]
F1x.25 Continuous use
F1x.26 Episodic use [dipsomani]
F1x.3 Withdrawal state
A group of symptoms of variable clustering and severity occurring on absolute or
relative withdrawal of a substance after repeated, and usually prolonged and/or highdose,
use of that substance. Onset and course of the withdrawal state are time-limited
and are related to the type of substance and the dose being used immediately before
abstinence. The withdrawal state may be complicated by convulsions.
Diagnostic guidelines
Withdrawal state is one of the indicators of dependence syndrome (see F1x.2) and
this latter diagnosis should also be considered.
Withdrawal state should be coded as the main diagnosis if it is the reason for referral
and sufficiently severe to require medical attention in its own right.
Physical symptoms vary according to the substance being used. Psychological
17
Simon Roberts, CTO Application, September 2012
disturbances (e.g. anxiety, depression, and sleep disorders) are also common features
of withdrawal. Typically, the patient is likely to report that withdrawal symptoms are
relieved by further substance use.
It should be remembered that withdrawal symptoms can be induced by
conditioned/learned stimuli in the absence of immediately preceding substance use. In
such cases a diagnosis of withdrawal state should be made only if it is warranted in
terms of severity.
7
Differential diagnosis. Many symptoms present in drug withdrawal state may also be
caused by other psychiatric conditions, e.g. anxiety states, and depressive disorders.
Simple “hangover” or tremor due to other conditions should not be confused with the
symptoms of a withdrawal state.
The diagnosis of withdrawal state may be further specified by using the following
five-character codes:
F1x.30 Uncomplicated
F1x.31With convulsions
F1x.4 Withdrawal state with delirium
A condition in which the withdrawal state (see F1x.3) is complicated by delirium (see
criteria for F05. - ).
Alcohol-induced delirium tremens should be coded here. Delirium tremens is a shortlived,
but occasionally life-threatening, toxic-confusional state with accompanying
somatic disturbances. It is usually a consequence of absolute or relative withdrawal of
alcohol in severely dependent users with a long history of use. Onset usually occurs
after withdrawal of alcohol. In some cases the disorder appears during an episode of
heavy drinking, in which case it should be coded here.
Prodromal symptoms typically include insomnia, tremulousness, and fear. Onset may
also be preceded by withdrawal convulsions. The classical triad of symptoms
includes clouding of consciousness and confusion, vivid hallucinations and illusions
affecting any sensory modality, and marked tremor. Delusions, agitation, insomnia or
sleep-cycle reversal, and autonomic overactivity are usually also present.
Excludes: delirium, not induced by drugs and alcohol (F05. - )
The diagnosis of withdrawal state with delirium may be further specified by using the
following five-character codes:
F1x.40Without convulsions
F1x.41With convulsions
F1x.5 Psychotic disorder
A cluster of psychotic phenomena that occur during or immediately after
psychoactive substance use and are characterized by vivid hallucinations (typically
auditory, but often in more than one sensory modality), misidentifications, delusions
and/or ideas of reference (often of a paranoid or persecutory nature), psychomotor
disturbances (excitement of stupor), and an abnormal affect, which may range from
intense fear to ecstasy. The sensorium is usually clear but some degree of clouding of
consciousness, though not severe confusion, may be present. The disorder typically
resolves at least partially within 1 month and fully within 6 months.
Diagnostic guidelines
8
A psychotic disorder occurring during or immediately after drug use (usually within
48 hours) should be recorded here provided that it is not a manifestation of drugwithdrawal
state with delirium (see F1x.4) or of late onset. Late-onset psychotic
disorders (with onset more than 2 weeks after substance use) may occur, but should
18
Simon Roberts, CTO Application, September 2012
be coded as F1x.75.
Psychoactive substance-induced psychotic disorders may present with varying
patterns of symptoms. These variations will be influenced by the type of substance
involved and the personality of the user. For stimulant drugs such as cocaine and
amphetamines, drug-induced psychotic disorders are generally closely related to high
dose levels and/or prolonged use of the substance.
A diagnosis of psychotic disorder should not be made merely on the basis of
perceptual distortions or hallucinatory experiences when substances having primary
hallucinogenic effects (e.g. lysergic (LSD), mescaline, cannabis at high doses) have
been taken. In such cases, and also for confusional states, a possible diagnoses of
acute intoxication (F1x.0) should be considered.
Particular care should also be taken to avoid mistakenly diagnosing a more serious
condition (e.g. schizophrenia) when a diagnosis of psychoactive substance-induced
psychosis is appropriate. Many psychoactive substance-induced psychotic states are
of short duration provided that no further amounts of the drug are taken (as in the
case of amphetamine and cocaine psychoses). False diagnosis in such cases may have
distressing and costly implications for the patient and for the health services.
Includes: alcoholic hallucinosis
alcoholic jealousy
alcoholic paranoia
alcoholic psychosis NOS
Differential diagnosis. Consider the possibility of another mental disorder being
aggravated or precipitated by psychoactive substance use (e.g. schizophrenia (F20. ); mood [affective] disorder (F30-F39); paranoid or schizoid personality disorder
(F60.0, F60.1). In such cases, a diagnosis of psychoactive substance-induced
psychotic state may be inappropriate.
The diagnosis of psychotic state may be further specified by the following fivecharacter
codes:
F1x.50 Schizophrenia-like
F1x.51 Predominantly delusional
F1x.52 Predominantly hallucinatory
(includes alcoholic hallucinosis)
F1x.53 Predominantly polymorphic
F1x.54 Predominantly depressive symptoms
F1x.55 Predominantly manic symptoms
F1x.56 Mixed
9
F1x.6 Amnesic syndrome
A syndrome associated with chronic prominent impairment of recent memory; remote
memory is sometimes impaired, while immediate recall is preserved. Disturbances of
time sense and ordering of events are usually evident, as are difficulties in learning
new material. Confabulation may be marked but is not invariably present. Other
cognitive functions are usually relatively well preserved and amnesic defects are out
of proportion to other disturbances.
Diagnostic guidelines
Amnesic syndrome induced by alcohol or other psychoactive substances coded here
should meet the general criteria for organic amnesic syndrome (see F04). The primary
requirements for this diagnosis are:
(a) memory impairment as shown in impairment of recent memory (learning of new
material); disturbances of time sense (rearrangements of chronological sequence,
19
Simon Roberts, CTO Application, September 2012
telescoping of repeated events into one, etc.);
(b) absence of defect in immediate recall, impairment of consciousness, and of
generalized cognitive impairment;
(c) history or objective evidence of chronic (and particularly high-dose) use of
alcohol or drugs.
Personality changes, often with apparent apathy and loss of initiative, and a tendency
towards self-neglect may also be present, but should not be regarded as necessary
conditions for diagnosis.
Although confabulation may be marked it should not be regarded as a necessary
prerequisite for diagnosis.
Includes: Korsakov’s psychosis or syndrome, alcohol- or other psychoactive
substance-induced.
Differential diagnosis. Consider: organic amnesic syndrome (nonalcoholic) (see F04);
other organic syndromes involving marked impairment of memory (e.g. dementia or
delirium) (F00-F03; F05. - ); a depressive disorder (F31 – F33).
F1x.7 Residual and late-onset psychotic disorder
A disorder in which alcohol- or psychoactive substance-induced changes of
cognition, affect, personality, or behaviour persist beyond the period during which a
direct psychoactive substance-related effect might reasonably be assumed to be
operating.
Diagnostic guidelines
Onset of the disorder should be directly related to the use of alcohol or a psychoactive
substance. Cases in which initial onset occurs later than episode(s) of substance use
should be coded here only where clear and strong evidence is available to attribute
the state to the residual effect of the substance. The disorder should represent a
change from or marked exaggeration of prior and normal state of functioning.
The disorder should persist beyond any period of time during which direct effects of
the psychoactive substance might be assumed to be operative (see F1x.0, acute
intoxication). Alcohol- or psychoactive substance-induced dementia is not always
irreversible; after an extended period of total abstinence, intellectual functions and
memory may improve.
The disorder should be carefully distinguished from withdrawal-related conditions
(see F1x.3 and F1x.4). It should be remembered that, under certain conditions and for
certain substances, withdrawal state phenomena may be present for a period of many
days or weeks after discontinuation of the substance.
Conditions induced by a psychoactive substance, persisting after its use, and meeting
the criteria for diagnosis of psychotic disorder should not be diagnosed here (use
F1x.5, psychotic disorder). Patients who show the chronic end-state of Korsakov’s
syndrome should be coded under F1x.6.
Differential diagnosis. Consider: pre-existing mental disorder masked by substance
use and re-emerging as psychoactive substance-related effects fade (for example,
phobic anxiety, a depressive disorder, schizophrenia, or schizotypal disorder). In the
case of flashbacks, consider acute and transient psychotic disorders (F23. - ).
Consider also organic injury and mild or moderate mental retardation (F70 – F71),
which may coexist with psychoactive substance misuse. This diagnostic rubric may
be further subdivided by using the following five-character codes:
F1x.70 Flashbacks
May be distinguished from psychotic disorders partly by their episodic nature,
frequently of very short duration (seconds or minutes) and by their duplication
(sometimes exact) of previous drug-related experiences.
20
Simon Roberts, CTO Application, September 2012
F1x.71 Personality or behaviour disorder
Meeting the criteria for organic personality disorder (F07.0).
F1x.72 Residual affective disorder
Meeting the criteria for organic mood [affective] disorders (F06.3).
F1x.73 Dementia
Meeting the general criteria for dementia as outlined in the introduction to F00-F09.
F1x.74 Other persisting cognitive impairment
A residual category for disorders with persisting cognitive impairment, which do not
meet the criteria for psychoactive substance-induced amnesic syndrome (F1x.6) or
dementia (F1x.73).
F1x.75 Late-onset psychotic disorder
F1x.8 Other mental and behavioural disorders
Code here any other disorder in which the use of a substance can be identified as
contributing directly to the condition, but which does not meet the criteria for
inclusion in any of the above disorders.
F1x.9 Unspecified mental and behavioural disorder
v Van Putten T. The many faces of akathisia. Comprehensive Psychiatry. 1975 Jan-Feb;16(1):43-7.
vi Psychopharmacology (Berl). 2002 Jun;162(1):67-73. Epub 2002 Apr 20.
Maintenance therapy with zuclopenthixol decanoate: associations between plasma
concentrations, neurological side effects and CYP2D6 genotype.
Jaanson P, Marandi T, Kiivet RA, Vasar V, Vään S, Svensson JO, Dahl ML.
Source
Department of Psychiatry, University of Tartu, 31 Raja St., 50417 Tartu, Estonia.
Peeter.Jaanson@kliinikum.ee
Abstract
RATIONALE:
Several antipsychotic drugs are metabolised by the polymorphic cytochrome P(450) CYP2D6. The
impact of the polymorphism on the plasma levels and the occurrence of side effects have not been
clearly established.
OBJECTIVE:
To investigate the impact of the CYP2D6 polymorphism on the steady-state plasma concentrations of
zuclopenthixol and the occurrence of extrapyramidal side effects (EPS) and tardive dyskinesia (TD)
during treatment with zuclopenthixol-decanoate.
METHODS:
Fifty-two clinically stable schizophrenic outpatients on monotherapy with zuclopenthixol-decanoate
(100-400 mg/4 weeks) were genotyped for the CYP2D6 variants CYP2D6*3 and CYP2D6*4. Steadystate plasma levels of zuclopenthixol were analysed using high-performance liquid chromatography.
Assessments of EPS, TD and psychopathology were performed twice with an 8-week interval using
the extrapyramidal symptoms rating scale, the abnormal involuntary movement scale and the brief
psychiatric rating scale.
RESULTS:
Thirty-five patients were homozygous extensive metabolisers (EMs), 13 were heterozygous EMs and
4 were poor metabolisers (PMs). While there were no significant genotype-related differences in the
doses of zuclopenthixol decanoate, PMs as well as heterozygous EMs had significantly higher steadystate plasma levels of zuclopenthixol than homozygous EMs (median 9.5 nmol/l; 8.2 nmol/l and 5.9
nmol/l, respectively, P<0.05). The median dose-corrected plasma concentrations were 0.029, 0.038
and 0.048 nmol.l(-1).mg(-1) in homozygous EMs, heterozygous EMs and PMs, respectively, with
statistically significant differences between homozygous EMs and heterozygous EMs ( P=0.014) and
homozygous EMs and PMs ( P=0.03). Patients with neurological side effects were significantly older
than patients without ( P=0.02 in case of parkinsonism and P=0.04 in case of TD). Mutant CYP2D6*3
and *4 alleles tended to occur more frequently in patients with neurological side effects. An odds ratio
(OR) of 2.3 (95% confidence interval 0.7-6.9) for development of parkinsonism and an OR of 1.7 (95%
21
Simon Roberts, CTO Application, September 2012
confidence interval 0.5-4.9) for TD was calculated in an individual with at least one mutated allele.
However, the ORs were not statistically significant.
CONCLUSIONS:
The higher zuclopenthixol steady-state plasma concentrations in heterozygous EM and PM
schizophrenic patients receiving monotherapy with zuclopenthixol-decanoate than in homozygous
EMs indicates a significant role of CYP2D6 in the systemic elimination of zuclopenthixol. The
tendencies for patients carrying at least one mutated CYP2D6 gene to have an increased risk of
parkinsonism and TD are in accordance with previous studies. Age was a significant risk factor for
neurological side effects.
PMID: 12107620 [PubMed - indexed for MEDLINE]
vii DSM 333.99 Neuroleptic-Induced Acute Akathisia
Diagnostic Features
The essential features of Neuroleptic-Induced Acute Akathisia are subjective complaints of
restlessness and at least one of the following observed movements: fidgety movements or swinging of
the legs while seated, rocking from foot to foot or "walking on the spot" while standing, pacing to
relieve the restlessness, or a inability to sit or stand still for at least several minutes. In its most severe
form, the individual may be unable to maintain any position for more than a few seconds. The
subjective complaints include a sense of inner restlessness, most often in the legs; a compulsion to
move one's legs; distress if one is asked not to move one's legs; and dysphoria and anxiety. The
symptoms typically occur within 4 weeks of initiating or increasing the dose of a neuroleptic medication
and can occasionally follow the reduction of medication used to treat or prevent acute extrapyramidal
symptoms (e.g., anticholinergic agents). The symptoms are not better accounted for by a mental
disorder (e.g., Schizophrenia, Substance Withdrawal, agitation from a Major Depressive or Manic
Episode, hyperactivity in Attention-Deficit/Hyperactivity Disorder) and are not due to a non neuroleptic
substance or to a neurological or other general medical condition (e.g., Parkinson's disease, irondeficiency anaemia).
Associated Features and Disorders
The subjective distress resulting from akathisia is significant and can lead to noncompliance with
neuroleptic treatme nt. Akathisia may be associated with dysphoria, irritability, aggression or suicide
attempts. Worsening of psychotic symptoms or behavioural dyscontrol may lead to an increase in
neuroleptic medication dose, which may exacerbate the problem. Akathisia can develop very rapidly
after initiating or increasing neuroleptic medication.
The development of akathisia appears to be dose dependent and to be more frequently associated
with particular neuroleptic medications.
Acute akathisia tends to persist for as long as neuroleptic medications are continued, although the
intensity may fluctuate over time. The reported prevalence of akathisia among individuals receiving
neuroleptic medication has varied widely (20%-75%). Variations in reported prevalence may be due to
a lack of consistency in the definition of caseness, neuroleptic prescribing practices, study design, and
the demographics of the population being studied.
Differential Diagnosis
Neuroleptic-Induced Acute Akathisia may be clinically indistinguishable from syndromes of
restlessness due to certain neurological or other general medical conditions, to nonneuroleptic
substances, and to agitation presenting as part of a mental disorder (e.g., a Manic Episode). The
akathisia of Parkinson's disease and iron-deficiency anaemia are phenomenologically similar to
Neuroleptic- Induced Acute Akathisia. The frequently abrupt appearance of restlessness soon after
initiation or increase in neuroleptic medication usually distinguishes Neuroleptic-Induced Acute
Akathisia.
Serotonin-specific reuptake inhibitor antidepressant medications may produce akathisia that appears
to be identical in phenomenology and treatment response to Neuroleptic-Induced Acute Akathisia.
Akathisia due to nonneuroleptic medication can be diagnosed as Medication-Induced Movement
Disorder Not Otherwise Specified. Other situations that might be included under Medication-Induced
Movement Disorders Not Otherwise Specified are acute akathisia with only subjective or only objective
complaints, but not both; and akathisia occurring late in the course of treatment (e.g., 6 months after
22
Simon Roberts, CTO Application, September 2012
initiation of, or increase in the dose of, a neuroleptic). Neuroleptic-Induced Tardive Dyskinesia also
often has a component of generalized restlessness that may coexist with akathisia in an individual
receiving neuroleptic medication.
Neuroleptic-Induced Acute Akathisia is differentiated from Neuroleptic-Induced Tardive Dyskinesia by
the nature of the movements and their relationship to the initiation of medication. The time course of
symptomatic presentation relative to neuroleptic dose changes may aid in this distinction. An increase
in neuroleptic medication will often exacerbate akathisia, whereas it often temporarily relieves the
symptoms of Tardive Dyskinesia. Neuroleptic-Induced Acute Akathisia should be distinguished from
symptoms that are bettered accounted for by a mental disorder. Individuals with Depressive Episodes,
Manic Episodes, Generalized Anxiety Disorder, Schizophrenia and other Psychotic Disorders,
Attention-Deficit/Hyperactivity Disorder, dementia, delirium, Substance Intoxication (e.g., with
cocaine), or Substance Withdrawal (e.g., from an opioid) may also display agitation that is difficult to
distinguish from akathisia. Some of these individuals are able to differentiate akathisia from the
anxiety, restlessness and agitation characteristic of a mental disorder by their experience of akathisia
as being different from previously experienced feelings. Other evidence that restlessness or agitation
may be better accounted for by a mental disorder includes the onset of agitation prior to exposure to
the neuroleptic medication, absence of increasing restlessness with increasing neuroleptic medication
doses, and absence of relief with pharmacological interventions (e.g., no improvement after
decreasing the neuroleptic dose or treatment with medication intended to treat the akathisia)
Other books such as Kaplan and Sadock III (1980) (and all editions since) state:
Akathisia is a subjective desire to be in constant motion. A manifestation of drug sensitivity, it may be
confused with psychotic agitation and incorrectly treated by increasing the dose of the offending
medication. The symptom subsides promptly when the offending medication is discontinued and
replaced by another one better tolerated by the patient.
These are several pages in subsequent and current versions of the larger book, Kaplan and Sadock,
Comprehensive Psychiatry.
AkathisiaICD-10 code: G25.71, ICD-9 code781.0, DSM 333.99
Akathisia (or "acathisia") is an often extremely unpleasant subjective sensation of "inner" restlessness
that manifests itself with an inability to sit still or remain motionless, hence its the origin of its name:
Greek a (without) + kithesia (to sit). It is a common side effect of certain drugs, notably typical or
atypical antipsychotics (also called major tranquilizers), such as haloperidol (Haldol®) and droperidol,
olanzapine (Zyprexa®); SSRIs, such as paroxetine (Paxil®); tricyclic antidepressants, certain
antihistamines, such as promethazine and diphenhydramine (Benadryl®); and certain anti-emetic
drugs, particularly the dopamine blockers (e.g. metoclopramide (Reglan®) and prochlorperazine
(Compazine®).
Akathisia may range in intensity from a mild sense of disquiet or anxiety (which may be easily
overlooked) to a total inability to sit still with overwhelming anxiety and severe dysphoria (manifesting
as an almost indescribable sense of terror and doom). In the most severe cases, dysphoria can be so
severe that the patient is literally compelled to take action, leading, possibly, to suicide attempts. It is
not unknown to have patients literally run out of a hospital or emergency room.
Akathisia is often misdiagnosed and can lead the patient to commit suicide in or outside the hospital.
The presence and severity of akathisia can be measured using the Barnes Akathisia Scale.
Treatment
Treatment includes the discontinuation or reduction of dose of the causative agent and the use of
typical or atypical antipsychotics (also called major tranquilizers) to reduce the agitation and anxiety.
Unfortunately, these neuroleptics are often the cause of the condition and are known to cause
irreversible akathisia in some cases. While the administration of these drugs may temporarily
ameliorate the symptoms, there is a serious risk of worsening the condition over the long term.
Therefore, some consider the drug of choice for the treatment of akathisia to be propranolol, along
with other beta-blockers such as metoprolol. The antihistamine cyproheptadine is also effective,
though with shorter effect than beta-blockers. Second-line treatments include benztropine and
Benadryl, though excess use of Benadryl may worsen symptoms. Most of the clinical cases of
akathisia can be prevented by not administering the drugs that cause the condition.
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Comprehensive Textbook of Psychiatry III, Kaplan, Freedman, Sadock
Behavioural Toxicity
The term “behavioural toxicity” has been applied to adverse behavioural change produced by a
psychotropic drug. It is often difficult to evaluate such a change in seriously ill schizophrenic patients,
since it would be necessary to clearly separate non drug-related worsening of the schizophrenic state
from drug-induced toxicity. Symptoms such as insomnia, bizarre dreams, impaired psychomotor
activity, aggravation of schizophrenic symptoms, toxic confusional states, and somnambulism do
occur in patients undergoing treatment with psychotropic drugs. Akathisia or apparent worsening of
psychosis, which is thought to be an ideational analogue of extrapyramidal disorder, can be reversed
in minutes by intramuscular antiparkinson agents. Some of those effects may be dose related and can
be lessened by an alteration in the dose, the addition or deletion of antiparkinsonian drugs, or the use
of a different type of antipsychotic agent. Often treatment requires clinical judgment and flexibility.
Some of the confusional states may be related to anticholinergic properties of the drugs. In addition,
patients differ in their rate of metabolism of a specific drug, and slow metabolizers may build up
psychotoxic levels of drugs or metabolites.
Page 2284
Side Effects
The side effects of the antipsychotic drugs can be classified as follows: autonomic effects,
extrapyramidal effects, other central nervous system effects, behavioural toxicity, allergic reactions,
agranulocytosis, long-term skin and eye effects, and endocrine effects. Page 2273
Behavioural Toxicity
Cole sponsored the clinical application of the concept of behavioural toxicity, a term first used by
Brady to describe the objective adverse effects of drugs on animal response in operant conditioning.
Excessive sedation, paradoxical depression, agitation, hyperactivity, confusion and delirium are gross
examples. An exacerbation of psychotic symptoms that respond specifically to antiparkinsonian
medication, as well as psychotic symptoms that do not respond to antiparkinsonian agents, was
described by Van Putten (1973b) and Simpson (1976). That should not be confused with atropine-like
delirium that may be secondary to antiparkinsonian agents. Page 1207
Tardive dyskinesia
As its name implies, tardive dyskinesia is a late onset side effect, but there is often an earlier onset
than was previously supposed. In general, the early signs are facial tics, ill-defined chewing type
movements of the mouth, and abnormal movements of the tongue. The tongue movements are often
a very early sign and are best observed when the patient is distracted and the buccal cavity is
thoroughly inspected. Dimpling of the tongue, contraction of the tongue on its longitudinal axis, or mild
movements of the tongue may be seen. Those movements may spread to a variety of chewing,
mouthing, sucking, or opening movements of the jaw. Movements of the extremities and other parts of
the body may also be seen; choreoathetoid movements may be present in the fingers and feet, or
there may be to-and-fro or circulating movements of the pelvis or grunting respiration. Akathisia, with
or without subjective feeling of discomfort is frequently present. If the side effect is unrecognized, a
full- blown situation can be a serious complication. Page 1206
Akathisia again gets a mention In Kaplan. Freedman Sadock 1980 under the heading Iatrogenic
Emergency Disorders in chapter 29. Page 2108
The reaction can be frightening to the patient and can be misinterpreted clinically as an agitated
intensification of the basic psychiatric illness.
viii Diagnostic criteria for Schizophrenia
A. Characteristic symptoms: Two (or more) of the following, each present for a significant portion of
time during a 1-month period (or less if successfully treated):
(1) delusions
(2) hallucinations (
3) disorganized speech (e.g., frequent derailment or incoherence)
(4) grossly disorganized or catatonic behavior
(5) negative symptoms, i.e., affective flattening, alogia, or avolition Note: Only one Criterion A
symptom is required if delusions are bizarre or hallucinations consist of a voice keeping up a running
commentary on the person's behavior or thoughts, or two or more voices conversing with each other.
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B. Social/occupational dysfunction: For a significant portion of the time since the onset of the
disturbance, one or more major areas of functioning such as work, interpersonal relations, or self-care
are markedly below the level achieved prior to the onset (or when the onset is in childhood or
adolescence, failure to achieve expected level of interpersonal, academic, or occupational
achievement).
C. Duration: Continuous signs of the disturbance persist for at least 6 months.
This 6-month period must include at least 1 month of symptoms (or less if successfully treated) that
meet Criterion A (i.e., active-phase symptoms) and may include periods of prodromal or residual
symptoms. During these prodromal or residual periods, the signs of the disturbance may be
manifested by only negative symptoms or two or more symptoms listed in Criterion A present in an
attenuated form (e.g., odd beliefs, unusual perceptual experiences).
D. Schizoaffective and Mood Disorder exclusion: Schizoaffective Disorder and Mood Disorder With
Psychotic Features have been ruled out because either (1) no Major Depressive, Manic, or Mixed
Episodes have occurred concurrently with the active-phase symptoms; or (2) if mood episodes have
occurred during active-phase symptoms, their total duration has been brief relative to the duration of
the active and residual periods.
E. Substance/general medical condition exclusion: The disturbance is not due to the direct
physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical
condition.
F. Relationship to a Pervasive Developmental Disorder: If there is a history of Autistic Disorder or
another Pervasive Developmental Disorder, the additional diagnosis of Schizophrenia is made only if
prominent delusions or hallucinations are also present for at least a month (or less if successfully
treated).
ix False belief states known in clinical populations
Anorexia nervosa
A thin person sees themself as fat.
Autochthonous delusions
Beliefs which crystallise out of a confusing situation or mental state,
often the mechanism of false confessions in interrogation.
Belief in past lives
One has lived before in different personae.
Body Dysmorphic Disorder A strong belief that a part of the body is abnormal, unresponsive to
reason.
Personality Disorders
Personality Disorders are characterised by a disturbance in inner life
and systematic distortions of perception and self-presentation.
Cluster 'A' - Paranoid and Schizotypal are most likely to be involved.
Paranoid Personality Disorder
(A) (hard–done–by, persecuted). The paranoid believes in the
untoward intentions of others as a matter of course. See also erotomanic beliefs and delusions.
Schizotypal
(A) Suspicious of others' motives, likely to draw idiosyncratic
conclusions from events and signs. Communicates with spirits in an altered mode of consciousness,
senses a presence.
Cluster 'B' - Antisocial, Borderline, Histrionic, Narcissistic.
Histrionic
(B) (dramatic exaggeration, drama queen). Anxious,
concerned, and nervous, she presents herself as victimised, manipulated, coerced, and physically or
psychologically abused. May be organised intellectually, assertive, with a justified agenda with facts,
figures, and opinions supporting her evidence, presenting herself as justifiably outraged. However,
when clarification is sought on the details, becomes hostile, passively-aggressive and may make
ethical complaints or threaten suit.
Borderline Personality Disorder (unstable) 'Fatal Attraction.’ Highly dysfunctional, may lose contact
with reality and is prone to brief psychotic breaks which are not recognised as such. May be most
readily identified by peculiar and bizarre descriptions of events in her history.
Antisocial Personality Disorder (B) (delinquent, criminal) Tells lies as easily as the truth, by habit or
`for short term personal gain. Involved in street kid allegations against carers and 'The Abuse Excuse.'
Narcissistic Personality Disorder (B) (arrogant, grandiose, entitled). Entitled to say what they want and
take what they want, to override normal people's rules, indulge in grandiose fantasies and exaggerate
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their past with little concern for the truth. They will exploit the system to the utmost also see
pseudologia fantastica.
Confabulation
Product of therapy and other coercive conditions. When alcoholic,
brain-damaged and developmentally disabled persons fill in memory gaps with plausible scenarios.
Confusion
Temporary state caused by misinformation or misinterpretation which
might be carried on.
Chronic pain states
Mistaken but tightly held beliefs about non existent disease causing
symptoms.
Déjà vu
A sense of familiarity with a strange place.
Delusions
Beliefs inconsistent with culture, firmly held in the teeth of evidence to
the contrary.
Delusional jealousy
Recurrent or persistent belief that a significant other is unfaithful.
Delusional memory
Misremembering the past in accordance with present delusional
state. Also called retrospective delusion.
Delusional perception
Misinterpretation of real events in accordance with delusions.
Dissociative states
Belief and behaviour in accordance with ideas transmitted by
hypnosis or suggestion. Are easily generated in therapy. See Sibyl.
Delusional Disorder
A set of interrelated false but plausible firmly held beliefs for which
external evidence is lacking. 'Just knowing' something to be the case, without being able to provide a
reasonable source for that information.
Erotomania
Involves false beliefs about the erotic desires and intentions of others,
that another is secretly in love but cannot reveal it.
Folie à deux, en famille
Shared beliefs where dominant partner's influence is strong,
sometimes psychotic, sometimes malevolent. Provides the basis of the 'parental alienation syndrome'
associated with divorce.
Ganser states
On the borderline between hysteria and malingering, understanding
but missing for example two and two are five.
Hysteria
Unvalidated belief states achieved in a panic situation by shortcircuiting of reasoning.
Hysterical beliefs
Unvalidated beliefs which with short-circuiting of reasoning to explain
ambiguous phenomena.
Hysterical contagion
Several or more people sharing beliefs where each gets validation
from another which are unvalidated.
Jamais vu
An intense feeling of familiarity with a scene and conviction that one
has been there before, typically post epileptic.
Mistake
A belief acquired though acceptance of a mistaken source.
Morbid jealousy
Belief that a significant other is unfaithful. Often psychotic.
Multiple personalities
Belief that one has many alternate personalities, unaware of each
other and many different lives.
Panoramic, experience
An intense sensation of grandeur, importance, often associated with
psychotropic drugs.
Paranoid Schizophrenia
Bizarre delusions for more than six months in a psychotic individual.
Paranoid state
Tendency to perceive events as relating to the self, in a negative way,
but might be imputing 'significance' to the self.
Pseudologia Fantastica
Story–telling, not improbable, built upon a matrix of truth, enduring,
not told for personal profit but self-aggrandising. Distinct from delusions as the person can
acknowledge falsehoods.
Somatization
A strong belief, in the absence of evidence, that one has a disease.
Trance mediumship
Induced dissociative state for a specific purpose.
Toxic delirium
Confusional state caused by fever, psychotropic drugs or toxins.
Trans sexuality
The belief that one's sex is incorrectly assigned. Associated with
action on this belief.
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