Mad In America
Catherine Clarke SRN, SCM, MSSCH, MBChA.
and Jan Evans MCSP. Grad Dip Phys.
And the Winner IS: (Italic Emphasis is In the original)
"People who are classified as SMI i.e. with schizophrenia or bipolar often experience violent incidents following a diagnosis of SMI, even though they don’t consume alcohol or use street drugs, nor having a past history of violence or command hallucinations to harm others."
Yes, you read that Right. The violence erupts Following the Diagnosis, from people Without a previous history of violence.
Now, would someone please explain to us What actual Benefit Psychiatry is inflicting upon us?
"Neuroleptic
Drugs and Violence
Catherine Clarke SRN, SCM, MSSCH,
MBChA.
and Jan Evans MCSP. Grad Dip Phys.
August 19th, 2012
Introduction
We address the
fact that the treatment for Severe Mental Illness (SMI) is neuroleptic
medication. One has to give significant thought about the involvement of
neuroleptic medications with the tragic circumstances of individuals who have
perpetuated a progressive catalogue of catastrophic actions, and the many
victims and their families who so sadly are caught up in such tragedies.
It is
established that there is an increased risk of violence by people with a mental
health diagnosis. A greater risk of violent behaviour (27.6%) has been found
for patients who commit substance abuse, compared to non-abusers (8.5%). For
patients with schizophrenia, 13.2 % committed at least one violent offence,
compared with 5.3% of the general population.1
Violence is reported with
command hallucinations: 48% experienced harmful or dangerous actions and this
increased to 63% in medium secure units and was significantly higher, 83%, in
the forensic population.2
People who are classified as SMI i.e. with
schizophrenia or bipolar often experience violent incidents following a diagnosis of SMI, even though they don’t consume alcohol or use
street drugs, nor having a past history of violence or command hallucinations
to harm others.
Our purpose of
this document is to provide a referenced explanation of how neuroleptic
medications are a potential cause of violence. We take a physiological
perspective concerning pharmacogenetic variants and the disruption of
neurotransmitters. In Part 1 we discuss what is
known about Neuroleptics and Neurotransmitters; in Part 2, the Neuroleptic
Disruption of Neurotransmitters
Part 1
The first part of this document has the
following structure:
· Violence
· Neuroleptic Adverse Effects on
Behaviour
·
Neuroleptic
Withdrawal Adverse Effects on Behaviour
·
Neurotransmitter
Functioning and Behaviour
·
Serotonin Disruption
·
Noradrenaline/Norepinephrine
Disruption
·
Acetylcholine Disruption including
Neuroleptic Malignant Syndrome and Organophosphate Poisoning
·
Increased
Prescribing of Neuroleptics as a Risk for Increased Violence
Violence
This is an important
issue. In three acute psychiatric units in Australia it
was reported: “58 % of the incidents were serious violent incidents.”3 In an attempt
to address psychiatric violence in the UK, the National Institute for Health
and Clinical Excellence (NICE) has a full clinical guideline: Violence. The short-term management of disturbed/violent behaviour in
in-patient psychiatric settings and emergency departments.4 Although this addresses many issues, it omits the following
potential causes of violence:
- Neuroleptic medications - due to neuroleptic disruption of
neurotransmitter circuits such as dopamine, serotonin, norepinephrine/noradrenaline
and acetylcholine.
- Pharmacogenetics – the issue of inefficient neuroleptic
metabolising.
Adverse Effects on Behaviour of Neuroleptics
Neuroleptic toxic adverse reactions are related
to behavioural changes such as akathesia, which is known to be a predisposing
factor to violence5 and was formally recognised in the late 1970s.6
The symptoms of akathisia, an extreme,
involuntary internal physical and emotional restlessness, includes restlessness,
agitation and irritability.
When there is an
existing precondition of akathisia, any perceived untoward disrespectful
attitudes or verbal communications can trigger violence. When patients are
agitated or irritable, they are less able to cope with perceived disrespect and
are more prone to respond violently.
A marked increase of
violence has occurred with patients prescribed moderately high-doses of
haloperidol,7 and with Asian patients clozapine played a role
in causing aggression and disruptive behaviour.8 Both the older ‘typical’ and the newer
‘atypical’ neuroleptics are associated with adverse behavioural reactions
in a study reporting that “the newer antipsychotics did not reduce violence
more than perphenazine.”9
Chart Depicting Toxic Behavioural
Effects for Typical Neuroleptics:
Typical Neuroleptics
|
Adverse Reactions Related to Violence |
Clopixol
|
Agitation & akathisia
|
Haloperidol
|
Restlessness, agitation and violence
|
Stelazine
|
Restlessness
|
Sulpiride
|
Restlessness & akathisia
|
Refs 7, 10 &11
Chart Depicting the Toxic Behavioural
Effects for Atypical Neuroleptics:
Atypical Neuroleptics
|
Adverse Reactions Related to
Violence
|
Abilify
|
Restlessness, agitation and akathisia
|
Amisulpride
|
Agitation
|
Clozaril
|
Akathisia and agitation
|
Olanzapine
|
Restlessness and agitation
|
Palperidone/Invega
|
Akathisia and aggression
|
Quetiapine
|
Akathisia and irritability
|
Risperidone
|
Agitation
|
Sertindole
|
Akathisia
|
Zotepine
|
Akathisia
|
Ref 10
Observations in prison have also associated
neuroleptic treatment with increased aggressive behaviour. Inmates were better
able to control their aggression until they were prescribed neuroleptics and
then the aggression rate almost tripled.12
Neuroleptic Withdrawal Adverse Effects on Behaviour
There is also
the issue of violence experienced during withdrawal. Irritability and agitation
is reported in association with neuroleptic withdrawal,13
and a direct reference links akathisia following
the withdrawal of a depot in an inpatient setting.14 Irritability, agitation and akathisia need
to be recognised as reactions to neuroleptic withdrawal.
In order to
prevent violence in association with akathisia and withdrawal, this process
needs to be undertaken by a professional or lay-person who understands the
potential problems and can therefore guard against unwittingly appearing at all
antagonistic to the patient.
Neurotransmitter Functioning and Behaviour
Fundamentally, human behaviour is
determined by neurotransmitter functioning and “A rich literature exists to
support the notion that monoamine (i.e. serotonin, dopamine, and
norepinephrine) neurotransmitter functioning is related to human aggressive
behaviour.”15
Dopamine, serotonin and all other
neurotransmitter circuits are interdependent and any disturbance in one will
result in an imbalance in them all, disrupting normal functioning. Jackson's First Law of Biopsychiatry states:
“For every action, there is an unequal and frequently unpredictable
reaction.”16
Chronic neuroleptic treatment causes
unpredictable behavioural reactions due to dysregulation and disruptions
between dopamine, serotonin and acetylcholine neurotransmitters.
Neuroleptics and Serotonin Disruption
Some neuroleptics are known as
serotomimetic drugs, affecting serotonin receptors – some block the receptors
and some make them more active. "There are 14 different types of serotonin
receptors that may be targeted by neuroleptics, with risperidone, clozapine,
olanzapine, quetiapine and clopixol especially affecting the serotonin 5-HT2
receptor.”17
Mental status changes
occur in Serotonin Syndrome. This is caused by neuroleptic drugs due to
serotonin toxicity.
Animal research indicates that serotonin
disruption is associated with increased violence. Reduced levels of a specific
serotonin metabolite (5-HIAA) in cerebrospinal fluid has been linked with
increased aggression in both dogs and male rhesus macaques18-19 and low concentrations of 5-HIAA in different cultures have been consistently
reported to be associated with impulsive destructive behaviours, aggression and
violence.20
Since “Impulsive violence is closely linked
to serotonergic function and to several brain regions”21 and since impulsivity is also linked with both
low and high serotonin levels it is difficult to know which of these changes
play the most important role in treatment emergent violence.”17
The reciprocal
interaction between the dopaminergic and serotonergic systems disturbed by
either dopaminergic blockers or serotonergic enhancers leads to the disruption
of homeostasis.22 Although the serotonin system and its interactions with other
neurotransmitters are complex and full information is difficult to find, there
are clear research papers, which show that serotonin and aggression are related.
Chart depicting Neuroleptic Serotonin Disruption
associated Adverse Toxic Behavioural Effects:
Akathisia
|
Irritability
|
Suicidality
|
Violence
|
Arson
|
Aggression
|
Violent Crime
|
Self Destructiveness
|
Impulsive Acts
|
Agitation
|
Hostility
|
Violent
Suicide
|
Argumentativeness
|
Ref 23 & 24
Neuroleptics and
Noradrenaline/Norepinephrine Disruption
Neuroleptics
affect the norepinephrine neurotransmitter and akathisia induction with haloperidol is known to be
associated with increased noradrenaline turnover.25- 26
Neuroleptics and Acetylcholine Disruption
An important function of the acetylcholine
neurotransmitter is the control of psychological defence mechanisms including
fight or flight responses. Such responses are
impulsive and naturally include aggression and violence.
In varying degrees, all neuroleptic
drugs have anticholinergic properties. This means
that they block and cause disruption to the acetylcholine neurotransmitters.
The body compensates and responds by making and releasing more
acetylcholine.27
Acetylcholine Disruption and Increased
Violence
Aggressive responses such as defensive rage
and violence have been linked with excessive acetylcholine in animals28 –30 and a relative
acetylcholine increase is associated with neuroleptic drugs due to the
disruption of the dopamine-acetylcholine equilibrium.31-32
Since excessive acetylcholine is linked
with aggression and violence in animals, it is likely that neuroleptic induced
acetylcholine abundance triggers aggression and violence in humans.
Neuroleptic →
Disrupted dopamine-acetylcholine equilibrium → Relative acetylcholine increase
→ Aggression/Violence.
Neuroleptic Malignant Syndrome and
Organophosphate Exposure
Neuroleptic Malignant Syndrome (NMS) is an
adverse effect of neuroleptics, a potentially fatal condition with up to 76%
mortality rate. Symptoms of NMS
include aggression, agitation and violence.27
& 33 New research associates NMS with elevated
acetylcholine.34
Organophosphate chemicals form the basis of many
insecticides, herbicides and nerve gases. They block the action of the body’s
acetylcholinesterase enzyme, which breaks down acetylcholine so it may be
processed and recycled. Excessive acetylcholine accumulates in the nervous system
if the action of this enzyme is blocked.
Prolonged and repeated
exposure to Organophosphates results in Chronic Organophosphate-Induced
Neuropsychiatric Disorder (COPIND) e.g. in farmers who
handle pesticides, due to chronic Organophosphate Poisoning (OP). COPIND behavioural symptom changes include: Hostility,
Anger, Aggression and Violence.35-36 Since OP
results in excessive acetylcholine, which is linked with aggression and
violence in animals, the behavioural changes in COPIND are highly likely caused
by excessive acetylcholine.
The link between
Neuroleptic Malignant Syndrome and Organophosphate Poisoning
The symptoms of NMS and OP are similar. In
both NMS and OP the replication of symptoms is due to
autonomic instability and stems from disruption of the acetylcholine circuits and transmitters of the
Autonomic Nervous System, involved with vital involuntary functions.
Autonomic Instability includes profuse sweating, high
blood pressure, low blood pressure, respiratory distress, drooling, urinary or
faecal incontinence, increased and
decreased
heart rate.27
Chart Depicting the Symptom Similarities of NMS and OP
Neuroleptic Malignant Syndrome
|
Organophosphate Poisoning
|
Autonomic nervous system disturbance
|
Autonomic Instability
|
Aggression, agitation and
violence
|
Aggression
|
Muscle rigidity
|
Paralysis, Dystonia, Cranial nerve palsy
and polyneuropathy
|
Muscle breakdown
|
Weak respiratory and limb muscles
|
Coma, alterations of consciousness
|
Loss of consciousness
|
Confusion
|
Dementia, psychosis, anxiety, depression
|
Fever
|
Seizures
|
Refs 27 & 33
Conclusion: Organophosphates, Neuroleptics and Violence
Organophosphate Poisoning results in over stimulated acetylcholine
neuro-circuits and systems. The action of neuroleptics is similar. It is generally accepted that
Organophosphate Poisoning results in behavioural changes including violence.
Despite research to show that neuroleptics
are associated with disrupted acetylcholine, it is not yet generally accepted
that neuroleptics are a potential cause of
violence.
Antipsychotic/neuroleptic
drugs have strong anti-cholinergic properties and long-term use causes
behavioural changes, which replicate the same behavioural changes occurring in
chronic Organophosphate Poisoning:
“This adaptation (to psychiatric drugs -
author input) replicates the effect of organophosphate poisoning whether by
nerve gas, by insecticide, or by anti-Alzheimers pharmaceuticals by over
stimulating acetylcholine circuits of the brain.”27
Increased Prescribing of Neuroleptics
There has been
a distinct increase in neuroleptic medications, prescribed as part of treatment
for mental health issues.
In the UK
between 1998 and 2010, Neuroleptic drug prescriptions increased by an average of 5.1%
every year.37 Over twelve years, this is a total increase of
60%.
In England, the
approximate number of neuroleptic and depot (injection) prescriptions used by
outpatients:
2008 – 7.0
million
2009 – 7.3 million
2010 – 7.6
million
2011 – 7.9
million38
However, due to
confidentiality, the data for the number of neuroleptic prescriptions in
inpatient settings is not made available. So the actual
total increase of neuroleptic prescriptions in the UK is unknown.
Increased Prescribing as a Risk for Increased Violence
As outlined
above, neuroleptics are a possible cause of violence. With ever increased
prescribing of neuroleptic medications, it is reasonable to expect an increased
amount of violent behaviour amongst those with a severe mental health
diagnosis.
Since neuroleptic prescriptions are increasing by 300,000 per year in
the UK, it is hypothesized that the rise in violence for neuroleptic-treated
patients will escalate, whether in the community or in acute wards, secure
units, prisons or outpatient units.
Part 2. Neuroleptics and Pharmacogenetics
The second part of this document has the
following structure:
·
Introduction
to Pharmacogenetics regarding Neuroleptics
·
Pharmacogenetics
and Ethnic Black Populations
·
Black
Populations and Psychiatric Intensive Care Units
·
Black
Populations, detention under the UK Mental Health Act and UK Community
Treatment Orders
· Pharmacogenetics as an explanation for Black
Over-representation in
Psychiatric Intensive Care Units,
detentions within the UK Mental
Health Act and Community Treatment
Orders
Introduction to
Pharmacogenetics with regards to Neuroleptics
Pharmacogenetics is the science of how
drugs are broken down and used – i.e. metabolised in the body, mainly in the
liver, by the genetically diverse Cytochrome
P450 (CYP450) enzyme system and other drug metabolising systems. There are many CYP450 variants that affect
therapeutic efficacy and inefficacy of medications.
Extensive
Metabolisers are efficient metabolisers, whereby side-effects do not build up. Poor Metabolisers
are inefficient metabolisers that have no metabolising activity whatsoever;
this means that drug toxicities do build up and cause side effects.
Intermediate Metabolisers have approximately 50% drug metabolising capacity and
produce lesser side-effects than Poor Metabolisers.39 Ultra Rapid Metabolisers/ Hyperinducers
have higher than normal rates of drug metabolism; Those medications which are
classified as prodrugs are inactive until metabolised in the body, therefore
Ultra Rapid Metabolisers are at increased risk of drug-induced side effects due
to increased exposure to prodrug active drug metabolites.40
Neuroleptic drugs are metabolised
through CYP450 enzymes e.g.CYP450 1A2, 2D6 and 2C19. A single neuroleptic can
necessitate a combination of CYP450 enzymes for metabolisation.
All SMI patients
who are Poor and/or Intermediate Metabolisers of neuroleptics, and Ultra
Metabolisers of neuroleptic prodrugs;
e.g. paliperidone, the active metabolite of risperidone; will inevitably suffer
neurological and behavioural changes due to toxicities incurred from the inability to metabolise neuroleptics efficiently.
Polypharmacy compounds the toxicities.
CYP450 1A2 Metabolising Pathway and Neuroleptics
CYP450 1A2 enzyme
pathway has many variants and metabolises
olanzapine and haloperidol and is the major metabolising enzyme for clozapine.
CYP1A2*1C and *1D Poor Metabolisers have been associated with increased
clozapine exposure and adverse reactions.41 CYP1A2*1K is also Poor Metaboliser genotype.42
In one study, Asian
patients who were prescribed clozapine, experienced aggression and disruptive
behaviour who, following clozapine discontinuation, had marked improvement.8
The genotype of the Asian patients in the study is unknown, however since
25% of Asians have CYP1A2*1C Poor Metaboliser genotype,43 it
is possible these patients were either CYP1A2*1C, *1D or *1K or a combination
of these Poor Metaboliser genotypes.
Additionally15-20%
of Asians are Poor Metabolisers for CYP2C19 and 2% are Poor Metabolisers for
CYP2D6.44 CYP2C19 and CYP2D6 metabolise clozapine as
well as CYP1A2; any of these combinations are possible and could have
predisposed to disruptive behaviour.
CYP450 2D6 Metabolising Pathway and Neuroleptics
75% of all psychotropic drugs, including
neuroleptics, are metabolised via CYP450 2D6.45 CYP450 2D6 is a highly variable enzyme with a
significant percentage of the population being Poor, Intermediate or Ultra
Metabolisers and is linked with a poor therapeutic response and adverse
reactions.
Violence in
relation with serotonin toxicity/akathisia has been linked with pharmacogenetic
CYP450 2D6 drug metabolising variants.46
Pharmacogenetics and Ethnic Black Populations
Due to genetic variations there is higher
incidence of Poor Metaboliser and Ultra Metaboliser status in Black populations,
compared with White and Asian populations for the CYP 450 2D6 pathway. “The
prevalence of poor metabolizers in Black populations has been estimated from 0
to 19%, compared with consistent reports of poor metabolizer status in Caucasians (5–10%) and
Asians (0–2%).”47
Recalling that 75% of
neuroleptic medications are metabolised via CYP450 2D6, the following table
shows the variation of metabolising ability in black ethnic populations for
CYP450 2D6.
Poor Metabolisers
|
Ultra
Metabolisers
|
||
South Africans
|
18.8%
|
||
Nigerians
|
8.6-8.3%
|
||
Ghanaians
|
6%
|
||
African – American
|
3.9%
|
2.4%
|
|
Zimbabwean
|
2%
|
||
Tanzanian
|
2%
|
||
American Black
|
1.9%
|
||
Ethiopians
|
1.8%
|
29%
|
Ref 48
29% of Ethiopians and 2.4% of North African Americans are Ultra Metabolisers
via CYP450 2D6 pathway.48 Furthermore,
10-20% of Africans are Poor
Metabolisers and 5% are Ultra Metabolisers via CYP450
2C19.49
Many prescription medications can lead to
“serious mental change.”50 Since black
populations statistically have difficulty in metabolising general and psychotropic medications
and cannabis via the CYP450 pathways, this factor could contribute to BME groups living in the UK who are more likely to be
diagnosed with a Mental Health problem and admitted to
hospital.51
Psychiatric Intensive Care Units and
Over-representation of Black Populations
In UK
Psychiatric Intensive Care Units (PICU), there is clear over-representation of
black ethnic patients.52
Another study showed fifty-five percent of PICU admissions came from ethnic
minorities (compared with 25.6% of total hospital admissions and
20.9% of the local catchment area population aged between 16 and 65
years).53
“Typical PICU patients are male,
younger, single, unemployed, suffering from schizophrenia or mania,
from a Black Caribbean or African background,
legally detained, with a forensic history. The most common reason
for admission is for aggression management.”54
UK Mental Health Act Detentions and Over-representation
of Black Populations
There is also a disproportionately large
representation of Black Minority and Ethnic (BME) origin
when considering those who are legally detained under the UK Mental Health Act.
The proportion of black and black British people legally detained rose
by 9.7%, with a 9% rise in the number of Asian or Asian British and
mixed-race people detained for treatment, compared to a 0.3% rise for the
overall number of people detained from 2007/8 to 2008/9. This disparity grew and 53.9% of black/black British inpatients
spent time compulsorily detained, as did almost half of mixed-race inpatients
and over 40% of Asian/Asian British inpatients, compared with 31.8% of all psychiatric
inpatients who spent some time detained during the year.55
UK Community Treatment Orders and Black
Populations
Legal
UK Community Treatment Orders are enforced when patients have received mental
health ‘treatment’ i.e. neuroleptics and history of violence; BME Groups have
more Community Treatment Orders than white populations.56
“There is a possible relationship for
psychiatric in-patients between compulsory detention, disturbed behaviour,
depot medication and being black, which is not satisfactorily explained by
diagnosis alone.”57
The higher incidence of mental health
problems in black populations is most likely due to the higher incidence of
Poor, Intermediate and Ultra Metabolisers and the associated problems with
metabolising medications.
Synopsis
Neuroleptics can be a cause of violence due
to neurotransmitter disruption.
Violence must be considered not simply
as an indication of how deeply schizophrenia /bipolar illness can worsen, but
as an adverse effect of neuroleptic treatment.
People who are inefficient metabolisers are
likely to suffer more severe adverse effects and become violent or aggressive.
BME populations have a higher incidence of
inefficient metabolisers and as such a higher incidence of violence leading to
PICU admissions and Mental Health Act detentions.
However
whatever the nationality, when individuals are Poor and Intermediate Metabolisers
and Ultra Rapid Metabolisers for prodrugs, the impact of neuroleptics in
triggering akathisia, aggression or irritability can trigger violence
indiscriminately.
Conclusion
There is a larger incidence of violence in
people with a severe mental health diagnosis than in the general population.
The severely mentally ill are invariably treated with neuroleptic medication
which itself can be the cause of violence since neuroleptic medications disrupt
neurotransmitter functions. This disruption of neurotransmitter functioning can
precipitate violent behaviour. Withdrawal of neuroleptic medication - due again
to the disruption of neurotransmitters - is also associated with violence.
Pharmacogenetics show that the some people
are unable to metabolise neuroleptic medication and this inability can result
in further disruption of neurotransmitter functioning with a likelihood of
increased violence.
The inability to metabolise neuroleptic
medication is particularly prevalent in BME populations. As a consequence this
population experience more violence which is confirmed in practice by an over
representation of BME individuals, both on Psychiatric Intensive Care Units (PICUs) where
a common reason for admission is aggression, and the use of Mental Health Act
detentions and Community Treatment Orders.
With the trend towards increased
prescribing of neuroleptic medications, a level of increased violence can be
anticipated for the future.
There is the possibility of ameliorating
the presence of violence in the severely mentally ill by ensuring
pharmacogenetics is more fully recognised as a significant factor, and that
genotype testing is adopted in order to assess the ability of the individual to
metabolise neuroleptic medication. Without this testing,
much of the violence in psychiatry can be
laid at the door of psychiatrists
and the pharmaceutical companies.
References:
Ref 2 Birchwood et al. (2011)
Ref 3 Owen C. et al, (1998) http://ps.psychiatryonline.org/article.aspx?Volume=49&page=1452&journalID=18
Ref 6 GB. Leong, M.D. and JA Silva, M.D. (2003)
Ref 7 John N. Herrera et al (1998)
Ref 8 KA.Mansour, C.Willan and J.Follansbee (2003) http://bapauk.com/doc/Deteriorationofpsychosisinducedbyclozapine_41.doc
Ref 9 Jeffrey W. Swanson et
al, (2008) http://bjp.rcpsych.org/content/193/1/37.full
Ref 10 Drug Monographs, Prescribing information and UK NICE
Guidelines 2007 – 2012.
Ref 11 Jerome L. Schulte, (1985) http://psychrights.org/research/Digest/NLPs/RWhitakerAffidavit/Schulte.PDF
Ref 12 D.G.
Workman and D.G. Cunningham (1975) page 65
Ref 13 MIND http://www.mind.org.uk/help/medical_and_alternative_care/making_sense_of_coming_off_psychiatric_drugs
Ref 14 Theodore Van Putten, (1975)
Ref 15 Berman ME, Coccaro EF.
“Neurobiologic correlates of
violence: relevance to
criminal responsibility.” Behav Sci Law. 1998
Summer;16(3):303-18. Review.
Ref16 Jackson,
Grace E. MD, Appendix D, Transcript of
“What Doctors May Not Tell You About
Psychiatric Drugs”
Public Lecture, Centre
for Community Mental Health –
UCE Birmingham June 2004
Ref 17 Jackson
Grace E. (2005) Rethinking Psychiatric Drugs: A
Guide for Informed Consent. Bloomington, IN: Author House.
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Ref 25 Naveed
Iqbal, MD, et al, (2007) http://www.cnsspectrums.com/aspx/articledetail.aspx?articleid=1262
Ref 27 Grace Jackson MD (2009) Drug
Induced Dementia. A Perfect Crime Bloomington, IN: Author House.
Ref 31 Imperato A.
et al, (1993) “Evidence that neuroleptics
increase striatal acetylcholine release through stimulation of dopamine D1
receptors” http://jpet.aspetjournals.org/content/266/2/557.abstract
Ref 32 Donald W. Black, Nancy C. Andreasen - Introductory Textbook of Psychiatry - (2011) 5th Edition p.544 American Psychiatric
Publishing Inc.
Ref 36 Singh S, Sharma N. Neurological syndromes following
organophosphate poisoning. Neurol India 2000;48:308. http://www.neurologyindia.com/text.asp?2000/48/4/308/1510
Ref 37 Trends
in prescriptions and costs of drugs for mental disorders in England, 1998–2010 Stephen Ilyas and Joanna Moncrieff (2012)
http://bjp.rcpsych.org/content/early/2012/03/10/bjp.bp.111.104257.abstract
Ref 38 NHS The Information Centre for Health and
Social Care “Copyright © 2012, Re-used with the
permission of the Health and Social Care Information Centre. www.ic.nhs.uk
Ref 41 Clinical
and Translational Science: Principles of Human Research by David Robertson and Gordon H. Williams Academic Press
Inc; 1 edition (16 Jan 2009) Chapter 21 page 303
Ref 42 Aklillu
et al, 2003 CYP1A2 allele nomenclature http://www.imm.ki.se/CYPalleles/cyp1a2.htm
Ref 44 Asian PM for 2D6 Cozza et al 2003 and
Richelson 1997 in Clinical Manual of Geriatric
Psychopharmacology By Sandra A. Jacobson, Ronald
W. Pies, Ira R. Katz Publisher:
American Psychiatric Press Inc.; 1 edition (30 Jan 2007) Page 44 & 45
Ref 45 Joan Arehart-Treichel (2005)
Ref 46 Lucire Y, Crotty C, (2011)
http://www.dovepress.com/articles.php?article_id=7993
Ref 48 Benny K. Abraham, C. Adithan (2001) http://medind.nic.in/ibi/t01/i3/ibit01i3p147.pdf
Ref 50 APRIL, Adverse Psychiatric Reactions Information Linkhttp://www.april.org.uk/main/index.php?uid=269
Ref 51 Mental
Health Foundation - Black and Minority Ethnic Communities
Ref 53 Anthony Feinstein
and Frank Holloway(2002)
Ref 54 Len Bower (2008)
Ref
55 Community Care For everyone in social care “Mental Health Act
detentions rise sharply for BME groups”
Ref 56
National Mental Health Development Unit. BME Groups and Mental Health – Presentation and
Evidence to the Centre for Social Justice Mental Health Review 18 October 2010.
www.nmhdu.org.uk/silo/files/bme-groups-and-mental-health-.doc
Ref 57 Violence: The Short-Term Management of
Disturbed/Violent Behaviour in Psychiatric In-patients and Emergency
Departments Guideline, Appendix
1: Ethnicity review evidence tables. p.447 http://www.rcn.org.uk/__data/assets/pdf_file/0003/109812/003017_appendices.pdf
Thank You Mad In America: Catherine Clarke SRN, SCM, MSSCH, MBChA. and Jan Evans MCSP. Grad Dip Phys.
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