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WHO/MNH/MND/93.27
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4
ESSENTIAL DRUGS
IN PSYCHIATRY
DIVISION OF MENTAL HEALTH
WORLD HEALTH ORGANIZATION
GENEVA
■■S
'\
This document is not issued to the general public, and all rights are reserved by the World
Health Organization (WHO). The document may not be reviewed, abstracted, quoted,
reproduced or transplanted, in part or in whole, without the prior written permission of WHO.
No part of this document may be stored in a retrieval system or transmitted in any form or
by any means - electronic, mechanical or other - without the prior written permission of
WHO.
The views expressed in documents by named authors are solely the responsibility of those
authors.
I
t
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a
ON THE INITIATIVE
I
WHO’s Initiative of Support to People Disabled by Mental Illness is
part of WHO’s work on the prevention and treatment of mental disorders. It is
an attempt to speed up the dissemination of information to governments and
professionals about good community services for those with chronic mental
illness and about new developments in this field.
The Initiative aims to help in reducing the disabling effects of chronic
mental illness and to highlight social and environmental barriers which hinder
treatment and rehabilitation efforts and which add to the stigma of chronic
mental illness. It also stimulates consumer empowerment and involvement with
planning, delivery and evaluation of mental health services.
The following sites have so far officially joined the Initiative and have
participated in its various activities:
*
The Queensland Northern Peninsula and Mackay Region Mental
Health Service (centred in Townsville, Australia).
*
British Columbia Ministry of Health - Mental Health Services
(Vancouver, Canada).
*
Centro Studi e Ricerche Salute Mentale - Regione Autonoma
Friuli Venezia-Giulia (Trieste, Italy).
*
Highland Health Board - Mental Health Unit and Highland
Regional Council (Inverness, Scotland, UK).
*
Stichting Overlegorgaan Geestelijke Gezondheidszorg (SOGG),
(Rotterdam, the Netherlands)
I
The Dowakai Chiba Hospital (Funabashi, Japan) also takes part in some
of the Initiative activities; other centres are at different levels of discussion
concerning their joining the Initiative.
Further information on this Initiative can be requested from:
Dr J.M. Bertolote
Senior Medical Officer
WHO - Division of Mental Health
1211 Geneva-27 Switzerland
INITIATIVE OF SUPPORT TO PEOPLE DISABLED BY MENTAL ILLNESS
t
CONSULTATIVE NETWORK
P. Alterwain, Uruguay
L. Bachrach, USA
P. Barham, UK
V. Basauri, Spain
J. Chamberlin, USA
P. Chanoit, France
F. Costa, Sweden
M. Farkas, USA
G. Harnois, Canada
T. Held, Germany
B. James, Australia
M. Jansen, USA
L. Lara Palma, Spain
G. Long, Canada
V. Nagaswami, India
D. Peck, UK
A. Pitta, Brazil
T. Powell, USA
H Richards, UK
F. Rotelli, Italy
B. Saraceno, Italy
K. Schilder, The Netherlands
G. Scribner, Canada
T. Takizawa, Japan
R. Warner, USA
I
I
<
ESSENTIAL DRUGS
IN PSYCHIATRY
J. M. Bertolote
G. de Girolamo
(Editors)
This document describes the use of essential
drugs for the treatment of people with mental
disorders, following the WHO List of Essential
Drugs.
It is the second in a series of four issues.
The first one introduced the concept of essential
treatments; the following two issues will deal with
psychological and social essential interventions,
respectively.
This document is part of WHO’s Initiative of
Support to People Disabled by Mental Illness.
Key-words:
mental disorders, essential drugs,
psychiatry, psychopharmacology,
psychiatric treatment.
DIVISION OF MENTAL HEALTH
WORLD HEALTH ORGANIZATION
GENEVA
1993
WHO/MNH/MND/93.27
FOREWORD
*
Although the impact of the introduction
of chlorpromazine in psychiatric practice in
the 1950s may have not been the same as
that of the introduction of penicillin a
decade earlier, it has nevertheless been
heralded by some as a revolution in the
history of psychiatry. Besides the
remarkable quietening of some up to then
ceaselessly agitated patients, it reinforced
the notion that some mental disorders could
indeed have a biological, biochemical
nature, and hence be rendered manageable
through biochemical means.
This notion, however, was not
immediately and easily accepted, and at
least some sceptical critics of it exist even
today. The resistance or refusal to accept the
benefits brought about by the introduction
of modern pharmacological treatments in
psychiatric practice, stemmed not only from
ideological viewpoints about the etiology
and nature of mental disorders, but also
from the sometimes severe adverse
consequences these new medicaments
produce. Added to this, there was also the
soon-discovered potential for abuse, either
by individual users themselves or by those
in power who indulged in the unacceptable,
unethical chemical control of human mind
and behaviour. In the long run, however,
benefits supplanted risks and
pharmacological treatment of mental
disorders became not only acceptable but
also mandatory in many cases.
One of the consequences of the
utilizations of medicaments for mental
disorders was the development of a sector
in industry mobilizing huge amounts of
money with proportional profits, with
concerns in some quarters that less
consideration might be given to patient's
well-being. Further the constantly increasing
number of pharmaceutical products
available on the market inevitably created
confusion about their best use among many
practitioners. Advertisements suggesting the
superiority of a particular product tended to
mislead the significant number of medical
practitioners who had had less than
adequate instruction in medical schools
concerning the identification of mental
disorders and the use of pharmacotherapy.
However, although some problems remain,
increasing dialogue between the
pharmaceutical companies and professional
bodies, together sometimes with the
intervention of governments, has led to the
development of more responsible and
helpful promotional strategies.
Several authoritative textbooks on
psychopharmacology and on
pharmacological treatment of mental
disorders exist. They are usually addressed
to psychiatrists and other mental health
professionals. To the average general
practitioner, however, this field remains
wrapped in an aura of obscurity which they
refrain from entering, greatly to the
disadvantage of those suffering from mental
disorders. Yet, several independent studies
have now confirmed that the majority of
people with mental disorders, many with
severe forms, are seen at the primary health
care level, by general physicians; indeed,
some of these patients never come to the
notice of mental health professionals.
Hence the paradoxical situation in
which trained mental health professionals
see a minority of patients - who certainly
benefit from their knowledge and skills and yet the majority of patients are seen by
health professionals untrained to care
effectively with these problems,
thus
missing the excellent occasion of receiving
a more thorough benefit.
That paradox is exactly the point of
departure of this book. It aims at providing
general doctors with simple, adequate and
updated information on the use of
medicaments in the management of mental
disorders, useful at the primary health care
level. In this sense, it naturally stems from
the strategy of Health For All, and more
specifically from the work of WHO
concerned with the use of essential drugs
and the introduction of a mental health
component into primary health care. As a
consequence, it heavily relies on WHO
experience and previous publications1
The precursor of this document is
WHO's experience with the Essential Drugs
List (EDL) (1), from which several criteria
were adopted and adapted to the field of
mental disorders. Starting in 1975 from the
experience gained in some countries, WHO
produced a list of selected drugs essential
for the treatment of the majority of diseases
of public health importance. This EDL
WHO/MNH/MND/93.27
represented a considerable reduction of an
almost endless and unmanageable list of all
existing medicines. From the very beginning
medicines essential for the treatment of
most mental disorders were included in the
EDL.
This work, therefore, aims to:
i) present the rationale for the
identification of essential medicines for the
care of people with mental disorders;
ii) identify biological interventions
essential for the care of people with mental
disorders;
iii) briefly describe those interventions.
At any rate, medicaments are but one of
the components of proper treatment of
mental disorders. They should not be seen and certainly not employed as such - as the
only form of treament for those conditions.
Essential treatments for most mental
disorders include biological, psychological
and psychosocial interventions; together,
these three modalities of treatment represent
the best and recommended approach for the
management of mental disorders. Most
mental disorders cannot be managed with
medicines only: psychological and social
interventions arc essential for their
management.
The document ESSENTIAL
TREATMENTS IN PSYCHIATRY (4)
discusses this approach in greater detail
readers are strongly recommended to
become acquainted with its content. This
one is the second in a series of four
documents. Two other issues will follow,
each one concentrating on particular aspects
of psychological and social components,
respectively, of this comprehensive
approach. Specific elements of and
information on each component should be
sought in the forthcoming issues.
This document does not aim to
represent a norm. It is rather an example of
guidelines for the selection of essential
treatments for mental disorders.
The
transformation of guidelines into norms
with the necessary modifications can only
be done at the local level, taking into
consideration several
socio-economic,
epidemiological, cultural, historical and
developmental factors, in addition to
scientific background information. It was
conceived to be used in a variety of
countries with distinct socio-cultural and
economic characteristics. In some its
utilization will be straightforward, whilst in
others it will have to face particular
difficulties, e.g. deep rooted beliefs and
practices opposing the use of medicaments,
or problems in the procurement and
sustainability of supplies, or lack of
properly trained personnel, thus making its
utilization more difficult. Any comments in
this respect are welcome and should be
forwarded to the address below.
Dr J.M. Bertolote
Senior Medical Officer
Division of Mental Health
World Health Organization
1211 Geneva 27 Switzerland
II
WHO/MNH/MND/93.27
ACKNOWLEDGEMENTS
The production of the series of
documents on essential treatments for
mental disorders involved contributions
from several people who graciously
dedicated their time as well as their
invaluable knowledge and expertise. We are
therefore profoundly indebted to the
following experts who participated with
different levels of involvement at different
stages of its development:
The collaboration of the World
Association for Psychosocial Rehabilitation
and the World Psychiatric Association is
also greatly appreciated.
J.M. Bertolote / G. de Girolamo
Editors
Dr A. Ahmad
Department of Child and Family Psychiatry
King Edward Medical College and Mayo
Hospital
Lahore, Pakistan
Dr C. Bellantuono
Cattedra di Psicologia Medica
Policlinico Borgo Roma
Verona, Italy
Dr J. Arboleda-Florez
Department of Psychiatry
Calgary General Hospital
Calgary, Canada
Dr D. Caetano
Department of Medical Psychology and
Psychiatry
Faculdade de Ciencias Medicas/UNICAMP
Campinas, Brazil
Dr M. Argandona
Programme on Substance Abuse
World Health Organization
Geneva, Switzerland
Dr S.M. Channabasavanna
National Institute of Mental Health and
Neurosciences
Bangalore, India
Dr T. Baasher
Department of Psychiatry
Faculty of Medicine
University of Khartoum
Khartoum, Sudan
Dr J.A. Costa e Silva
Faculdade de Ciencias Medicas
Service de Psiquiatria-UERJ
Rio de Janeiro, Brazil.
Dr L. Balant
Clinique de Psychiatrie I
Institutions Universitaires de Psychiatrie
Geneva, Switzerland
Dr A.E. Balant-Gorgia
Clinique de Psychiatrie I
Institutions Universitaires de Psychiatrie
Geneva, Switzerland
Dr M. E. Cruz
Academia Ecuatoriana de Neurociencias
Quito, Ecuador
Dr E. d'Arrigo Busnello
Department of Psychiatry
Universidade Federal de Rio Grande do Sul
Porto Alegre, Brazil
iii
WHO/MNH/MND/93.27
Dr M. de Francesco
Psychiatric Unit
Consorzio Mario Negri Sud
Santa Maria Imbaro, Italy
Dr R. de la Fuente
Instituto Mexicano de Psiquiatria
Mexico City, Mexico
Dr G.A. German
Department of Psychiatry and Behavioural
Science
Queen Elizabeth II Medical Centre
Nedlands, Australia
Dr G.P. Harnois
Douglas Hospital Center
Montreal, Canada
Dr C. Hoschl
Prague Psychiatric Center
Prague, Czech Republic
Dr Assen Jablensky
Department of Psychiatry and Behavioural
Sciences
The University of Western Australia
Perth, Australia
Dr B. James
Regional Mental Health Services
Queensland Health
Townsville, Australia
Dr M. Kastrup
Department of Psychiatry
Hvidovre Hospital
Hvidovre, Denmark
Dr T. Lambert
Department of Psychiatry and Behavioural
Sciences
The University of Western Australia
Perth, Australia
Dr S. Lebovici
Departement de Psychopathologie Clinique,
Biologique et Sociale
Universite Paris Nord
Bobigny, France
Dr C. A. Leon
Unidad de Salud Mental
Hospital Universitario del Valle
Cali, Colombia
iv
Dr J. J. Lopez Ibor
Department of Psychiatry
Hospital Universitario San Carlos
Universidad Complutense
Madrid, Spain
Dr I. Levav
Regional Adviser, Mental Health
WHO Regional Office for the Americas/
Pan American Sanitary Bureau
Washington, USA
Dr A. K. Malhotra
Experimental Therapeutics Branch
National Institutes of Health
Bethesda, USA
Dr A. Mohit
Regional Adviser on Mental Health
WHO Regional Office for the Eastern
Mediterranean
Alexandria, Egypt
Dr S. Montgomery
Academic Department of Psychiatry
St. Mary's Hospital Medical School
London, U.K.
Dr D. Moussaoui
Psychiatric University Centre
Medical Faculty of Casablanca
Casablanca, Morocco
Dr M.H. Mubbashar
Department of Psychiatry
Rawalpindi General Hospital
Rawalpindi, Pakistan
Dr N.P.V. Nair
Douglas Hospital Research Centre
Montreal, Canada
Dr A.D. Nikapota
Consultant Child & Adolescent Psychiatrist
Brixton Child Guidance Clinic
London, U.K.
Dr J. Orley
Division of Mental Health
World Health Organization
Geneva, Switzerland
Dr D. Pickard
Experimental Therapeutics Branch
National Institutes of Health
Bethesda, USA
♦
WHO/MNH/MND/93.27
Dr Prabha S. Chandra
National Institute of Mental Health and
Neurosciences
Bangalore, India
Dr H. Sell
Regional Adviser, Health & Behaviour
WHO Regional Office for South East Asia
New Delhi, India
Dr P. S. Prado Lima
WHO-Brazil Collaborating Centre for
Research and Training in Mental Health
Porto Alegre, Brazil
Dr N. Shinfuku
Regional Adviser for Mental Health
WHO Regional Office for Western Pacific
Manila, Philippines
Dr R. Priest
University of London
St Mary's Hospital Medical School
London, U.K.
Dr M. Tansella
Institute of Psychiatry
Cattedra di Psicologia Medica
University of Verona
Verona, Italy
Dr U. Rydberg
Karolinska Hospital
Magnus Huss Clinic
Stockholm, Sweden
Dr B. Saraceno
Psychiatric Unit
Laboratory of Clinical Pharmacology
Istituto di Ricerche Farmacologiche Mario
Negri
Milan, Italy
Dr B. Saxena
Psychopharmacology Research and Training
Centre
Hamilton Psychiatric Hospital
Hamilton, Canada
Dr K. Tareen
Department of Child and Family Psychiatry
King Edward Medical College and Mayo
Hospital
Lahore, Pakistan
Dr Shen Yucun
Department of Psychiatry
Beijing Medical College
Third Teaching Hospital
Beijing, China
Dr F. Workneh
Department of Psychiatry
Medical Faculty
University of Addis Ababa
Addis Ababa, Ethiopia
Dr M. Schou
Aarhus University Psychiatric Hospital
Risskov, Denmark
V
WHO/MNH/MND/93.27
16. F80-F99 BEHAVIOURAL AND EMOTIONAL DISORDERS WITH ONSET
USUALLY OCCURRING IN CHILDHOOD ......................................
67
16.1
Current treatments
17. APPENDICES
67
69
I.
CLASSIFICATION OF PSYCHOACTIVE DRUGS
71
IL
TABLES OF EQUIVALENCY
73
III.
PSYCHOACTIVE MEDICINES IN PREGNANCY
76
IV.
PSYCHOACTIVE MEDICINES IN OLD AGE
77
V.
WHO CONSENSUS STATEMENTS ON THE PROPHYLACTIC USE OF
ANTICHOLINERGICS IN PATIENTS ON LONG-TERM NEUROLEPTIC
TREATMENT..............................................................................................
78
WHO CONSENSUS STATEMENT ON PHARMACOTHERAPY OF
DEPRESSIVE DISORDERS ................................................................
79
VII.
RULES FOR BETTER SLEEP HYGIENE
80
18.
NOTES
81
19.
REFERENCES
82
VI.
lx
WHO/MNH/MND/93.27
A
PART I
GENERAL INTRODUCTION
WHO/MNH/MND/93.27
1. ESSENTIAL TREATMENTS AND
ESSENTIAL DRUGS IN
PSYCHIATRY
Since the introduction of chlorpromazine
in psychiatric clinical practice in 1957, drug
treatment has gradually become a very
common treatment modality in psychiatry
across cultures, health and mental health
care systems and different psychiatric
schools. It would undoubtedly be very hard
to conceive of a clinical psychiatric practice
without any psychoactive drug nowadays.
Thanks to psychoactive drugs, significant
progress has been achieved in the
prevention and management of several
severe and disabling mental disorders. This
progress has also not only contributed to a
significant reduction in the hospitalization
needs for many patients and to a much
greater emphasis being placed on
community care, but has also had a
significant impact in terms of real reduction
in human suffering.
However, in a number of countries,
mental health services are totally lacking
and large segments of the population do not
even have ready access to health facilities,
which tend to be based in hospitals and
oriented predominantly towards urban
conditions. In an attempt to strengthen the
health care system and achieve low-cost but
effective and efficient health services,
attention is being increasingly focused on
the development of a primary health care
strategy. Moreover, it has been repeatedly
shown that much of psychiatric morbidity is
seen at the primary care level. For these
reasons the role of primary health care
doctors becomes crucial for the delivery of
effective and widespread mental health care.
Unfortunately the training of general
doctors in the rational prescribing of
psychotropic drugs is not satisfactory
everywhere, and it is sometimes clearly
deficient. In addition, the practising doctor
not only has to keep abreast with the
development of new drugs and treatments,
but is also exposed to a variety of
sometimes conflicting influences
continuing education is therefore essential.
This manual is addressed primarily to
general doctors and is intended to be a
basic tool for their continuing education. It
should be read in the framework of the
context of essential treatments, subject of a
previous WHO publication (4). In brief, this
approach considers that medicines are not
the only form of the proper treatment of
mental disorders; they are but one
component, besides psychological and social
interventions.
Essential treatments in
psychiatry are those
interventions both
necessary and sufficient
for the care of people with
specific mental disorders.
During recent years WHO has devoted
a great deal of effort to disseminating
balanced information on both the benefits
that can be derived from the use of
psychotropic drugs and the dangers
associated with their use. Efforts have been
made to improve the training of physicians
and other mental health workers in
prescribing psychotropic drugs for patients
in need of them.
Projects aimed at
improving prescribing practices and at
suggesting methods for evaluating the
effectiveness of treatment methods,
including drug treatment, have been carried
out (2), among others. It was nevertheless
felt that there was a need to produce a
clear, comprehensive manual which would
first discuss general issues of prescribing
and would then provide specific guidelines
for the use of selected psychoactive drugs:
a manual to specifically help the practitioner
in prescribing drugs for the management of
mental disorders.
In this document, terms like
"psychoactive", "psychotropic", and
"psycho-therapeutic" will be used
synonymously to designate drugs, which,
when compared with others, have the
power to affect aspects of mind and
behaviour, including thought patterns,
mood, anxiety, cognitive performance and
well-being.
The need for such a manual also has to
be seen in the framework of the WHO
policy on essential drugs, which, following
resolution WHA28.66, has been carried out
1
WHO/MNH/MND/93.27
by the Organization in an attempt to advise
Member States on the selection and
procurement, at reasonable cost, of essential
drugs of an established quality
corresponding to their national health
needs.
Essential drugs have therefore been
identified to mean that "they are of the
utmost importance and are basic,
indispensable and necessary for the health
needs of the population" (1).
In the WHO Essential Drugs List (EDL),
the following have been selected for the
treatment and control of mental disorders:
amitriptyline
chlorpromazine
diazepam
fluphenazine
haloperidol
lithium carbonate
detailed explanation and suggestions for a
rational use were provided.
Clearly, the description of an
appropriate medicine is only the first step in
using it: issues such as education about the
medicine, about compliance, about
unwanted side effects, about failure to
respond, given adequate dosage for a
sufficient length of time, and further
education about early signs of relapse once
recovered, are all vital in determining the
effectiveness of any drug treatment. Yet
these issues are seldom subjected to scrutiny
and controlled research.
Moreover, an
effective psychiatric treatment can best be
the result of an adequate and balanced
combination of pharmacological,
psychological and psychosocial treatment
methods. Didactic and practical reasons
nevertheless point to the need for issuing
separate manuals instead of a single
textbook on psychiatric treatments.
It should be noted that in the WHO
EDL with the exception of lithium
carbonate, all others are indicated as
"an example of a therapeutic group
and that various drugs could serve
as alternatives. It is imperative that
this is understood when drugs are
selected at national level, since
choice is then influenced by the
comparative cost and availability of
equivalent products."
Thus, in the EDL
amitriptyline represents tricyclic anti
depressants;
chlorpromazine, phenothiazines;
diazepam, benzodiazepines;
fluphenazine, injectable long-acting
neuroleptics; and
haloperidol, butyrophenones.
Although this list is basically valid at a
global level, on the whole there is a wide
variation between countries in the quality
and capabilities of primary health care
doctors, in drug policies and in disease
prevalence. It was therefore felt, according
to opinions of experts from the WHO
Expert Advisory Panel and collaborating
centres that other drugs of significant
importance for daily clinical practice should
be added to the original EDL. Following
tliis, a wider list of psychoactive drugs was
prepared and for each of these drugs a
2
CARE FOR PEOPLE
instead of just
TREATING DISEASES
In Section I of this manual several basic
aspects relevant to the pharmacological
treatment of mental disorders - such as
influencing factors, prescribing practices and
ethical issues, the role of pharmacotherapy
at different levels of the health system, and
evaluation of pharmacotherapy in
psychiatry are reviewed and discussed.
Section II presents some basic principles for
rational prescribing, and of
pharmacokinetics relevant to a more
efficient utilization of medicine.
In Section III, all the categories in the F
chapter of ICD-10 are briefly described,
followed by an indication of the most
efficient treatment available - whether
pharmacological or not - based on the most
updated scientific evidence.
Specific
strategies for the acute phase as well as for
the maintenance treatment are described;
wherever pertinent, a section on special
problems is also present.
In many countries prescribing is a
prerogative of doctors and, as indicated
earlier, they constitute the target audience of
this manual. It is our belief, however, that
WHO/MNH/MND/93.27
non-prescribing members of the health care
team will benefit from its reading. It will
not only help them better understand the
field of pharmacotherapy of mental
disorders in itself, but will also give them a
more comprehensive view of mental health
care as a whole, adding to their own
professional or functional perspective.
3
WHO/MNH/MND/93.27
2. PSYCHIATRIC MEDICINES
PRIMARY HEALTH CARE
IN
Not all countries can afford to have all
patients treated by a medical doctor. In
many of the developing countries over 80 %
of outpatient consultations are done by
medical assistants, clinical officers, nurses
and village health workers operating from
district hospitals, health centres,
dispensaries, and dressing stations right
down to the village level. In many other
countries, all consultations are done by
doctors, and the health centre or hospital
outpatient clinic may be the first level of
care, rather than a referral level.
The criteria for selection of drugs to be
used at the primary health care level are:
efficacy, optimal benefit/risk ratio,
satisfactory therapeutic margin and low
cost. For several diseases for which long
term treatment is needed, such continued
treatment can be given and its effect
monitored at a lower level than that at
which the diagnosis was made and
treatment initiated. Such "down-referral"
has important implications in countries with
scarce resources.
Harding and Chrusciel (3) have outlined
the following five essential steps to facilitate
the rational use of psychiatric medicines in
primary health care. The steps listed imply
a series of interdependent actions, designed
to increase the rational and effective use of
psychotropic drugs. It is not implied that
such steps be carried out in any particular
sequence.
Focus on a limited number of
conditions.
Effective training will not be
possible if the target conditions are poorly
defined or too numerous. Health workers
at most levels should not be expected to
master the complex psychiatric
classifications used by psychiatrists; nor can
they be expected (in view of the limited
time available) to cope with the whole range
of mental disorders, even if they are clearly
defined.
In the preliminary phase,
therefore, it is necessary to focus on a very
limited range of conditions, i.e. those:
i) that are known to be prevalent;
ii) that have marked harmful consequences;
and
iii) for which drug therapy is of clear benefit.
4
The selection of priority conditions must
be carried out in each country and should
reflect, in addition to prevalence, the
expressed needs of the people, and the
general level of socio-economic
development. These conditions will have to
be defined clearly with an agreed
terminology that is precise and easily
understood.
This requires close collaboration
between those responsible for training and
those concerned with services. In general,
the list of priority conditions is likely to
include psychiatric emergencies and acute
psychoses, chronic psychoses, severe
depression, severe anxiety disorders and
certain problems related to drug and alcohol
abuse; local conditions may require that this
list be modified or added to.
Availability of a limited range of drugs for
defined situations.
The definition of a
limited range of psychotropic drugs for use
in a particular country facilitates bulk
purchase or local manufacture and helps to
ensure a relatively cheap and constant
supply, adequate quality control and a
lesser risk of drug abuse. It also allows a
more rational and efficient approach to
training, since trainers can ensure that
information is relevant to subsequent
practice. Unnecessary duplication, different
dosage regimes, and confusing
nomenclature should be avoided.
Psychiatrists and physicians may resist
"restriction of freedom to prescribe". In
countries with a large private health sector,
there will be problems of implementation.
There would inevitably be disagreements
concerning which drugs should be included
in the limited range, and this could lead to
a situation in which drug suppliers might
use pressure of various kinds to influence
decisions.
Nevertheless, the potential
advantages of a defined, limited range of
drugs are such that it is essential to
overcome these problems with the help of
professional organizations and health
authorities.
Simplification of the division of tasks in the use
of medicines.
The division of tasks in the
use of medicines is usually rather rigid. A
physician makes a decision concerning the
choice of medicine and its dose, route of
administration, and duration. This decision
is translated into a written "prescription’’,
WHO/MNH/MND/93,27
often supplemented by direct verbal
information and explanation to the patient.
The prescription is interpreted by a
pharmacist or a nurse who supplies the
medicine to the patient. Further decisions
concerning change of dose, cessation of
treatment, use of other medicines, etc, are
taken by the physician on the basis of
clinical observation and information given
by the patient. In some cases this may be
supplemented by information from nurses
and/or relatives of the patient. The limiting
factor in such a system is the physician,
since he/she must be available for all
decision-making. In view of the great
shortage of physicians, particularly those
with adequate training in the use of
psychiatric medicines, the effective use of
these drugs is severely limited.
Coordinated training programmes.
The
successful introduction of the approach
described above would depend primarily on
the institution of appropriate and effective
training (and retraining) of all health
workers involved. This would require an
integrated approach so that training of each
category of health worker matched the
subsequent work requirements.
Sensible training programmes must also
take into account problems posed by side
effects, by abuse potential, by failure to take
drugs as prescribed, by the risks of
overdose, and by the fact that for some
psychiatric conditions effective drug
treatments are not yet available.
There is often too little continuity
between the training of health workers and
their subsequent work. Physicians and
nurses are usually trained in hospitals
where teaching on psychotropic drugs may
be based on selected populations and may
reflect the particular views and practices of
one or more hospital-based psychiatrists. In
actual practice the physician or nurse may
have to deal with a different range of
conditions in a different environment.
Drugs used in the training hospital may not
be available or may have a different name.
Lack of coordination may lead to drugs
being supplied for which health personnel
have not received training.
The setting up of a central policy body. None of
the steps above can be instituted without
the full agreement and cooperation of
practising psychiatrists, nurses, and those
responsible for training, administration and
health planning. There may problems of
legal responsibility and professional rivalry.
There need to be safeguards and regulations
to limit the abuse of drugs. This could be
achieved by a central planning body for
mental health within the health ministry
with access to the various professionals
groups, training schools and institutions
involved.
Secondary and tertiary levels of
2.1
health care
The secondary level of health care is
generally represented by district hospitals or
by large health centres serving between
50,000 and 500,000 people. In some systems
smaller health centres occupy an
intermediate position between these and
community clinics. Depending on their
size, district hospitals will probably have a
number of specialists and at least one
general clinician. These centres should have
a qualified psychiatrist, or a psychiatric
assistant or a senior nurse with specialized
psychiatric training. In many situations these
general health care centres will serve as the
main resources for the delivery of mental
health care to more complex cases;
moreover, in some countries where there is
a shortage of psychiatric hospital units,
there is now extensive experience with
patients with psychiatric disorders in need
of hospitalization and being admitted to
general medical wards. Examples are
patients with severe depression, mania,
schizophrenia. In these situations,
pharmacological treatment becomes one of
the most important treatment options and
needs to be adequately administered by
medical personnel working in these units
supervised by a psychiatrist.
In mental health care, the tertiary, or
second-referral level is represented by
qualified psychiatric personnel working in
specialized mental health facilities, which
may be independent or may be part of large
general hospitals. Such specialized facilities
may also be teaching institutions. At this
level, mental health specialists will deal
with complex problems of diagnosis and
treatment referred from secondary and
primary levels; in terms of drug treatment,
the most complex treatments will be
administered, at least during the initial
phase, at this level, as well as treatment still
at an experimental stage.
5
WHO/MNH/MND/93.27
3. ETHICAL ISSUES
In ’’ESSENTIAL TREATMENTS IN
PSYCHIATRY" (4) this issue has been dealt
with in some detail. Interested readers
might wish to consult it. Some of the key
topic areas discussed in that publication
include:
i)
right and access to treatment;
ii) right to information;
iii) consent to/refusal of treatment; and
iv) clinical responsibility.
While variations in dominant lay
opinion between cultures impose differences
in what may be perceived to be proper
medical behaviour, these differences may
relate more to divergence between what is
habitual than to real ethical disparities.
All persons have the right
to the best available mental
health care, which should
be part of the health and
social care system.
Principle 1
UN Resolution 46/119
6
WHO/MNH/MND/93.27
4. RATIONAL PRESCRIBING
4.1
Principles of rational prescribing
According to a report of the Council on
Medical Services of the American Medical
Association (5) care of high quality is the
one that:
a) produces the optimal improvement in
the patient's physiological status,
physical function, emotional and
intellectual performance and comfort at
the earliest time possible consistent with
the best interests of the patient and
relatives;
b) emphasizes the promotion of health, the
prevention of disease or disability, and
the early detection and treatment of
such conditions;
c) is provided in a timely manner, without
either undue delay in the initiation of
care, inappropriate curtailment or
discontinuity, or unnecessary
prolongation of such care;
The above elements are certainly helpful
for the establishment of principles for good
treatment and rational prescribing as well.
More specifically, the following, adapted
from Ghodse & Khan (6), are indicated as
additional principles for the rational
prescribing of psychoactive medication:
1. There should be a clear target symptom
or symptoms that the medicine is
known to affect, e.g., depressive mood,
thought disorder, anxiety, restlessness,
insomnia or the like.
2. The dosage should be adjusted
according to risk/benefit principles,
taking into account the target symptom
and its severity; patient's characteristics
such as sex, age, weight, ethnic
background, nutritional status and
eventual special states such as
pregnancy or lactation; other
concomitant medical conditions and
treatments; environmental factors such
as temperature; and availability and
access to emergency care, if needed.
3.
As little amount of the drug as possible
should be supplied, based on an
assessment both of how much of it is
required to affect the target symptom
and of the patient's social, psychological
and geographical situation, e.g., a
patient from a rural area who must
make an arduous journey to obtain
treatment will require a larger supply
than one with easier access to a
pharmacy.
4.
The physician should be aware of all the
drugs, both medical and non-medical,
being taken by the patient and the
possible interactions, e.g., between
alcohol and drugs with sedative
properties. Synergism, the multiplicative
effect of drugs when taken together, is
a possibility for which the clinician must
be constantly on guard. Many drugs
taken for a variety of conditions, such as
hypertension, interact with psychoactive
drugs either to enhance sedation or to
cause hypotension. Reading package
inserts as a routine is a good practice in
this regard. Other reference works also
carry information on interactions.
Investigation of history of substance
abuse, including alcohol and illicit
drugs, should also be included.
d) seeks to achieve the informed
cooperation and participation of the
patient in the care process and in
decisions concerning that process;
e) is based on accepted principles of
medical science and the proficient use of
appropriate technological and
professional resources;
f)
is provided with sensitivity to both the
stress and anxiety that illness can
generate among the relatives and with
concern for the patient's overall welfare;
g) makes efficient use of the technology
and other health system resources
needed to achieve the desired treatment
goal; and
h) is sufficiently documented in the
patient's medical record to enable
continuity of care and peer evaluation.
Treatment should have the
shortest possible duration
7
WHO/MNH/MND/93.27
5. The expected duration of the treatment
should be made clear to the patient: in
some cases it may be for a limited
period of time. This period may be
related to the pharmacological
properties of the drug employed, e.g., it
takes 2-3 weeks for dependence on
barbiturates to develop; or, in a patient
who has not previously abused alcohol
or used central nervous system
depressants, it may be 20 weeks or so
until dependence on long-acting
benzodiazepines, in therapeutic dose
ranges, begins. This is a natural
pharmacological window and illustrates
the kinds of factors that determine the
length of the period. Another example is
the rapid appearance of tolerance to
many sedative hypnotics. In other
instances it may have a much longer
duration or be eventually for life, e.g. in
some cases of chronic, severe
schizophrenia, or for the prevention of
rapid-onset and severe relapses of
mania with lithium salts.
6. The patient should be informed of
possible side-effects, e.g., morning
dullness after taking sedative hypnotics;
effects on driving performance after
taking tranquillizers or sedative
hypnotics; effects on the fetus if
pregnancy occurs while patients are
taking psychoactive drugs; hypotension
caused by pheno thia zines, etc. The
occurrence of side-effects and the
measures taken to respond to them, e.g.
reassurance that they are temporary or
perhaps a reduction in the dose, should
also be entered in the patient's records.
7. The patient should be monitored for
general progress, for compliance and
misuse and specifically to assess the
effects of the drug on the target
symptom. The response should be
measured and entered in the patient's
records.
8. If at all possible, family members
should be involved as part both of
the management plan and of the
monitoring. They usually play an
important part in adequate
prescribing and monitoring.
9. Suicide is more frequent in patients
with some mental disorder, such as
8
depressive disorders. Rapidly escalating
life stress frequently triggers suicidal
thoughts and behaviour. A history of
previous suicidal thoughts or attempts
and a family history of suicide are
important indications of possible
suicidal behaviour. Such patients should
be specifically asked about suicide and,
if it is possible, the clinician must limit
the amount of psychoactive drug
prescribed and should also construct a
regimen in which there is frequent
clinical monitoring and also, if at all
possible, monitoring by family and
friends. Talk of suicide should always
be taken seriously. The physician should
be alert to respond by hospitalization if
the clinical situation of a patient with
suicidal potential deteriorates. If there is
severe physical or psychiatric disorder
and, in particular, a history of substance
abuse, the risk of suicide is high.
10. The physician should always take a
history of substance abuse. A past
history of alcoholism, for example, is
often present in patients liable to misuse
drugs. However, a history of alcoholism
or drug abuse does not preclude the use
of psychoactive drugs for diagnosed
psychiatric disorders, but the level of
control and monitoring must be greater
and such monitoring more frequent than
would otherwise be necessary.
11. The drug or drugs with the least
potential for abuse should be used for
any given indications.
More often than not, nonpharmacological means, such as counselling,
will be both applicable and effective, and
without risk of drug misuse or drug
dependence. The decision to treat with
drugs should be based on a clinical
determination that the patient's
psychological and social resources have
been, or are in danger of being,
overwhelmed; for example, a sustained
period of inability to sleep following the
death of a loved one represents a typical
case in which pharmacological treatment of
insomnia may be considered. The clinical
question is, can this patient, within the
limits of the available resources, regain
equilibrium without drug therapy? If the
answer is yes, and particularly if the answer
is yes with relatively bearable suffering or
WHO/MNH/MND/93.27
with relatively little discomfort, then non
drug approaches are indicated. Counselling
or participation with others undergoing life
stress in self-help groups, or still other
approaches discussed elsewhere in this
publication may be tried before drug
therapy is attempted. If the answer is no,
then the next clinical question is, what are
the dangers to this patient from drug
treatment? If the risks and benefits are
carefully assessed, the decision to treat or
not to treat with psychoactive drugs will
emerge from the assessment.
Some disorders, such as phobic states,
panic disorders, and the like, may require
long-term therapy with drugs which have a
definite dependence liability, such as the
benzodiazepines. The clinician needs to
monitor such cases carefully and to discuss
with the patient and the family the possible
development of dependence. With most
such patients, dependence is not a problem
if the dose is tapered off when the drug is
no longer needed or a drug "holiday" is
being taken.
A general principle is that psychoactive
drugs should be used on a short- or
long-term basis depending on the chronicity
of the disorder. Fear of development of
dependence, or of abuse or possible resale
of the drugs prescribed, should not prevent
the physician from providing the indicated
therapy. Fear of these possibilities should
rather be the motive for careful monitoring,
not only of the progress of the drug
regimen but also of the person to whom the
drugs are prescribed. It is also important for
the physician to keep up with the literature.
For instance, many psychoactive drugs, e.g.
the benzodiazepines, are metabolized much
more slowly by the elderly than they are by
younger patients. This has only been widely
realized in the last decade or so. The
difference in age and in metabolism is
clinically meaningful and requires dose
reduction and more frequent monitoring in
the elderly than with younger patients. For
insomnia in the elderly, the use of sedatives
or drugs with sedative properties, e.g.
phenothiazines or antidepressants, 2-3 times
per week instead of on a daily basis may be
a way to avoid the possibility of
dependence while still providing relief for
what is frequently a trying clinical problem.
The same strategy is, of course, applicable
in any clinical situation in which the aim is
to avoid dependence or perhaps just not to
provide too large a drug supply.
Numerous drug interactions, as noted
above, dictate that drugs should be
prescribed only after the data from the
history, physical examination and laboratory
results have been reviewed and a diagnosis
established, and the costs and benefits of a
particular therapy assessed. The attitude
that addiction is to be avoided at all costs,
cannot be justified. When such an attitude
does determine clinical decisions, it
frequently causes much unnecessary
suffering.
Prescribe
as few different drugs
as possible in
as few doses per day
as possible
Finally, it should be stressed that several
studies have shown that the dosage of
psychotropic drugs sufficient to obtain
therapeutic effects may be lower among
specified ethnic groups, e.g. Asians.
Therefore the dosages indicated in this
document should be considered with
caution and possibly adapted to the needs
of special ethnic groups, in particular people
of Asian origin, including Native
Americans.
4.2
Topics
prescribing
4.2.1
relevant
to
rational
History taking
Interviewing is probably the oldest and
most frequently used of the assessment
procedures. As it usually takes place during
the first meeting between patient and health
care worker, the interview has a significant
influence on the patient's expectations and
on the outcome of subsequent interventions.
The interview may vary from being highly
structured, in which the topics discussed
follow a questionnaire or prearranged
format, to being flexible or unstructured, in
which the interviewer follows cues given by
the patient and does not restrict questioning
to specific topics. Often both techniques are
used, background information about age,
previous medical history, etc. being elicited
in the structured interview, while flexible
questioning elicits additional information.
9
WHO/MNH/MND/93.27
Before any treatment strategies can be
initiated, patient and therapist must discuss
and agree on the behavioural changes to be
effected and the approach to be used. Such
discussions are repeated periodically so that
treatment effectiveness can be assessed and
new goals for behavioural change may
emerge. One aspect of a behavioural
assessment based on a typical diagnostic
interview is that not only are problem
behaviours targeted but behavioural
strengths are identified; this is important,
since they are useful in the treatment
approach.
Apart from its value in assessment, the
interview may be therapeutic in its own
right, because helping the patient to identify
the underlying problem can be very useful,
as can the relationship between patient and
health care worker, initiated at the
interview.
Other assessment procedures may also
be used, including questionnaires,
self-monitoring, behavioural observation
and psychophysiological measurement. The
importance of thorough assessment cannot
be overemphasized, because behavioural
intervention is not like using a recipe book
- there cannot be a single recipe for every
symptom. Rather, the process is tailored to
the individual's unique problems in their
particular context, and these problems must
be clearly defined. The purpose of all the
different assessment procedures, therefore,
is to specify and select target behaviours,
identify antecedent and consequent
variables relating to the target behaviour,
and collect data about the target behaviour
and the variables affecting it.
4.2.2
Diagnostic assessment
A careful diagnosis is the first, essential
step for a rational prescribing and ensures
that the treatment is being delivered for the
disorder likely to be responsive to that
treatment. Up until a few years ago,
psychiatric practice had been hampered by
the existence of variable, different diagnostic
criteria; in the field of treatment, this has
led to marked differences in the choice of
the target symptoms for treatment, in the
selection of patients to be admitted to
certain treatments and in the assessment of
treatment response. The recent introduction
of the ICD-10 will undoubtedly foster the
adoption of uniformed, specified diagnostic
criteria in different countries of the world
10
and will facilitate the achievement of more
homogeneous, adequate standards of drug
treatment.
4.2.3
Doctor-patient relationship
The establishment of an effective doctor
patient relationship represents an essential
step in any drug treatment; indeed, it is the
core of the practice of medicine. A good
relationship, even more than a cure, is
expected by the patient; it is typical of
patients to be tolerant of the therapeutic
limitations of medicine. It has been often
stressed that there are no diseases; there are
only sick people. Therefore failure of the
doctor to establish good rapport accounts
for much of the ineffectiveness in the care of
patients.
Drugs can play an important role in the
doctor-patient relationship. The doctor
should make an effort to enlist, recruit and
involve the patient in a collaboration with
him/her related to the prescribed
medication: Gutheil (7) has called this "the
pharmacotherapeutic alliance", characterized
by "participant prescribing". In this way, by
making the patient a partner in treatment,
the doctor emphasizes and reinforces the
patient's strengths as a person instead of his
weaknesses in a dependent, sick, role thus,
opening the door for more flexible,
appropriate, responsive, and responsible
drug therapy.
Given the many and often disturbing
side effects associated with drug treatment,
it is important that a systematic, routine
inquiry be made into the patient's eating,
eliminating, sleeping, and sexual functions.
An open discussion about these aspects of
the patient's life and the changes induced
by the medication will reassure the patient
and will prevent both a breakdown in the
relationship and
non-compliance with
treatment.
4.2.4
Problems of treatment compliance
Making sure that patients take the
medicines prescribed to them by doctors has
always been a problem. The problem varies
from the patients who forget the occasional
tablet, to those who never even bother to
get their prescriptions dispensed. Among
medical patients non-compliance range
between 31 to 59% of patients in long-term
drug treatment, as shown in a number of
studies (&). Non-compliance can therefore
WHO/MNH/MND/93.27
represent a serious obstacle to the
achievement of therapeutic objectives. It also
can indicate a breakdown of confidence and
mutual respect between the patient and his
doctor.
Compliance increases if
less than three
medicines
are prescribed
at the same time
In psychiatry non-compliance is made
more problematic by the reduced insight
accompanying many mental disorders. The
lack of adequate insight, especially in
psychotic disorders, can act as an important
obstacle for the patient in understanding the
need for a regular, careful compliance with
the drug treatment administered.
Among factors affecting compliance, an
important one is the complexity of the drug
regime. Several studies have found that, if
three or more medicines are being
prescribed concurrently, compliance falls
significantly. This fact stresses the need for
a simplification of the drug treatment
schedule and the need to avoid prescribing
more than one medicine at the same time,
which is also known as polytherapy, in
addition to the other reasons which induce
refraining from such a practice.
Other important reasons to explain noncompliance, frequently given by patients
who abandoned treatment, include the
occurrence of side-effects and the absence of
any noticeable subjective feeling of
improvement, or worsening of the
condition. In psychiatry, where side effects,
sometimes severe, are quite common during
many pharmacological treatments, this is an
especially important reason of noncompliance. Greater awareness by the
doctor about this problem can therefore
minimize the risk of occurrence of side
effects, through a more careful selection of
the needed drug and the therapeutic
regime, and can prevent many unnecessary
cases of adverse effects. An improved
communication between the doctor and the
patient, with availability of the former to
give the patient all the information he/she
may require about the drug treatment
administered, and its possible or likely
adverse effects, can significantly reduce the
non-compliance phenomenon and create the
best climate for a shared inquiry about the
treatment, the establishment of mutual goals
and a mutual participation in both
experiencing and observing the process.
4.2.5
Therapeutic failures
The failure of a specific drug trial
should prompt the clinician to consider a
number of possibilities.
First:
was the original diagnosis
correct? This reconsideration should include
the possibility of an undiagnosed organic
mental disorder.
Second: are the observed remaining
symptoms actually the medicine's adverse
effects and not related to the original
disease? Antipsychotic drugs, for example,
can produce both akinesia, which resembles
psychotic withdrawal, or akathisia and
neuroleptic malignant syndrome, which
resemble increased psychotic agitation.
Third: was the medicine administered
in sufficient dosage for an appropriate
period of time? Patients can have different
drug absorption and metabolic rates for the
same drug, and plasma drug levels should
be obtained to assess this variable, although
the high costs associated with plasma drug
levels measurements make it hardly
affordable by the large majority of
psychiatric institutions in the world.
Fourth: was there a pharmacokinetic or
pharmacodynamic interaction with another
drug the patient was taking that reduced
the efficacy of the psychotherapeutic drug?
Fifth: did the patient actually take the
medicine as prescribed? As mentioned
above, drug non-compliance is a very
common clinical problem.
4.2.6
Choice of medicine
The first two steps in selecting a drug
treatment, the diagnosis and identification
of target symptoms, should be carried out,
whenever possible, when the patient has
been in a drug-free state for 1 to 2 weeks.
The drug-free state should include the
absence of medications for sleep (e.g.
hypnotics), as the quality of sleep can be
both an important diagnostic guide and a
target symptom. Psychiatrists often evaluate
symptomatic patients who are already on
one or more psychoactive medications, and
11
WHO/MNH/MND/93.27
so it is usually necessary to wean the
patient from current medications and then
to make an assessment. An exception to this
practice occurs when patients present
themselves to the psychiatrist on a suboptimal regimen of an otherwise
appropriate drug. In such cases, the psychi
atrist may decide to continue the drug at a
higher dose in order to complete a full
therapeutic trial. From among the drugs
appropriate to a particular diagnosis, the
specific drug should be selected according
to the patient's past history of drug
response (compliance, therapeutic response,
and adverse effects), the patient's family
history of drug response, the profile of
adverse effects for that drug with regard to
a particular patient and the psychiatrist's
usual practice. If a drug has previously been
effective in treating a patient or a family
member, it should be used again unless
there is some specific reason not to use the
drug. A past history of adverse effects from
a specific drug is a strong indicator that the
patient would not be compliant with that
drug regimen.
It is unfortunate that patients and their
families are often quite ignorant of what
drugs have been used before, in what doses,
and for how long. This finding may reflect
the tendency of psychiatrists not to explain
drug trials to their patients, and should
encourage psychiatrists to give their patients
written records of drug trials for their
personal medical records. A caveat to
obtaining a past history of drug response
from patients is that, because of their mental
disorder, they may inaccurately report the
effects of a previous drug trial. If possible,
therefore, the patients' medical records
should be obtained to confirm their reports.
Most psychotherapeutic drugs of a single
class have been demonstrated to be equally
efficacious; however, these drugs do differ
in their adverse effects on individuals. Thus
the drug selected should minimally
exacerbate any pre-existing medical
problems that a patient may have.
4.2.7
Therapeutic trials
A drug's therapeutic trial should last for
a previously determined length of time.
Because behavioural symptoms are more
difficult to assess than other physiologic
symptoms (e.g. hypertension), it is
particularly important for specific target
symptoms to be identified at the initiation
12
of a drug trial. The doctor and the patient
can then assess these target symptoms over
the course of the drug trial to help
determine whether the drug has been
effective. There are a number of objective
rating scales available to assess a patient's
progress over the course of a drug trial. If a
drug has not been effective in reducing
target symptoms within the specified length
of time and if other reasons for the lack of
response can be excluded, use of the drug
should be tapered off and stopped. Another
common clinical mistake is the routine
addition of medications without the
discontinuation of a prior drug. Although
this practice is indicated in specific
circumstances (e.g. lithium potentiation of
an unsuccessful trial of antidepressants), it
often results in increased adverse effects,
unwanted pharmacokinetic interactions and
non-compliance, as well as the clinician's
not knowing whether it was the second
drug alone or the combination of drugs that
resulted in a therapeutic success.
4.2.8
Adverse effects
Patients will generally have less trouble
with adverse effects if they have previously
been told to expect them. It is not
unreasonable to explain the appearance of
adverse effects as evidence that the drug is
working. But clinicians should distinguish
between probable or expected adverse
effects and rare or unexpected adverse
effects.
An extreme adverse effect of drug
treatment is an attempt by a patient to kill
himself by overdosing on a
psychotherapeutic drug. Whatever the
motivation, doctors should be aware of this
risk and prescribe the safest possible drugs.
It is good practice to write non-refillable
prescriptions for small quantities of drugs
when suicide is a possibility. In extreme
cases, attempts should be made to verify
that patients are actually taking the
medication and not hoarding the pills for a
later overdose attempt. It is a common
clinical observation that patients may
attempt suicide just as they are beginning to
get better. Clinicians, therefore, should
continue to be careful about prescribing
large quantities of medication until the
patient is almost completely recovered.
Another consideration for psychiatrists is
the possibility of accidental overdose,
particularly by children in the household.
WHO/MNH/MND/93.27
Patients should also be advised to keep
psychotherapeutic medications in a safe
place.
4.2.9
Patients’ attitudes toward medicines
Some patients' ambivalent attitudes
toward medicines often reflect the erroneous
belief that taking a psychotherapeutic drug
means that they are really sick or not in
control of their lives or that they may
become dependent on the medicine and
have to take it forever. A simplified
approach to these concerns is to describe the
psychiatric disorder partially as any medical
disease. Doctors should also explain the
difference between drugs of abuse that
affect the normal brain and psychiatric
medicines that are used to treat emotional
disorders. They should point out to patients
that antipsychotic, antimanic and
antidepressant medicines usually do not
create dependence.
Patients and families
want to know
what is going to happen
to them
13
WHO/MNH/MND/93.27
5. PRINCIPLES OF
PHARMACOKINETICS AND
PHARMACODYNAMICS
Pharmacokinetics is the quantitative study
of the processes involved in the absorption,
distribution, biotransformation and
elimination of a drug in the human body.
Pharmacodynamics describe the effects of a
drug on the body. The knowledge of the
kinetic profile of a drug and the
characteristics linked to the patient can lead
to a rational choice of the drug and/or an
appropriate modification of the treatment
schedule in order to achieve and keep
adequate concentrations of the drug at the
various action sites. Despite this,
pharmacokinetics remains poorly known
and outside daily clinical practice. Some
basic concepts related to pharmacokinetics
will be discussed here.
The principal steps studied by
pharmacokinetics are:
o
o
o
o
drug absorption,
distribution,
metabolism, and
excretion.
Regarding absorption, a psychotropic
drug can only reach the brain if it is carried
by blood. Orally administered drugs must
dissolve in the fluid of the gastrointestinal
tract before the body can absorb them, the
absorption depending on the drug's
concentration and lipid solubility and the
gastrointestinal tract local pH, motility and
surface area. If the pharmacokinetic
absorption factors are favourable, the drug
may reach therapeutic blood concentrations
more quickly if it is administered
intramuscularly (i.m.). If a drug is coupled
with an appropriate carrier molecule,
intramuscular administration can sustain the
drug's release over a long period of time, as
in the case of the depot antipsychotic drugs.
Finally, intravenous (i.v.) administration is
the quickest route to achieve therapeutic
blood levels, although it does not
necessarily lead to faster steady-state
concentrations; it also carries the highest
risk of sudden and life-threatening adverse
effects.
14
The distribution of a drug is dependent
on the amount of drug freely dissolved in
the blood plasma, bound to dissolved
plasma proteins (primarily albumin) and
dissolved within the blood cells. The
distribution of a drug to the brain is
determined by the blood-brain barrier, the
brain's regional blood flow, and the drug's
affinity with its receptors in the brain, and
can vary accordingly.
Metabolism is somehow equivalent to
'biotransformation'. The four major
metabolic routes for drugs are oxidation,
reduction, hydrolysis, and conjugation.
Although the usual result of metabolism is
to produce inactive metabolites that are
more readily excreted than is the parent
compound, several psychaoctive substances
have active metabolites. The liver is the
main site of metabolism and bile, faeces and
urine are the major routes of excretion. First
pass metabolism refers to the liver
metabolism of the drug which follows the
oral administration and, to a much minor
extent, the rectal administration. The first
pass metabolism consists in the pre-systemic
metabolism performed by the liver on the
drug absorbed by the gastro-intestinal tract
before it can enter into the systemic
circulation. In this case a pre-systemic
elimination of the drug will take place,
reducing its bioavailability, but not its
percentage of absorption. This mechanism
regards only some selected psychotropic
drugs (e.g., pheno thiazines and haloperidol).
It should be stressed that psychotropic
drugs can have very different
bioavailabilities: for instance, phenothiazine
bioavailability can be up to 100 fold
different between individuals. Similarly, a
reported 30-40 fold variation exists with
TCAs.
Two important concepts regarding
metabolism and excretion are time of peak
plasma level and half-life of a drug. The
time between the administration of a drug
and the appearance of peak concentrations
of the drug in plasma (peak plasma level)
varies primarily according to the route of
administration and absorption. The half-life
of a drug is defined as the amount of time
it takes for one half of a drug's peak level to
be metabolized and excreted from the body.
A general guideline is that if a drug is
administered in repeated doses, it will reach
97% of its steady state plasma
concentrations in a time equal to five times
its half-life.
WHO/MNH/MND/93.27
The major pharmacodynamic
considerations include:
o
o
o
o
o
receptor mechanism,
the dose response curve,
the therapeutic index and
the development of tolerance,
dependence and withdrawal
phenomena.
The receptor site for most psychoactive
drugs is also a receptor for an endogenous
neurotransmitter. For example, the primary
receptor site for chlorpromazine is the dopa
mine receptor. However, for other
psychotherapeutic drugs, this may not be
the case.
The dose response curve plots the drug
dosages against the effects of the drug. The
potency of a drug refers to the relative dose
required to achieve a certain effect.
Haloperidol, for example, is more potent
than is chlorpromazine because generally
only 5 mg of haloperidol are required to
achieve the same therapeutic effect obtained
with 100 mg of chlorpromazine. Both
haloperidol and chlorpromazine, however,
are equal in their maximal efficacies, that is,
the maximum clinical response achievable
by the administration of a drug.
The side effects of most drugs are often
a direct result of their primary
pharmacodynamic effects and are better
conceptualized as adverse effects. The
therapeutic index is a relative measure of
a drug's
toxicity
or
safety.
It is defined as the ratio of the median toxic
dose (TD50) to the median effective dose
(ED50). Haloperidol, for example, has a very
high therapeutic index, as evidenced by the
wide range of doses in which it is
prescribed. Conversely, lithium salts have a
very low therapeutic index, thereby
requiring careful monitoring of serum
lithium levels when on this drug. There can
be both inter- and intra-individual variation
in the response to a specific drug. An
individual patient may be hypo-reactive,
normally reactive, or hyper-reactive to a
particular drug. For example, some patients
with schizophrenia require 1 mg a day of
haloperidol, others require a more typical 10
mg a day, and still others may eventually
require a higher daily dosage to achieve a
therapeutic response. Idiosyncratic drug
responses occur when a person experiences
a particularly unusual effect from the drug.
For example, some patients become quite
agitated when given benzodiazepines.
A person may become less responsive to
a particular drug as it is administered over
time, which is referred to as tolerance. The
development of tolerance is associated with
the appearance of dependence, which may
simply be defined as the necessity to
continue administering the drug in order to
prevent the appearance of withdrawal
symptoms. However, it should be stressed
that tolerance and dependence are not seen
with the majority of the drugs which will be
discussed below.
15
WHO/MNH/MND/93.27
PART II
DRUG INFORMATION SHEETS
17
WHO/MNH/MND/93.27
6. INTRODUCTION TO
INFORMATION SHEETS
to provide a single treatment or groups
of treatments. Consideration should also
be given to the competence of the
personnel to make a correct diagnosis.
In some instances, whilst individuals
with advanced training are necessary to
prescribe initial therapy, individuals
with less training could be responsible
for maintaining therapy.
DRUG
In establishing a list of essential
medicines for the care of persons with
mental disorders the following general
principles were followed: (9)
1. Adoption of a list of essential medicines
for mental disorders implies giving
priority to achieving the widest possible
coverage of the population, with
treatments of proven efficacy and safety,
in order to meet the needs for treatment
of the most prevalent and severe
disorders.
2. Only those medicines for which
adequate scientific data are available
from well- controlled studies should be
selected.
3. Each selected product must
adequate standards of quality.
4. The influence on the health status of
local physical or psychosocial
conditions, or of local diseases, should
be considered when making the
selections: e.g. nutritional status,
climate, housing and employment
levels, natural social networks.
5. When two or more treatments or
interventions are therapeutically
equivalent, preference should be given
to:
meet
the treatment which has been most
thoroughly investigated;
ii) the treatment with the imost
favourable properties, e.g. to
compliance or to
improve
risk
in various
minimize
pathophysiological states;
iii) the medicine, pharmaceutical
product and dosage form that
provide the highest benefit/risk
ratio;
iv) medicines, pharmaceutical products
and dosage forms with favourable
stability, or for which storage
facilities exist.
v) the cheapest medicine with similar
pharmacological properties.
i)
4. Concise, accurate and comprehensive
information on each different medicine
drawn from unbiased sources should
accompany each list of essential
medicines.
In addition, the following guidelines
were also followed, and are recommended,
to ensure a process of selection of essential
medicines that is unbiased and based on the
best available scientific information, yet
allowing for a degree of variation to take
into account local needs and requirements:
1.
The list of essential medicines should be
established at a national level by an
appointed committee including
individuals competent in the fields of
clinical psychiatry,
psychopharmacology, psychotherapy
and social and behavioural sciences, as
well health workers at the peripheral
level.
2. Cost represents a major selection
criterion. In cost comparisons between
medicines, the cost of the total
treatment, and not only the unit cost,
must be considered.
3.
Local health authorities should
determine the level of expertise required
6. Preference should be given to the
international non-proprietary (generic)
names of medicines.
7
The list should be reviewed periodically
- at least once every two years and
whenever necessary. New treatments
should be introduced only if they offer
distinct
advantages
over
treatments
previously selected; if new information
becomes available on treatments already
in the list which clearly shows that they
no longer have a favourable benefit/risk
ratio, they should be deleted and
replaced by a safer treatment. It should
be remembered that for the treatment of
19
WHO/MNH/MND/93.27
certain conditions no psychotropic drug
treatment at all may be preferable.
and
□ biperiden: other antiparkinsonian drugs.
For the preparation of WHO List of
Essential Drugs (EDL) it was recognized
that there was a need to identify the widest
range of drugs that can be safely and
adequately handled by health workers with
minimum training to perform this task at
the community level. Tliis implies the
development of guidelines for a limited
selection of drugs to be used at the primary
health care level.
As already mentioned in Chapter 1
(page 2), the WHO EDL includes the
following drugs of great relevance for the
treatment of psychiatric disorders:
in Section 24. Psychotherapeutic drugs:
□
amitriptyline
□
chlorpromazine
□
diazepam
□
fluphenazine
□
haloperidol
□
lithium carbonate
Considering this as background, after
extensive consultations and discussions with
experts in different parts in the world, a list
of essential psychiatric medicines - as specific
substances - was compiled and includes:
1. Amitriptyline - a standard tricyclic
antidepressant;
2. Biperiden - a standard antiparkinsonian
drug, for the management of adverse
reactions caused by neuroleptics:
3. Chlorpromazine
phenothiazine neuroleptic;
a
standard
4. Clomipramine - a tricyclic
antidepressant, to be used for the treatment
of specific disorders, e.g. panic attacks and
obsessive-compulsive disorders;
5.
Diazepam - a standard benzodiazepine;
6. Fluphenazine decanoate - a standard
long-acting neuroleptic;
7. Haloperidol - a standard nonphenothiazine neuroleptic (butyrophenone);
in Section 9. Antiparkinsonian drugs:
□
biperiden
It must, however, be noted that the
square symbol preceding the drugs listed
above indicates that those drugs represent
classes of drugs, rather than a specific
substance. They are examples of a therapeutic
group and various drugs could serve as
alternatives. Examples of acceptable
substitutions include:
□
amitriptyline:
antidepressant;
□
chlorpromazine: any other phenothiazine;
□
diazepam: any other benzodiazepine;
any
other
tricyclic
□ fluphenazine: any other injectable long-acting
neuroleptic;
□ haloperidol: any other butyrophenone;
20
8. Imipramine - a standard tricyclic
antidepressant, with a profile of adverse
effects different from that of amitriptyline,
and also used for the treatment of other
specific disorders, e.g. panic attacks and
obsessive-compulsive disorders;
9. Lithium carbonate - a standard drug for
the prophylaxis of bipolar and unipolar
affective disorders;
10. Temazepam
benzodiazepine.
a
short-acting
It should be noted that during this
widespread consultation, the need was felt
for only three additional psychotropic drugs
as compared to the WHO EDL.
This
confirms the adequacy and appropriateness
of a limited number of psychotropic drugs,
sufficient to meeting clinician's needs.
Detailed information on each of these
drugs follows.
WHO/MNH/MND/93.27
6.1.
Amitriptyline
General information
completely eliminated, and then gradually
discontinued (i.e. over 2-3 weeks). In many
cases it may be advisable to take it in a
single dose at bedtime.
Amitriptyline, a dibenzazepine
derivative, is one of the first antidepressants
provided for clinical use. It is still now one
of the standard drugs for the
pharmacological treatment of depression.
Its main metabolite nortriptyline
(demethylated amitriptyline) is also an
equally potent antidepressant agent. It is
well absorbed after oral administration. Its
plasma level reaches the peak 2-4 hours
after oral intake and its half-life ranges from
10 to 20 hours.
The inactivation and
excretion occurs over a period of several
days. There is a wide inter-patient variation
in the metabolism and plasma
concentrations of amitriptyline (and other
tricyclic antidepressants, including
imipramine and clomipramine), to be
discussed below. This is due to the fact that
the metabolism of these antidepressants is
under the control of a polymorphic enzyme.
This may lead, in some patients, to
excessively high drug concentrations even at
normal doses. In particular, this can be true
in the case of subjects of specific ethnic
background (e.g., Asians).
Contraindications
Storage
Amitriptyline should not be used by
pregnant women, and non-drug alternatives
should be used for treating depression
during pregnancy, if needed.
Women taking amitriptyline should not
breast-feed.
Amitriptyline should be stored in wellclosed containers protected from light and
not be allowed to freeze.
Clinical information
Uses
Treatment of depressive disorders.
Dosage and administration
It is advised to start with a lower dose
(45-60 mg/day) the first day and increase
the dose gradually to 75-300 mg/day within
a few days or weeks. When it is seen that
the drug is effective enough and adverse
effects are well-tolerated, the dose should be
maintained until depressive symptoms are
sufficiently improved and then gradually
reduced to a lower dose. The treatment
should be continued for at least 2 to 4
months even after the symptoms are
Closed-angle glaucoma.
Severe cases of heart, kidney and liver
diseases, particularly in the period
following an acute myocardial
infarction.
Marked malnutrition.
Impending danger of suicidal attempt.
Precautions
The dosage should be reduced in elderly
patients, and in patients with former cardiac
disease. Routine examination of cardiac,
hepatic and other functions should be
performed during the course of treatment.
Ambulatory patients should take extra
precautions while driving or operating
machinery during treatment with
amitriptyline since reaction times can be
impaired by the drug, especially with
higher dosages and at the start of the
treatment.
Use in pregnancy and in breast-feeding
Adverse effects
Because of its central H!-alpha!adrenergic receptor blockade properties,
amitriptyline is more sedating than most
antidepressants. This may help if insomnia
is a problem, but it may also cause daytime
drowsiness - especially early in the course
of treatment. The most common and
troublesome side-effects of amitriptyline are
also due to its anticholinergic effects, which
may produce dry mouth, gastric discomfort,
constipation, blurred vision, dysuria,
urinary retention, increased heart rate,
precipitation of close-angle glaucoma.
Older patients suffer more from these
anticholinergic effects.
Orthostatic
hypotension, dizziness and sleepiness are
also observed in some patients. These side21
WHO/MNH/MND/93.27
effects, if not marked, may often be
considerably lessened within a few weeks
(generally three) while taking the same
amount of the drug.
Persistent fine tremor, skin rashes,
obstructive jaundice, and mild parkinsonian
syndrome may appear occasionally. There
may be complaints about sexual difficulties
such as erectile difficulties and delayed
ejaculation. Delirium can be induced in as
many as 6% of patients who get standard
doses of this drug.
Drug interactions
Side-effects and sedative effects of
amitriptyline are potentiated by neuroleptic,
anxiolytic and hypnotic drugs and alcohol
in various ways, depending on the
pharmacological actions of each drug.
Clinically, benzodiazepines are often used in
association with amitriptyline to alleviate
anxiety and insomnia of depression.
22
Particularly important is the interaction of
amitriptyline with mono-amine oxidase
inhibitors (MAOI): this interaction is
especially dangerous and must be avoided.
Overdosage
Acute ingestion of amitriptyline (and
other tricyclic antidepressants) can be fatal
in the dose range of 1-2 g or more. Smaller
doses can also be dangerous in children and
in those with pre-existing illness. Signs of
overdose include difficulty breathing, shock,
agitation, delirium and coma.
Gastric lavage should be carried out
without delay. Patients should be treated in
an intensive care unit, with continuous
monitoring of vital signs and
electrocardiogram (ECG). It is reported that
physostigmine salicylate 1 to 4 mg
intramuscularly may reverse the
anticholinergic manifestations of severe
poisoning, such as coma, delirium and
myoclonus.
WHO/MNH/MND/93.27
6.2
Biperiden
Contraindications
Known hypersensitivity to biperiden.
Closed-angle glaucoma.
Enlarged prostate, mechanical stenosis
of the gastrointestinal tract, megacolon,
lung atonia.
Myasthenia gravis.
General information
Biperiden is one of the antiparkinsonian
drugs used to treat Parkinson's disease and
to control extra-pyramidal adverse effects
(EPSEs) commonly provoked by
antipsychotic drugs, which include the
classical 'parkinsonian' triad of
bradykinesia, rigidity and tremor. Other
EPSEs include akathisia, dystonic reactions
and excessive salivation. The prevalence of
EPSEs seems to vary widely across studies;
an overall figure of around 40%, among
those in treatment with neuroleptics, seems
the most reasonable estimate of the
prevalence of EPSEs (10).
Biperiden, as other antiparkinsonian
drugs, decreases stiffness and tremors and
improves muscle control, and this action is
obtained through a marked central
anticholinergic action; the drug also has
peripheral cholinergic blocking effects.
Biperiden is well absorbed after oral
administration. It is already ascertainable in
the plasma 30 minutes after first
administration, and its half-life lasts several
hours. The metabolism of this drug occurs
through hydroxylation, and its metabolites
are largely excreted in the urine.
Clinical information
Uses
Treatment of Parkinsonian side effects
associated with the administration of
antipsychotic medicines.
Dosage and administration
It is advised to start with 2 mg/day and
increase the dose up to a maximum of 6-8
mg daily, depending on response and
tolerance. For the treatment of acute
dystonic reactions it is possible to
administer the drug i.m. or in slow i.v.
infusion; in this case the daily dosage is in
the range of 5-10 mg/day.
Precautions
As stated in a WHO Consensus
Statement (11 - see the Appendices), the
prophylactic use of anticholinergics in
patients on neuroleptic treatment is not
recommended and may be justified only
early in treatment (after which it should be
discontinued and its need should be re
evaluated). As a rule, anticholinergic drugs
should be used only when Parkinsonism
has actually developed, and when other
measures, such as the reduction of
neuroleptic dosage or the substitution of the
administered drug by another less prone to
induce Parkinsonism, have proven
ineffective.
This drug should be used cautiously in
patients suffering from heart problems
(especially patients with a recent myocardial
infarction or cardiac arrhythmias), or in
patients with urinary problems due to
enlarged prostate.
Use in pregnancy and in breast-feeding
Although there are no final data
showing that biperiden may increase
occurrence of fetal damage, it is advisable,
except in highly selected cases,
for
pregnant women not to use this drug.
Women taking biperiden should not breast
feed, since it is still unclear in which
quantity biperiden is present in maternal
milk.
Adverse effects
As with other antiparkinsonian drugs,
biperiden can cause anticholinergic effects,
represented by drowsiness, dry mouth,
gastric discomfort, constipation, blurred
vision, dysuria, urinary retention,
tachycardia and dysrhythmias, precipitation
of close-angle glaucoma. Older patients
suffer more from these anticholinergic
effects. In some patients, especially in the
23
WHO/MNH/MND/93.27
elderly, this drug can cause psychiatric
disturbances ranging from mild memory
problems to acute confusional states.
Drug interactions
Additive effects may become visible
when other drugs having anticholinergic
properties, such as tricyclic antidepressants
and antihistamines are used at the same
time with biperiden.
24
Overdosage
In cases of gross overdosage an initial
acute hyperactivation is followed by
depression of the central nervous system.
Disturbances of the CNS, resulting in
psychosis, hypersensitivity to external
stimuli, may be followed by circulatory
collapse, hypotension and coma. Death may
occur due to respiratory failure. The
treatment is only symptomatic and
supportive.
9
WHO/MNH/MND/93.27
6.3.
Chlorpromazine
Clinical information
Uses
General information
Chlorpromazine belongs to the
phenothiazine group of antipsychotics and
is an aliphatic class phenothiazine. It is
generally not so well absorbed from
gastrointestinal tract and injection sites, with
significant first pass metabolism in the liver
following an oral administration. Several
metabolites are active. Peak blood levels
occur after 1.5-3 hrs of oral administration
and 30 minutes of IM injections.
Chlorpromazine has a plasma half-life of 6-8
hrs and steady state plasma levels are
reached in 5-7 days. It should be noted that
the steady state is reached at a slower pace
in comparison with the statement made on
page 17, section 5, because of the presence
of active metabolites with longer half-lives.
Chlorpromazine is an enzyme inducer,
thereby decreasing its own plasma
concentrations after a few weeks of
administration and then stabilizing at this
lower level. There are also substantial
interpatient variations in plasma
concentrations and daily variations in the
same patient. For these various reasons the
correlations between plasma concentration
and clinical response have been minimal
and not very significant, although generally
positive. Thus, currently, plasma
antipsychotic concentrations, however
measured, do not usefully predict response
in psychotic patients and are not to be
recommended in routine clinical situations.
Distribution in the body is rapid, with
highest concentration occurring in the liver,
lungs, spleen and adrenal glands; within the
CNS highest concentrations are found in
hypothalamus, basal ganglia, thalamus and
hippocampus. Chlorpromazine remains
bound to tissues for long periods and
metabolites are excreted for up to 6 months.
Storage
Chlorpromazine should be stored in
well-closed containers protected from light
and should not be allowed to freeze.
Chlorpromazine is a low-potency
antipsychotic used in the acute and long
term management of schizophrenia and
other psychotic disorders, including acute
and transient psychotic disorders, mania
and organic mental disorders. It is
sometimes used to treat severe psychiatric
problems in children. This drug is quite
sedating, and often causes hypotension, in
particular if administered by IM injection.
The sedative properties may be beneficial in
calming people with acute agitation or
violent behaviour.
The clinical efficacy of chlorpromazine
as an antipsychotic agent is probably due to
its affinity for dopamine receptors,
particularly D2 receptors. It possesses
powerful adrenergic receptor blocking
properties as well as some cholinergic and
histamine receptor blocking properties.
Its other effects include ganglion
blocking, quinidine-like, and atropine-like
activities and local anaesthetic actions.
Dosage and administration
Acute phase: 300-800 or more mg/per day.
In the acute phase chlorpromazine may
eventually be administered by an intra
muscular injection in a dose of 100-200 mg
which can be repeated while observing the
patient for possible hypotension. However,
IM administration may cause sterile
abscesses, is acutely painful and is not seen
as appropriate by many clinicians; therefore
oral administration is to be preferred
whenever possible. A maximum daily dose
of up to 1,200-1,600 mg may be necessary,
although doses above 800 mg per day are
rarely required.
Early Treatment: 300-800 mg/per day.
400 mg/day in divided doses is an
adequate treatment for most patients.
However, dosage of up to 800 mg can be
administered provided the patient is closely
monitored for hypotension, which can be a
serious side effect.
Various patients respond to widely
different doses and it is reasonable to start
with a lower dose and increase it as
necessary. It is important to remember that
25
WHO/MNH/MND/93.27
maximal effect of a particular dose may
only be evident after 4-6 weeks.
Maintenance treatment: 100-500 mg/per day.
In the maintenance phase the drug
should be given for at least 6 months
following improvement, the dosage then
being reduced by 50% gradually over 3-6
months and another 50% after another 6
months. In general, maintenance doses
should be as low as possible and still be
able to control the psychotic symptoms. All
dosages indicated above may be reduced in
very hot climates and with special ethnic
groups (e.g., Asians).
Contraindications
Known hypersensitivity to
phenothiazine derivatives (since cross
sensitivity may occur).
Impaired consciousness due to cerebral
depression.
Cardiovascular or liver disease.
Precautions
Chlorpromazine should be used in
reduced dosages in the elderly and in
patients with cardiovascular insufficiency,
Parkinson's disease, hepatic or renal
insufficiency.
Ambulatory patients should take extra
precautions while driving or operating
machinery during treatment with
chlorpromazine since reaction times can be
impaired by the drug, especially with
higher dosages and at the start of the
treatment.
Use in pregnancy and in breast-feeding
Chlorpromazine should not be used in
pregnant women, unless there is a very
urgent need of control of a severe
psychiatric psychotic condition affecting the
mother for which the need outweighs any
possible risk to the fetus.
Women taking chlorpromazine should
not breast-feed.
Adverse effects
Orthostatic hypotension is quite
common in patients treated with
chlorpromazine and is due to the alphaadrenergic blocking actions of the drug,
which also cause delayed or iinhibited
.... ........
26
ejaculation. This adverse effect is more
common and may be particularly severe in
elderly patients.
Other side effects include acute dystonic
reactions, akathisia, drowsiness, ECG
changes, anticholinergic effects (e.g., dry
mouth, constipation, blurring of vision,
difficulty in micturition), weight gain,
menstrual irregularities, gynaecomastia,
reduced libido and impotence in males,
seizures, skin pigmentation. Because of this
latter adverse effect, chlorpromazine should
be used with particular caution in sunny
climates, and eventually other antipsychotic
medicines should be preferred.
Parkinsonism is the commonest
neurological adverse effect of
chlorpromazine, as well as of the other
neuroleptics. In its mildest forms it is
represented by bradykinesia and akinesia,
while in more severe forms it is represented
by loss of associated movements, rigidity,
stooped posture, mask-like facies, excess
salivation and seborrhoea. It is more
common in women, in the elderly and in
patients who have relatives with idiopathic
parkinsonism. It usually appears within the
first two months of treatment, and some
degree of tolerance to this extrapyramidal
effect develops within a few months. At a
dosage of 600 mg of chlorpromazine per
day, it has an incidence of 15-25 per cent
among patients consuming this drug.
Prolonged use of chlorpromazine is
associated with increased risk of developing
tardive dyskinesia (TD), a potentially
irreversible side effect involving disfiguring
movements of the face, tongue and limbs
(see section on TD).
Idiosyncratic reactions to
chlorpromazine include agranulocytosis,
cholestatic jaundice, malignant neuroleptic
syndrome and light sensitive dermatoses.
Cholestatic jaundice is perhaps allergic in
nature since fever, eosinophilia, and rashes
generally accompany the syndrome. The
jaundice is generally benign, and it remits
when the drug is stopped. Neuroleptic
malignant syndrome is a severe condition
provoked by the association of antipsychotic
drugs (especially chlorpromazine,
haloperidol and fluphenazine) with
muscular rigidity, hyperthermia, autonomic
dysfunction, leucocytosis and increase in
creatine-phosphokinase activity. The
incidence of neuroleptic malignant
syndrome is less than 0.5 per cent of
patients taking antipsychotic drugs but
WHO/MNH/MND/93.27
mortality of this condition is about 20 per
cent.
Anticonvulsants: Barbiturates increase
the metabolism of chlorpromazine and
chlorpromazine lowers seizure threshold.
Drug interactions
Anticholinergics: These drugs decrease
the absorption and additive anticholinergic
activity may result in anticholinergic
toxicity.
They further enhance the
probability
of tardive dyskinesia.
Antacids and Cimetidine: These reduce
the absorption of chlorpromazine.
Anticoagulants:
Chlorpromazine
reduces plasma concentration of warfarin.
Overdosage
CNS depressants (Alcohol, opioids,
antihistamines and sedatives):
Chlorpromazine
further potentiates
their CNS depressant activity.
Antidepressants:
If administered
simultaneously with chlorpromazine, they
each decrease the metabolism of the other,
resulting in increased plasma concentrations
of both. The anticholinergic, sedative and
hypotensive effects of these drugs may also
be additive.
Symptoms include light-headedness,
sedation, confusion, agitation, disorientation,
restlessness, convulsions, fever and coma.
Treatment is usually symptomatic and
hypotension can be especially difficult to
counteract, noradrenalin being relatively
ineffective because of the alpha adrenergic
blockade. The use of drugs acting on the
blood vessels, such as angiotensin, has been
suggested.
27
WHO/MNH/MND/93.27
6.4.
Clomipramine
General information
Clomipramine is a dibenzazepine
derivative: its main metabolite desmethylclomipramine (desmethylated clomi
pramine) is also an equally potent
antidepressant agent; it has a half-life of
about 3 days and its steady state
concentrations are usually 2.5 higher than
those of the parent compound. It is well
absorbed after oral administration.
Its
plasma level reaches a peak 2-4 hours after
oral intake and the half-life ranges from 10
to 20 hours. The inactivation and excretion
occurs over a period of several days. There
is a wide inter-patient variation in the
metabolism and plasma concentrations of
clomipramine (and other tricyclic
antidepressants).
Storage
Clomipramine should be stored in wellclosed containers protected from light and
should not be allowed to freeze.
Clinical information
Uses
Clomipramine, although a tricyclic
antidepressant and therefore encompassed
within this category under imipramine, has
been added to the list of essential drugs
because it has been recommended
specifically for the treatment of obsessivecompulsive disorders and panic attacks.
Like imipramine it can also be used to treat
depression and panic attacks with or
without agoraphobia.
Dosage and administration
For the treatment of depression, and
panic attacks, the same advice holds as for
imipramine. should be continued for 2 to 4
months even after the symptoms are
completely eliminated, and then gradually
discontinued.
For the treatment of OCD,
clomipramine may be administered at a
higher dosage in order to be therapeutically
effective. Therefore, it is usually advisable
28
to start at a dosage of 25-50 mg per day,
administered in a single dose at bedtime.
The dose then can be increased by 25-20 mg
every second day.
It seems that the
desirable dosage is in the range of 200-300
mg per day, but if the patient cannot
tolerate a dose in this range, a lower dosage
can be administered.
For panic attacks
dosage is similar to those indicated for
depression.
There are scanty data as regards the
length of treatment with clomipramine in
OCD.
Some authors recommend
maintaining the patient for many months
(even more than 12 months) before
attempting to discontinue the treatment.
Contraindications
Closed-angle glaucoma.
Severe cases of heart, kidney and liver
diseases, particularly in the period
following an acute myocardial
infarction.
Marked malnutrition.
Impending danger of a suicidal
attempt.
Precautions
The dosage should be reduced in elderly
patients, and in patients with former cardiac
disease. Routine examination of cardiac,
hepatic and other functions should be
performed in the course of treatment.
This drug should not be used
simultaneously with monoamine-oxidase
inhibitors or within two weeks after
withdrawal of these agents.
Ambulatory patients should take extra
precautions while driving or operating
machinery during treatment with
clomipramine since reaction times can be
impaired by the drug, especially with
higher dosages and at the start of the
treatment.
Use in pregnancy and in breast-feeding
Clomipramine should not be used in
pregnant women, and non-drug alternatives
should be used for treating depression in
pregnancy.
Women taking clomipramine should not
breast-feed.
WHO/MNH/MND/93.27
Adverse effects
The most common and troublesome
side-effects of clomipramine are represented
by its anticholinergic effects, which may
produce dry mouth, gastric discomfort,
constipation, blurred vision, dysuria,
urinary retention, increased heart rate,
precipitation of close-angle glaucoma.
Older patients suffer more from these
anticholinergic effects.
Orthostatic
hypotension, dizziness and sleepiness are
also observed in some patients. These side
effects, if not marked, may often be
considerably lessened within a few weeks
(generally three) while taking the same
amount of the drug.
Complaints of sexual difficulties such as
erectile difficulties, delayed ejaculation may
sometimes occur. Delirium can be induced
in aged patients.
Drug interactions
Side-effects of clomipramine are
potentiated by neuroleptics,
benzodiazepines and hypnotic drugs, and
alcohol, in various ways depending on the
pharmacological actions of each drug.
Clinically, benzodiazepines are often used in
association with clomipramine to alleviate
anxiety and insomnia of depression.
Particularly important is the interaction of
clomipramine with MAO inhibitors: this
interaction is especially dangerous and must
be avoided. Antidepressants and
phenothiazines can also interact between
themselves, and under these circumstances
TCA concentrations may reach toxic levels.
Overdosage
Acute ingestion of clomipramine (and
other tricyclic antidepressants) can be fatal
in the dose range of 1-2 g or more. Smaller
doses can also be dangerous in children and
in those with pre-existing illness. Signs of
overdose include difficulty breathing, shock,
agitation, delirium and coma.
Gastric lavage should be carried out
without delay. Patients should be treated in
an intensive care unit, with continuous
monitoring of vital signs and ECG. It is
reported that 1 to 4 mg of physostigmine
salicylate given intramuscularly may reverse
the anticholinergic manifestations of severe
poisoning, such as coma, delirium and
myoclonus.
29
WHO/MNH/MND/93.27
Diazepam
6.5
Precautions
Diazepam is a benzodiazepine with
anxiolytic and sedative/hypnotic properties,
a centrally mediated muscle-relaxant effect
and, if used intravenously, an
anticonvulsant action. It is metabolized in
the liver to several metabolites, which are
mainly excreted in the urine as
glucuronides.
The response, which persists for 12-24
hours, becomes evident 30-90 minutes after
oral administration and 1-5 minutes after
intravenous injection. The plasma half-life is
20-50 hours.
In case of i.v. administration, equipment
for resuscitation should be immediately
available.
Diazepam should be administered with
particular caution to patients with
myasthenia gravis as well as to patients
with obstructive airway disease, who are at
risk of respiratory depression. Diazepam
should be used with great caution, in
substantially lower doses, and only when
essential in elderly and debilitated patients,
and in patients with chronic pulmonary
insufficiency or chronic renal or hepatic
disease.
Ambulatory patients should take extra
precautions while driving or operating
machinery during treatment with diazepam
since reaction times can be impaired by the
drug, especially with higher dosages.
Storage
Tolerance and dependence
Diazepam should be stored in tightly
closed containers protected from light.
Diazepam administration, as for any
other BDZ, can be associated with the
development of tolerance and dependence
phenomena. They are discussed in detail in
Section 12.3.
General information
Clinical information
Use
Use in pregnancy and in breast-feeding
In psychiatry diazepam is used
primarily to provide short-term relief for
mild to moderate anxiety; it is also used to
treat symptoms of acute alcohol withdrawal.
Use in pregnancy should be avoided
whenever possible. Some studies have
reported an increased incidence of
malformations among infants bom to
mothers who were administered diazepam
during the first trimester of pregnancy,
although other, large-scale prospective
studies have failed to confirm these results.
Dosage and administration
For the relief of symptoms of anxiety,
the drug is used orally at a dosage ranging
between 2 and 5 mg per day, with the
possibility of increasing the dosage as
needed to control symptoms. The maximum
daily dosage does not generally exceed 40
mg.
For the treatment of symptoms of acute
alcohol withdrawal, diazepam is generally
used in i.v. infusion at the dose of 10-20 mg
as needed, and is eventually repeated.
Contraindications
Age less than 12 years.
Known hypersensitivity
benzodiazepines.
30
Adverse effects
Paradoxical reactions, including
irritability, disinhibition, excitability,
hallucinations, increased muscle spasticity
and sleep disturbances have been reported,
particularly in elderly patients and in
children.
Rare but serious adverse reactions
include leucopenia, jaundice and
hypersensitivity reactions.
Drug interactions
to
The effects of phenothiazines,
barbiturates, monoamine-oxidase inhibitors
4
WHO/MNH/MND/93.27
and other
potentiated.
antidepressants
may
be
Overdosage
Signs of overdosage include somnolence,
ataxia, dysarthria, diminished reflexes,
confusion and coma. Paradoxical excitement
may occur in children. Unless the specific
benzodiazepine antagonist flumazenil is
available, treatment should be symptomatic
and directed to the management of
respiratory depression and shock.
(si
\ <v eV
*5
V
/
J
31
WHO/MNH/MND/93.27
6.6
Fluphenazine Decanoate
General information
Fluphenazine decanoate is a depot drug
consisting of a pro-drug, an esterase of the
active ingredient (fluphenazine) held in an
oily vehicle. Its slow release from the
vehicle is the step which determines the
drug's effective half-life. The drug is
injected i.m. into gluteal (or deltoid) muscle,
every 2 to 4 weeks. This drug may have
three main advantages over oral
neuroleptics:
1.
avoidance of first-pass hepatic
metabolism which may be a source of
wide variation in plasma levels;
2.
prevention of deliberate or accidental
overdose;
3.
improved compliance.
The last of these factors circumvents the
patient's unreliability and ambivalence at
taking tablets, especially when supervision
is minimal. However, injections may not be
acceptable to all subjects and determined
non-cooperation is a barrier to treatment via
any route.
Storage
Fluphenazine decanoate should be
stored in well-closed containers protected
from light and should not be allowed to
freeze.
Dosage and administration
Fluphenazine decanoate is
therapeutically active even at very small
doses. Because of a large inter-individual
variability in plasma concentrations, doses
should be carefully adjusted to the needs
and response of each patient. Age, severity
of symptoms, and general conditions should
be taken into account. There is often the
need for an upward titration in the acute
phase and a gradual reduction in the
maintenance phase. However, since the
effective half-life is about 22 days, adjusting
the dose by looking at changes in target
symptoms actually requires adequate time.
It should also be mentioned that it takes
some 2-5 months to wash out a person on
this depot medication should the physician
wish to stop medication.
When used for maintenance therapy,
12.5-50 mg every 15-30 days should be
regarded as an average dose.
Recent well-designed studies seem to
show that even lower dosages (as low as 2.5
mg every 15-30 days) may represent an
effective maintenance treatment.
Contraindications
Known hypersensitivity to
phenothiazines.
Impaired consciousness due to
cerebral depressants or of other
origin.
Precautions
Ambulatory patients should take extra
precautions while driving or operating
machinery during treatment with
fluphenazine decanoate since reaction times
can be impaired by the drug, especially
with higher dosages and at the start of the
treatment.
Use in pregnancy and in breast-feeding
Clinical information
Uses
Fluphenazine decanoate is a highpotency antipsychotic used as maintenance
treatment of people with a reliable diagnosis
of schizophrenia.
32
Fluphenazine decanoate should not be
used in pregnant women, unless there is a
very urgent need for control of a severe
psychiatric psychotic condition affecting the
mother for which the need outweighs any
possible risk to the fetus.
Women taking fluphenazine decanoate
should not breast-feed.
WHO/MNH/MND/93.27
Adverse effects
The earliest neurological effect arising in
the course of a treatment with fluphenazine
decanoate is acute dystonia, which may be
seen even after a single dose of the drug. It
occurs in some 2.5-5% of patients treated
with antipsychotic drugs and it is more
common in men and children than in
women. The features of this side effect
include torticollis, retrocollis, facial grimaces
and distortion, tongue protrusion,
dysarthria, opisthotonus, scoliosis, and
oculogyric crises.
Parkinsonism is the commonest
neurological adverse effect of fluphenazine
decanoate. In its mildest forms it is
represented by bradykinesia and akinesia,
while in more severe forms it is represented
by loss of associated movements, rigidity,
stooped posture, mask-like facies, excess
salivation and seborrhoea. It is more
common in women, in the elderly and in
patients who have relatives with idiopathic
parkinsonism. It usually appears within the
first two months of treatment, although
acute EPS can be seen within the first 24
hours of injection - a release peak from the
depot site. It is important to be aware of
this in order to prevent long term
anticholinergic prophylaxis being initiated
incorrectly. Some degree of tolerance to this
extrapyramidal effect develops within a few
months. It has an incidence of 15-25 per cent
among patients treated with fluphenazine.
Other adverse effects of fluphenazine
decanoate include akathisia, depression,
vertigo, confusion, seizures,
hyperprolactinemia, lactation, menstrual
irregularities, hyperglycaemia, tachycardia,
hypotension, dysrhythmias, EEG changes,
anorexia, constipation, dyspepsia, skin
rashes, photosensitivity, leucopenia.
Idiosyncratic reactions to fluphenazine
decanoate include agranulocytosis and
malignant neuroleptic syndrome.
Neuroleptic malignant syndrome is a severe
condition provoked by the association of
antipsychotic drugs (especially
chlorpromazine, haloperidol and
fluphenazine) with muscular rigidity,
hyperthermia, autonomic dysfunction,
leucocytosis and increase in creatine
phosphokinase activity. Its incidence is less
than 0.5 per cent of patients taking
antipsychotic drugs but the mortality is
about 20 per cent among patients suffering
from neuroleptic malignant syndrome.
Prolonged use of fluphenazine
decanoate is associated with increased risk
of developing tardive dyskinesia (TD), a
potentially irreversible side effect involving
disfiguring movements of the face, tongue
and limbs (see section on TD).
Drug interactions
Anticholinergics: These drugs decrease
the absorption and additive anticholinergic
activity may result in anticholinergic
toxicity.
They further enhance the
probability of tardive dyskinesia.
CNS Depressants (Alcohol, opioids,
antihistamines and sedatives):
Fluphenazine further potentiates their CNS
depressant activity.
Antidepressants:
If administered
simultaneously with fluphenazine, they each
decrease the metabolism of the other,
resulting in increased plasma concentrations
of both. The anticholinergic, sedative and
hypotensive effects of these drugs may also
be additive.
Anticonvulsants: Barbiturates increase
the metabolism of fluphenazine and
fluphenazine lowers seizure threshold.
33
WHO/MNH/MND/93.27
6.7
Haloperidol
moderate symptoms: 1.0-4.0 mg per
day;
severe symptoms: 3.0-15 mg per day
maintenance therapy: 2.0-6.0 mg per
day.
*
General information
Haloperidol is an antipsychotic drug of
the butyrophenone series. It functions as a
potent neuroleptic which blocks dopamine
receptors, particularly D2 receptors, in the
CNS. It has a mean plasma half-life of 24
hours and is metabolized in the liver, being
excreted in the faeces and urine. In addition
to the central dopamine blocking effects,
haloperidol also shows antiemetic properties
and induces relaxation of gastrointestinal
sphincters and increases prolactin release. It
does not have antihistaminic or
anticholinergic activities.
Even recent trials have shown that
dosages higher than 15 mg/day of
haloperidol for most patients have no
additional beneficial effect in the treatment
of acute or exacerbated schizophrenia.
Contraindications
known hypersensitivity
butyrophenones;
impaired consciousness due
cerebral depressants or drugs
other origin;
history of seizures.
to
to
of
Storage
Precautions
Haloperidol should be stored in wellclosed containers protected from light and
should not be allowed to freeze.
Clinical information
Uses
34
Ambulatory patients should be warned
not to drive or operate machinery during
treatment with haloperidol since reaction
times can be impaired by the drug,
especially with higher dosages and at the
start of the treatment.
Use in pregnancy and in breast-feeding
Haloperidol is a high-potency
antipsychotic used to treat people with a
reliable diagnosis of schizophrenia or
schizophrenia-like disorders. It can also be
used for the treatment of organic, including
symptomatic, mental disorders, when the
clinical picture is characterized by
disorganized and/or excited behaviour; for
the treatment of manic episodes and finally
of acute and transient psychotic disorders.
Haloperidol should not be used in
pregnant women, unless there is a very
urgent need of control of a severe
psychiatric psychotic condition affecting the
mother for which the need outweighs any
possible risk to the fetus.
Women taking haloperidol should not
breast-feed.
Dosage and administration
Adverse effects
Haloperidol is therapeutically active
even at very small doses. It can be given in
liquid form as taste-free drops. Because of a
large inter-individual variability in plasma
concentrations, doses should be carefully
adjusted to the needs and response of each
patient. Age, severity of symptoms, and
general conditions should be taken into
account. There is often the need for a higher
dosage in the acute phase and a gradual
reduction in the maintenance phase. When
used as an antipsychotic, the following
doses should be regarded as an average:
The earliest neurological effect arising in
the course of a treatment with haloperidol is
acute dystonia, which may be seen even
after a single dose of the drug. It occurs in
some 2.5-5% of patients treated with
antipsychotic drugs and it is commoner in
men and children than in women. The
features of this side effect include torticollis,
retrocollis, facial grimaces and distortion,
tongue protrusion, dysarthria, opisthotonus,
scoliosis, and oculogyric crises.
Parkinsonism is the commonest
neurological adverse effect of haloperidol.
WHO/MNH/MND/93.27
In the mildest forms it is represented by
bradykinesia and akinesia, while in the
more severe forms it is represented by loss
of associated movements, rigidity, stooped
posture, mask-like facies, excess salivation
and seborrhoea. It is more common in
women, in the elderly and in patients who
have relatives with idiopathic parkinsonism,
whereas it is more likely to occur in its
severe forms in young males. It usually
appears within the first two months of
treatment, and some degree of tolerance to
this extrapyramidal effect develops within a
few months. It has an incidence of 15-25 per
cent. Akathisia is another disturbing and
serious adverse effects, which often leads to
poor compliance.
Haloperidol, compared with other
neuroleptics, causes less hypotension,
sedation and cardiovascular side-effects; at
usual doses it does not have anticholinergic
effects. However, it causes more
extrapyramidal side-effects due to its
blocking activity at the level of the basal
ganglia.
Other adverse effects of haloperidol
include akathisia, depression, vertigo,
confusion, seizures, hyperprolactinemia,
lactation, menstrual irregularities,
hyperglycaemia, tachycardia, hypotension,
dysrhythmias, EEG changes, anorexia,
constipation, dyspepsia, skin rashes,
photosensitivity, leucopenia.
In addition, sudden and unexplained
cases of death have been reported in a few
patients receiving haloperidol. It has been
impossible to determine the role of the drug
in the occurrence of the sudden death.
Idiosyncratic reactions to haloperidol
include agranulocytosis and malignant
neuroleptic syndrome. Neuroleptic
malignant syndrome is a severe condition
provoked by the assumption of
antipsychotic drugs (especially
chlorpromazine,
haloperidol
and
fluphenazine) with muscular rigidity,
hyperthermia and autonomic dysfunction.
Its incidence is less than 0.5 per cent of
patients taking antipsychotic drugs but the
mortality is about 20 per cent.
Prolonged use of haloperidol is
associated with increased risk of developing
tardive dyskinesia (TD), a potentially
irreversible side effect involving disfiguring
movements of the face, tongue and limbs
(see section on TD).
Drug interactions
Anticholinergics: These drugs decrease
the absorption and additive anticholinergic
activity may result in anticholinergic
toxicity.
They further enhance the
probability of tardive dyskinesia.
CNS depressants (Alcohol, opioids,
antihistamines and sedatives): Haloperidol
further potentiates their CNS depressant
activity.
Antidepressants:
If administered
simultaneously with haloperidol, they each
decrease the metabolism of the other,
resulting in increased plasma concentrations
of both. The sedative and hypotensive
effects of these drugs may also be additive.
Anticonvulsants: Barbiturates increase
the metabolism of haloperidol and
haloperidol lowers seizure threshold.
Overdosage
Symptoms include light-headedness,
sedation, confusion, agitation, disorientation,
restlessness, shock, muscle tremors and
coma. Treatment is usually symptomatic.
Gastric lavage is of value if undertaken
within a few hours of ingestion. Emetics
may be ineffective. Oxygen and assisted
ventilation are required in the event of a
respiratory depression. Seizures may be
controlled with diazepam.
35
WHO/MNH/MND/93.27
Imipramine
6.8
General information
Imipramine was one of the first
antidepressants provided for clinical use,
and is still widely used for the
pharmacological treatment of depression. It
is also used for the treatment of panic
attacks with or without agoraphobia. Its
main metabolite desipramine (demethylated
imipramine) is also an equally potent
antidepressant agent. It is well absorbed
after oral administration. Its plasma level
peaks 2-4 hours after oral intake and the
half-life ranges from 8 to 20 hours, and
between 10 and 30 hours for its main
metabolite desipramine. The inactivation
and excretion occurs over a period of
several days.
There is a substantial
presystemic metabolism which reduces the
systemic availability of the drug to 27-77%
of the dosage. There is a wide inter-patient
variation in the metabolism and plasma
concentrations of imipramine (and other
tricyclic antidepressants).
Storage
Imipramine should be stored in wellclosed containers protected from light and
not allowed to freeze.
Antipanic dosages are approximately the
same to begin with, although they may also
be increased to 200 mg or even higher to
become effective.
Contraindications
closed-angle glaucoma;
severe cases of heart, kidney and liver
diseases, particularly in the period
following an acute myocardial
infarction;
impending danger of suicidal attempt.
Precautions
The dosage should be reduced in elderly
patients, and in patients with former cardiac
disease. Routine examination of cardiac,
hepatic and other functions should be
performed in the course of treatment.
This drug should not be used
simultaneously with monoamine-oxidase
inhibitors or within two weeks after
withdrawal of these agents.
Ambulatory patients should be warned
not to drive or operate machinery during
treatment with imipramine since reaction
times can be impaired by the drug,
especially with higher dosages and at the
start of the treatment.
Use in pregnancy and in breast-feeding
Clinical information
Treatment of depressive disorders.
Treatment of panic attacks with or without
agoraphobia.
Imipramine should not be used in
pregnant women, and non-drug alternatives
should be used for treating depression in
pregnancy.
Women taking imipramine should not
breast-feed.
Dosage and administration
Adverse effects
It is advisable to start with a lower dose
(25-50 mg/day) the first day and increase
the dose slowly - in order to reduce adverse
effects - to a maximum of 300 mg within a
few days or weeks. When it is seen that the
drug is effective enough and adverse effects
are well tolerated, the dose should be
maintained until depressive symptoms are
sufficiently improved and then gradually
reduced to a lower dose.
The treatment should be continued for 2
up to 6 months after the disappearance of
the symptoms, and then gradually
discontinued over 1-2 months.
The most common adverse effects of
imipramine are represented by its
anticholinergic effects, which may produce
dry mouth, gastric discomfort, constipation,
blurred vision, dysuria, urinary retention,
increased heart rate, precipitation of close
angle glaucoma. Older patients suffer more
from these anticholinergic effects.
Orthostatic hypotension, dizziness and
sleepiness are also observed in some
patients. These adverse effects, will often
decrease within a few weeks (generally
three) even while the patient remains on the
same dose. If side effects are severe, a
lower dose of drug may be tried.
Uses
36
1
WHO/MNH/MND/93.27
Drug interactions
Overdosage
Side-effects of imipramine are
potentiated by neuroleptics,
benzodiazepines and hypnotic drugs and
alcohol, in various ways depending on
pharmacological actions of each drug.
Clinically, benzodiazepines are often used in
association with imipramine to alleviate
anxiety and insomnia frequent in depressive
states.
Particularly important is the
interaction of imipramine with MAO
inhibitors: this interaction is especially
dangerous and must be avoided.
Antidepressants and phenothiazines can
also interact between themselves, and under
these circumstances TCA concentrations
may reach toxic levels.
Acute ingestion of imipramine (and
other tricyclic antidepressants) can be fatal
in the dose range of 1-2 g or more. Smaller
doses can also be dangerous in children and
in those with pre-existing illness. Signs of
overdose include difficulty in breathing,
shock, agitation, delirium and coma.
Gastric lavage should be carried out
without delay. Patients should be treated in
an intensive care unit, with continuous
monitoring of vital signs and ECG. It is
reported that 1 to 4 mg of physostigmine
salicylate given intramuscularly may reverse
the anticholinergic manifestations of severe
poisoning, such as coma, delirium and
myoclonus.
I.
37
WHO/MNH/MND/93.27
Lithium Carbonate
6.9
General information
Lithium carbonate (and other soluble
lithium salts, active ingredient: the lithium
ion) is mainly used for the amelioration or
prevention of relapses in bipolar and
unipolar affective disorders but can also be
employed in the treatment of mania or
hypomania..
The mechanism of action may involve
modulation of second messenger systems
(cyclic adenosine monophosphate and
guanosine monophosphate, the
phosphoinositide cycle, G-protein).
Lithium is not metabolized in the
organism, and it is excreted almost
exclusively through the kidneys. Under
normal circumstances the renal lithium
clearance is about one-fourth of the
creatinine clearance, and its half-life is 24-30
hours.
Storage
Tablets should be stored protected from
light and out of the reach of children.
Monitoring of serum lithium levels is
needed in order to keep lithium at safe
blood concentrations.
The recommended range of serum
lithium concentrations during maintenance
therapy is 0.6-0.8 mmol /I in blood samples
drawn 12 hours after the last intake of
lithium; lower levels may be indicated in
some elderly and higher levels in some
young patients.
Lithium should be discontinued or the
dosage reduced during "risk situations"
especially when there is prolonged loss of
liquid from the body (e.g. vomiting,
diarrhoea, excessive sweating, dehydration
due to various reasons);
other risk
situations include physical disease with
fever, prolonged unconsciousness, surgery
with narcosis, low salt intake, rigorous
slimming, and concurrent treatment with
diuretics, with non-steroidal antirheumatics,
or with ACE inhibitory antihypertensives.
Use in pregnancy
Maintenance treatment in bipolar and
unipolar affective disorders with frequent
and severe relapses. Treatment of mania
and hypomania.
Because of evidence of teratogenic action
on the heart and large vessels, lithium
should generally be avoided during the first
trimester of pregnancy, but in the individual
case the mother's risk of manic or
depressive relapse must be weighed against
the child's risk of malformations.
It is advisable to discontinue lithium a
few weeks before delivery and to resume
treatment a few days after.
Dosage and administration
Adverse effects
Dosage adjustment should be based on
clinical response and serum lithium levels
(see later). Daily maintenance doses are
often 900-1500 mg of lithium carbonate in
patients aged under 60 years, 450-900 mg in
These are usually dose-dependent and
can often be prevented or relieved by a
moderate reduction of dosage.
Adverse effects may include: hand
tremor (counteracted by 10 - 20 mg of
propranolol as needed), goitre or
hypothyroidism (counteracted by the
concurrent administration of thyroxine),
lowered renal concentrating ability and
polyuria, weight gain (which can be
alleviated by moderate dieting, exercise),
defecation urge and loose stools (reduction
of dosage), and, in a few cases, memory
impairment, and reduced reaction speed.
Clinical information
Uses
older patients divided into one or two daily
administrations.
Contraindications
kidney disease with variable
glomerular filtration rate;
severe heart disease;
disturbance of fluid and salt balance.
hypothyroidism.
38
Precautions
L
WHO/MNH/MND/93.27
Drug interactions
Lithium may interact adversely with
diuretics, non-steroidal antirheumatics,
some antihypertensive drugs (calcium
channel blockers, e.g. verapamil; conversion
enzymes blockers, e.g., captopril) and
neuroleptics in high dosage.
Overdosage
Lithium intoxication can be caused by
overdosage or by a fall in elimination rate
(kidney disease, "risk situations"). Signs of
impending intoxication may include:
dullness, difficulty concentrating, muscle
weakness, unsteady gait, indistinct speech,
vomiting and diarrhoea. Fully-developed
intoxication (serum lithium usually higher
than 1.5-2 mmol/I) resembles narcotic
poisoning; it should be treated with
correction of water and salt balance and
with hemodialysis or arteriovenous
hemofiltration.
39
WHO/MNH/MND/93.27
6.10 Temazepam
General information
Temazepam is a benzodiazepine with
anxiolytic and hypnotic properties. It is
metabolized in the liver to several inactive
metabolites, which are mainly excreted in
the urine as glucuronides.
The drug response becomes evident 3090 minutes after oral administration. The
plasma half-life is 6-8 hours, although some
recent studies seem to show that the half
life may be longer, about 15 hours.
Storage
Temazepam should be stored in tightly
closed containers protected from light.
risk of respiratory depression.
Temazepam should be used with great
caution and only when essential in elderly
and debilitated patients, and in patients
with chronic pulmonary insufficiency or
chronic renal or hepatic disease.
Ambulatory patients should be warned
not to drive or operate machinery during
treatment with temazepam since reaction
times can be impaired by the drug.
Use in pregnancy and in breast-feeding
Use in pregnancy should be avoided
whenever possible. Some studies have
reported an increased incidence of
malformations among infants bom to
mothers who were administered
benzodiazepines during the first trimester of
pregnancy, although other, large-scale
prospective studies have failed to confirm
these results.
Adverse effects
Clinical information
Uses
Temazepam, although a benzodiazepine,
and therefore encompassed within the
category under diazepam, has been added
to the list of essential drugs because it
represents the group of short-acting
benzodiazepines, more suitable for use as a
hypnotic than diazepam. Like diazepam, it
can also be used to treat anxiety but the
effects of a single dose is shorter lived.
Dosage and administration
As an hypnotic, temazepam is used at
the dosage of 20-30 mg. As an anxiolytic
the dose can range from 2-10 mg per day.
Contraindications
age less than 12 years.
known hypersensitivity
benzodiazepines.
to
Precautions
Temazepam, as any other
benzodiazepine, should be administered
with particular caution to patients with
myasthenia gravis as well as to patients
with obstructive airway disease, who are at
40
Paradoxical reactions, including
irritability, excitability, hallucinations,
increased muscle spasticity and sleep
disturbances have been reported,
particularly in elderly patients and in
children.
Rare but serious adverse reactions
include leucopenia, jaundice and
hypersensitivity reactions.
Drug interactions
The effects of phenothiazines,
barbiturates, monoamine oxidase inhibitors
and other antidepressants may be
potentiated.
Overdosage
Signs of overdosage include somnolence,
ataxia, dysarthria, diminished reflexes,
confusion and coma. Paradoxical excitement
may occur in children. Unless the specific
benzodiazepine antagonist flumazenil is
available, treatment should be symptomatic
and directed to the management of
respiratory depression and shock.
WHO/MNH/MND/93.27
PART III
EVALUATION OF TREATMENT
41
WHO/MNH/MND/93.27
7. EVALUATION OF PHARMACO
LOGICAL TREATMENTS IN
PSYCHIATRY2
7.1
Non-specific factors affecting the
evaluation of pharmacological
treatments
The chief problem in evaluating
treatment is that four non-specific factors
can be associated with a reduction of
symptoms and an increase in well-being,
and thereby mimic a treatment effect.
Firstly, some disorders, given time, remit
completely in the absence of treatment.
Secondly, other disorders, although chronic,
vary in intensity; patients tend to present
themselves for treatment when their
disorder is severe and do not come when it
is mild; even without treatment the severity
of symptoms will reduce with time. If a
treatment is offered when the symptoms are
severe, then it may appear more effective
than it is, simply because severe symptoms
will, in due course, regress back to their
mean level of severity.
Thirdly, positive expectations of being
treated can bring about improvement in
many mental disorders. This non-specific
effect of being in treatment can be time
limited, and may affect the benefits of a
specific treatment in an uneven manner.
Fourthly, the very administration of a
medication (regardless of its content) may
also produce an effect (placebo effect) which
must also be assessed and discounted in the
evaluation of a treatment.
The factors, spontaneous remission,
regression to the mean, the non-specific effect of
being in treatment, and the placebo effect, can
confound results and make treatment
evaluation complicated.
In any clinical situation the observed
improvement is therefore due to the
additive effect of non-specific benefits of
being in treatment, together with the
benefits which result from the skilled
application of specific therapies. Good
clinical treatment will seek to maximize the
effects of both, whereas in treatment outcome
research, the magnitude of the effect of the
specific intervention must be isolated in a
precise manner and assessed, to be
compared to the total effect of the treatment
in the particular setting, by a particular
practitioner to a given patient.
Clinicians should maintain a critical
attitude about the "pharmacological” value
of the treatment. While it is true that a
clinician who is very positive about the
likely effects of the treatment will induce a
greater non-specific response (and this is to
be praised); nevertheless this enthusiasm
should not blind the clinician to the fact that
the effect may be non-specific rather than
specific.
It seems sensible to be wary of treatments
with dropout rates that exceed 40%: in fact
high drop-out rates are more likely to be
seen where the treatment effect, if any, is
weak; low drop-out rates (below 20%), on
the other hand, often identify good
treatments. Patients can be good judges of
where value lies, and administrators might
usefully adopt drop-out rates as an early
indicator of the utility and benefit of various
treatment programmes.
7.2
Methodological problems
7.2.1
Levels of evaluation
Techniques for evaluating the efficacy of
treatment are often based on the assumption
that single modes of treatment are the topic
of interest. Efficacy measures the degree to
which a given treatment produces a desired
effect; it does not take into effect other
aspects such as adverse effects.
In practice, however, treatment is
multifaceted and involves several types of
intervention aiming to achieve a variety of
objectives which include: the removal or
reduction of symptoms; stopping the
disease process; preventing impairments
and disabilities; restoring function; and
maintaining or improving the quality of life.
Interventions required for adequate
management of impairment, disability and
disadvantage differ from acute treatment
methods, if only in degree. They require
continuing involvement on the part of the
therapist, and necessitate that this
involvement extends more comprehensively
over the patient's life and relationships; they
demand a slower pace of approach, one
with which more action-oriented
43
WHO/MNH/MND/93.27
practitioners may become impatient. They
also require that consideration be given to a
host of interacting variables which, although
they may have some relevance in acute
treatment situations (e.g., cultural
considerations) assume much greater
importance in the management and
rehabilitation of disabilities which may
permeate every aspect of a person's life.
Different as they are from one another,
conditions which are often chronic, such as
schizophrenia and agoraphobia, can be used
to illustrate this matter. In both syndromes,
there is impairment in the patient's sense of
well-being; in both, the impairment can
result in patients being disabled, and to a
very large extent, housebound; and in both
the disability may result in the patient
leaving the workforce, and becoming
socially isolated. Both conditions have, in
randomized controlled trials, responded
best to a combination of medication and
behavioural therapy. But here the apparent
similarity of these two conditions ends; the
treatment of each patient, regardless of
diagnosis, has to be considered on an
individual basis if it is to be optimal.
It is therefore worth distinguishing
between the number of different levels at
which effectiveness
can be tested.
Effectiveness indicates if the results obtained
from a given treatment are in accordance
with objectives for reducing the disease or
improving health; it also indicates the
distance between efficacy in an ideal
situation (e.g. in vitro) and its actual effect in
real life situation. The simplest level relates
only to whether participants subjectively
rate a particular experience as being of
value to them. This subjective assessment is
a relevant first step in evaluation. Similarly,
peer review can contribute to this
preliminary step of evaluation.
Two other additional important
variables to be evaluated are efficiency and
cost-effectiveness.
Efficiency measures the relationship
between cost and results and how to obtain
best results from given economic resources.
It can be measured by means of process
evaluation, where the roles of various
participants are analyzed and their
interactions monitored in order to determine
how well an attempt to generate
improvements worked in terms of its
operational functions.
Cost-effectiveness indicates the
relationship between cost and effectiveness;
44
it measures the relative cost of alternative
ways of achieving an objective. It involves
greater attention to comparability, both with
other similar programmes and also with
some, less arbitrary standard of what the
outlay should be (in terms of funding, man
hours, or transfer of resources) in order to
achieve a stated outcome. It relies, therefore,
on process evaluation as well as a more
objective assessment of the inputs which
have been made, but also requires a clear
understanding of what the outcome is.
To achieve this, an analysis of impact is
also necessary. Indeed, there are those who
argue that this is the only really important
measure of the effectiveness of an
intervention.
7.2.2
Indicators of treatment outcome
Occasionally treatments produce such a
large effect that no further research seems
necessary. Benefits are self-evident. A
striking example of this is the impact of
streptomycin on tuberculous meningitis; a
uniform mortality rate was cut so drastically
that it would have been unethical to do a
controlled trial. A large treatment effect,
whereby the average treated patient is better
than 99% of untreated patients, is almost
certain to be due to the treatment that has
been administered. If this effect can be
shown to persist after treatment has
concluded, and if the effect can be
replicated, this provides robust evidence of
the effectiveness of an element in the
treatment package.
The issue of replication is important,
and the advent of empirical techniques to
aggregate the findings of many research
studies has allowed the importance of small
but significant treatment effects to emerge.
Meta-analysis is the technique that has been
used in psychiatry to add up the benefits to
be expected from treatments used in
cognitive impairment, schizophrenia,
affective disorder, the anxiety disorders and
eating disorders. One can estimate from the
average benefit, or effect size, and the
number of studies, just how likely it is that
the finding of significant benefit is real and
not a spurious effect.
Furthermore, the magnitude of the effect
size is a direct indication of the magnitude
of benefit, a property which allows the
benefits of different treatments to be
compared. Meta-analysis, in a sense, is a
method which permits the salvaging of
WHO/MNH/MND/93.27
meaningful results from flawed studies; and
one must assume that all studies of
treatment effects, on real patients, will be
less than perfect.
7.2.3
Randomized placebo-controlled trials
Ideally, any treatment in use should be
supported by the results of a randomized,
placebo-controlled trial that involved a large
enough number of carefully diagnosed
patients, and employed reliable, valid,
accurate and appropriate measurements
made at relevant measurement-occasions
and over a period of time appropriate to the
known clinical course of the disorder.
Randomization is to make certain that
the experimenter did not, consciously or
unconsciously, allocate patients with a good
prognosis to the treatment group, and those
with a poor prognosis to the control group.
The placebo control ensures that the
effects of remission, regression and placebo
are offset against the improvement observed
in the treated group. However, parallel
design double-blind trials are often used
instead of placebo due to ethical reasons.
These trials still allow for natural recovery
effects to be evenly distributed between the
different study groups.
The number of patients studied should
be large enough to permit the study to have
the statistical power to detect the superiority
expected from the treatment and to avoid
missing a real but small effect.
Careful diagnosis ensures that the
treatment is being delivered to the disorder
likely to be responsive to that treatment.
When an established treatment for a
condition already exists, it may be very
difficult to use a randomized placebocontrolled trial to demonstrate more than
relatively short-term control-of-symptom
effects; drop-out rates with placebo
treatments that continue for more than eight
weeks are unacceptably high. Furthermore,
it is unethical to deny active treatment to
anyone seriously ill for more than very
short periods of time.
45
WHO/MNH/MND/93.27
PART IV
\-
PHARMACOLOGICAL TREATMENT OF
MENTAL DISORDERS
47
WHO/MNH/MND/93.27
8. FOO - F09
ORGANIC,
INCLUDING SYMPTOMATIC,
MENTAL DISORDERS
8.1
Principles of treatment
The clinical manifestations of these
disorders are broad but fall into two groups.
First are the syndromes with prominent and
invariably present features which are either
cognitive disturbances (dysmnesia, intellec
tual deterioration and learning problems), or
disturbances of the sensorium (e.g.
disorders of consciousness and attention).
Second are the syndromes with prominent
manifestations in the areas of perception
(hallucinations), contents of thinking
(delusions), mood and emotion (depression,
elation, anxiety), or in overall personality
and/or behaviour patterns; cognitive or
sensory dysfunction is minimal or hard to
assess.
The pharmacological treatment
approaches in this area should focus on the
following groups:
1.
Dementias (Chronic Brain Syndromes),
including those of the Alzheimer type.
Vascular Dementias, and dementias of
specific origin;
2.
The organic amnesic syndrome
(Korsakov Syndrome) other than due to
drugs or alcohol;
3.
Delirium (Acute Brain Syndrome or
Confusional State) other than deliria due
to drugs or alcohol;
4
Mental Disorders without cognitive
impairment, but due to organic
pathology of the brain, primary or
secondary (Symptomatic psychoses);
5
Organic Personality and Behaviour
Disorders.
Treatment options for this entire group
of disorders remain limited, apart from the
specific treatment of the primary disease or
disorder, where it is possible and effective,
particularly among the deliria, dementias of
specific origin and symptomatic
psychoses.
Thus in delirium due to cerebral malaria
or typhoid fever, precise and effective
treatment is available; the specific dementia
of neurosyphilis may dramatically improve
with penicillin therapy, and the dementia of
hypothyroidism responds dramatically to
treatment with thyroxin; organic
hallucinatory psychoses due to
trypanosomiasis or Haemophilus influenzae
meningitis, for example, will also usually
respond to specific treatment. This reflects
the fact that the clinical features of all the
organic psycho-syndromes are non-specific,
and are secondary to a variety of
pathologies, some of which are readily
treatable and others are not.
It follows logically that an etiological
diagnosis is the fundamental first step in the
proper treatment of all of these conditions.
This can be difficult and sometimes
demands complex investigation. Cost
benefit issues then become relevant. There
is evidence from developed countries that
the identification and treatment of treatable
specific dementias (including normal
pressure hydrocephalus, benign cerebral
tumours, and infectious, endocrine and
vitamin deficiency aetiologies), despite
requiring full investigation of all dementias,
is cost-effective, the costs of long-term care
of persons with treatable (but undiagnosed)
dementias outweighing the costs generated
by the adequate investigation of every case.
Specific pharmacological treatment,
however, is only available for a minority of
conditions. In the majority of these
conditions, attention has to be directed at
prevention; at drug and/or behavioural
therapies for symptom relief;
and at
methods for the preservation, maximization
and rehabilitation of specific areas of
psychosocial and interpersonal function.
8.1.1
The Dementias
The Dementias of the senium (over 65)
consist mainly of Senile Dementia of the
Alzheimer-type (SDAT) conditions
accounting for about 40% of cases; multi
infarct dementias (MID) accounting for
about 15-20% of cases, and a mixed group
(SDAT + MID) which represent 20-30%. The
geographical distribution of different
dementia types vary; amongst the Japanese
vascular causes of dementia are reportedly
49
WHO/MNH/MND/93.27
more frequent than Alzheimer-type
pathologies.
Specific treatment, especially of SDAT,
represents a major international research
goal but has yet to be achieved. So far
there is no evidence of effectiveness for socalled cerebrovascular dilating drugs, for
the use of dietary precursors of
acetylcholine (choline, lecithin), nor for the
deployment of cholinergic drugs
(physostigmine, tetrahydroamino-acridine).
Another group of drugs, the so-called
"metabolic activators", including ergot
derivatives (hydergine), naftidro furyl,
piracetam, pyritinol and others, is more
difficult to assess. Although many doubt
their efficacy, and evidence from wellcontrolled studies is lacking, there are a
number of anecdotal reports indicating
some benefit in the short- to medium-term.
The main treatment approach in these
dementias remains symptomatic.
Neuroleptic drugs are helpful for episodes
of agitation or superimposed deli ria. The
more anti-cholinergic members of this group
may, however, have an adverse effect on
residual memory; thioxanthine derivatives
have been recommended as useful in this
context. Insomnia and convulsions are
other symptoms which can respond usefully
to relevant medication. In the case of sleep
problems appropriate neuroleptics may
provide more useful help than anxiolytics providing better sleep and also controlling
nocturnal behaviour disorder, whereas
benzodiazepines frequently cause
paradoxical reactions with increased
psychomotor agitation and incoordination,
and may worsen memory and intellectual
functioning dramatically.
Anti-depressants are extensively used in part as a response to the possibility that
a depressive "pseudo-dementia" might be
missed. While they can be of some benefit,
tricyclic antidepressants, with their marked
anti-cholinergic properties, may add further
confusion and cognitive impairment. There
is considerable need to evaluate other types
of anti-depressants in the management of
dementia. Mono-amine oxidase inhibitors3,
in particular, may have an important role in
the management of depression; in addition
it has been suggested that they may also be
of benefit in modifying underlying
pathological mechanisms in SDAT.
50
8.1.2
The organic amnesic syndrome
In these disorders, where pathologies
are operating, they must be sought. Specific
treatment should be targeted at the primary
pathology (e.g. pyloric stenosis with
intractable vomiting) and treatment with B
Vitamins, especially thiamine. Irrespective
of the primary pathology, thiamine has
utility, and its administration may reverse
deficits in a striking manner. In the other
cases, the approaches discussed for
dementia are mostly applicable.
8.1.3
Delirium
Acute delirium always represents
primary or secondary cerebral dysfunction;
etiological diagnosis followed by precise
treatment of the causal pathologies is
crucial. Multiple pathologies may operate,
particularly in the elderly, and drugged
states, with interactions, resulting from
polypharmacy, superimposed on nutritional
or infectious problems, are particularly
important. In developing countries similar
considerations apply, but the range of
nutritional, toxic and infectious pathologies
to be considered is greater, and the
condition is common in much younger age
groups. If background cerebral reserve is
diminished due to infantile deprivation or
injury or both, very little may be required to
trigger a delirium. By the same token,
however, mere admission to hospital, with
food, hydration, rest and tranquillization,
may be all that is required by way of
treatment. Otherwise general measures as
discussed for dementia are appropriate;
neuroleptics have a particular role in
quietening agitation and fear resulting from
confusion.
8.1.4
Organic psychoses without cognitive
impairment - but due to organic pathology of
the brain, primary or secondary
(Symptomatic psychoses)
These symptomatic psychoses parallel
dementia (chronic) and delirium (acute) and
treatment is similar. Specific symptoms will
dictate choice of approach - e.g. Anti
depressant therapy in organic affective
disorder. Acute psychoses of this type,
especially in developing countries, are
frequently mixed with delirious symptoms.
WHO/MNH/MND/93.27
thus acquiring an amorphous quality, made
more confusing by various reactive and/or
released emotional symptoms - often
hysterical in quality. These atypical acute
psychoses should generally be managed as
for delirium.
6.1.5
Organic personality disorders
Important issues here relate to the
careful evaluation of target behaviours and
symptoms which may then be ameliorated
or controlled by appropriate drug therapy.
Impulsive aggressive outbursts, epileptic
phenomena, acute alcoholic excess, and
acute depressive episodes are examples of
behaviours which may respond well to
carefully planned drug treatment
interventions.
(
y
/o/
I <
health
ooc'
51
WHO/MNH/MND/93.27
during the weeks or months following
detoxification can be helped by the use
of prescribed drugs which offset the
lack of pleasurable effects of the
substance abused. Alternatively, with
opioid dependence, it is common for
controlled doses of an opioid to be
prescribed if abstinence cannot be
achieved.
9. F10 - F19
MENTAL AND
BEHAVIOURAL DISORDERS DUE
TO PSYCHOACTIVE SUBSTANCE
USE
9.1
Principles of treatment
There is an ever increasing range of
substances which produce dependence;
these can be conveniently categorized into
nine groups of compounds which share
similar properties:
o
o
o
o
o
o
o
o
o
alcohol
amphetamine and other
sympa thomimetics
cannabis
cocaine
hallucinogens
inhalants
opioids
phenylcyclidine (PCP) and similar
compounds
sedatives, hypnotics and anxiolytics.
Despite the wide coverage given by the
press to illegal drugs, most public health
problems are associated with abuse of
substances more or less easily available such
as alcohol, tobacco, volatile organic solvents,
amphetamines, sedatives and other "legal"
substances. Of these, only three - opioids,
sedatives and alcohol - produce a welldefined abstinence syndrome which can be
alleviated, in part, by pharmacotherapy;
pharmacological treatment of abuse of the
other drugs is not recommended.
In general, there are two central
components to the management of
dependence:
a) Detoxification. This covers the period
over which the substance of abuse is
completely withdrawn. A compound
which exhibits cross-tolerance may be
substituted, thereby minimizing the
highly noxious, and sometimes
dangerous, effects of abrupt withdrawal.
The substituted compound is then
withdrawn in a controlled manner.
b) Post-detoxification strategies. The
difficult period of complete abstinence
52
9.1.1
Opioid withdrawal: detoxification
Because the opioid abstinence syndrome,
although distressing, is rarely dangerous,
detoxification can be carried out as an
outpatient procedure, supervised by trained
non-medical staff. However, completion of
a withdrawal programme is more often
achieved as an inpatient because of the
additional support offered by experienced
staff.
Methadone3 is a controversial drug for
substitution in opioid dependence, used in
some developed countries. This is a
synthetic opioid which is inexpensive and
similar to morphine in action. However,
some properties, different from morphine,
render it a most suitable drug for opioid
detoxification:
i)
Methadone is absorbed well from the
gastrointestinal tract and can be given
orally, thus extinguishing the secondary
reinforcing properties of the injection
procedure. It is often wrongly stated
that methadone prevents the withdrawal
features of other opioids but in itself
does not produce euphoria. Methadone
is euphorigenic but, because it is taken
orally, the opioid "rush" experienced
after rapid injection of morphine or
heroin is absent.
ii) Methadone has a long half-life and can
be administered once a day thus
reducing the frequency of withdrawal
craving and drug-seeking behaviour.
iii) Withdrawal from methadone is similar
in quality but much less intense than
from morphine and is therefore better
tolerated.
The aim in opioid detoxification is to
substitute injectable opioid with oral opioid
so that the acute full-blown abstinence
syndrome is avoided. Abstinence is
ultimately achieved by supervised reduction
WHO/MNH/MND/93.27
of methadone which minimizes, but cannot
wholly prevent, the discomfort of
withdrawal.
9.1.2
Opioid post-detoxification
Once detoxified, however, many are
unable to embark upon rehabilitation
without pharmacological intervention.
In cases of very severe distress there is
probably no harm in giving
pharmacological sedation in the short term.
In primary care settings chlorpromazine is
likely to be the most useful agent.
9.1.3
Sedative withdrawal
The main drugs of abuse in this
category are: the short acting barbiturates
(e.g. pentobarbitone), meprobamate,
glutethimide, methyprylone, methaqualone
and the benzodiazepines. Particularly with
shorter acting agents in dependent
individuals, an abrupt withdrawal carries
the risk of inducing a grand-mal convulsion
which may proceed to status epilepticus.
For this reason detoxification should be an
inpatient procedure using drug substitution
and supervised by staff with some medical
training. The exception to this is with
benzodiazepine dependence, as the risk of
withdrawal seizures is very low, when no
antecedents have been recorded; in general
careful and gradual withdrawal can be
accomplished without admission or drug
substitution.
The features of the abstinence syndrome
are similar for all drugs of this group. The
barbiturates have been studied in most
detail. It appears that the intensity of the
abstinence syndrome depends in part on the
amount of drug taken and in part on the
rate of clearance from the central nervous
system. The short acting barbiturates are
cleared rapidly, thus withdrawal features
develop quickly and tend to be severe. This
is, however, not always the case and fits
have been known to occur as late as 12 days
after withdrawal from longer acting
barbiturates.
9.1.4
Alcohol withdrawal
Whenever a patient presents any of the
physical problems often associated with
alcoholism or demonstrates a tremor and
gives a history of alcohol misuse, the
possibility of withdrawal must be carefully
considered. Some 95 per cent of alcoholics
never evidence severe signs of withdrawal.
Mild reactions, usually lasting up to 48
hours, consist of insomnia, irritability and
tremor. More than one half of patients may
evidence some level of autonomic nervous
system dysfunction, including sweating, an
increase in
heart rate (100-120/min.)
increases in respiratory rate, mild elevations
in temperature and elevated blood pressure.
Other symptoms are anorexia or nausea and
vomiting, emotional complaints including
sadness and somatic complaints, headaches
and illusions. The severity of the syndrome
is related, among other things, to the
intensity and duration of the most recent
exposure to alcohol.
The most common of the more severe
withdrawal symptoms are visual
hallucinations involving threat of assault
and presence of dangerous animals, and
grand mal seizures.
Delirium Tremens, a serious and
potentially lethal condition, is characterized
by severe autonomic nervous system (ANS)
dysfunction, confusion with or without
seizures, is reported for fewer than one
percent of patients.
The acute and usually mild withdrawal
syndrome begins within 12 hours or less of
the decrease in blood-alcohol levels, in an
individual who has been drinking for days,
weeks or months. Symptoms are likely to
peak in intensity by 48-72 hours and are
usually greatly reduced by 4-5 days.
Many patients with mild withdrawal
can be managed safely and effectively at
home or in non-medical detoxification
centres. In such cases treatment should
include thiamine and diazepam in low
doses.
If possible, a relative or friend
should be enlisted to watch the patient
during the withdrawal phase.
The
treatment of the patient is carried out in
several stages and includes interventions
directed towards life support, prevention of
central nervous system damage, control of
various medical complications of the
condition, and recovery from the alcohol
dependence itself.
Oral multiple vitamins should be given
for a period of weeks, making sure that folic
acid and thiamine are included. It would
53
WHO/MNH/MND/93.27
be better if the vitamins also contained zinc
and magnesium, because some alcoholics
can develop deficiencies in these minerals.
Hydration may be required, although in
milder withdrawal, overhydration is more
typical.
Medication is used to decrease overall
symptoms, preferably using
benzodiazepines, particularly the longeracting ones, such as diazepam or
chlordiazepoxide. The needed dose should
be determined on day one, and then
decreased by 20 per cent for each day,
stopping the drug by day four or five.
Treatment of delirium tremens includes
a thorough physical examination and then
supportive measures (IV fluids if there is
objective evidence of dehydration) as well
as the prescription of multiple vitamins
including thiamine and folic acid.
9.1.5
Alcohol post-detoxification maintenance
Several compounds have been
investigated for their ability to maintain
abstinence in alcoholics.
Of these
disulfiram3 is the one most widely used. It
inhibits liver aldehyde dehydrogenase. As a
consequence alcohol intake (as little as 7 ml)
causes acetaldehyde to accumulate in the
blood which produces a very unpleasant
reaction consisting of sweating, nausea,
vomiting, palpitations, tachycardia and
throbbing headache. This can last from 30
minutes to several hours and can be
extremely frightening. Consequently, a form
of aversive conditioning occurs preventing
further alcohol intake. However, large doses
of alcohol on top of disulfiram can produce
fatal reactions such as cardiac arrhythmias
and hypertensive crises. Also, disulfiram is
contra-indicated in patients with a variety of
clinical conditions, including liver and brain
dysfunctions, which are not rare in alcohol
abusers.
9.2
Special issue:
dependence
benzodiazepine
The large majority of BDZ users - up to
two-thirds in some reports - take the drug
for 60 days or less. Small but substantial
numbers of adults have been found to take
the drug for one year or more. According to
the A.P.A. Task Force Report on
Benzodiazepine Dependence, Toxicity and
54
Abuse, these long-term consumers may
represent 1.74% of the population, and they
may be divided into four groups:
the first group includes older, medicallyill patients taking other medicaments as
well;
the second group comprises psychiatric
patients with panic or agoraphobia;
the third group includes patients with
mainly dysphoria complaints;
the fourth group is made up by patients
with chronic insomnia or other sleep
disorders.
While it is unlikely that there would be
any abuse in the first two groups, the
indications for long-term prescriptions are
less definite in the two remaining groups,
since their complaints are vague and illdefined. Moreover, with regard to long-term
users in the fourth group, there are not
consistent data about the effectiveness of
BDZ for night sedation if taken for periods
of over 30 days. Nevertheless many patients
claim that they are unable to sleep if they
do not take the drug.
Among these long-term users a
constellation of symptoms may appear if the
drug is stopped abruptly. These symptoms
fall within three main categories: rebound,
recurrence and withdrawal.
Rebound
symptoms are the mirror image of the
effects of the medicine, and include anxiety,
restlessness and insomnia, and may lead to
a return to drug administration. Recurrence
symptoms are more difficult to define and
may be identical to the original symptoms
for which the drug was originally
prescribed. It is often hard to determine
whether these symptoms represent a
recurrence of the original symptoms for
which the drug was taken, or a
manifestation of drug discontinuation or
both.
Withdrawal symptoms, on the contrary,
were not present when the drug was
initially prescribed. The symptoms are
generally mild and include anxiety,
insomnia, gastrointestinal disturbances and
headaches. Rare, but more severe
withdrawal symptoms include seizures and
WHO/MNH/MND/93.27
psychosis, and occur after high doses, long
duration of treatment and abrupt
discontinuation.
All these discontinuance symptoms can
occur even at therapeutic dosages, although
they are more frequent among people who
have used these drugs at higher than usual
doses and for prolonged periods of time.
There are some data showing that these
symptoms may be more frequent among
people who used high potency BDZ.
Although it is sometimes stated that
BDZ may induce a 'dependence state', it
should be clarified that, according to the
ICD-10 definition of dependence, the
existence of withdrawal symptoms does not
necessarily lead to dependence. In fact, 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 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;
(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 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
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.
While it is certainly true that BDZ may
induce a withdrawal state, it seems
appropriate to avoid the term of
dependence to refer to BDZ use.
In any event, the existence of problems
associated with long-term use should alert
physicians and suggest that BDZ should be
prescribed only for limited periods of time;
that each prescription should be regularly
monitored and re-discussed; that priority
should be given to alternative treatment
methods for long term use in the case of
disorders such as panic, agoraphobia and
insomnia; and finally that efforts should be
made with long-term users in order to
gradually taper off the drug. It is however
recommended that BDZ be discontinued
gradually (even in a 3-4 month period) and
not abruptly.
(d) evidence of tolerance, such that
increased doses of the psychoactive
substance are required in order to
achieve effects originally produced by
lower doses (clear examples of this are
found in alcohol- and opioid-dependent
individuals who may take daily doses
sufficient to incapacitate or kill nontolerant users);
55
WHO/MNH/MND/93.27
10.
F20 - F29 SCHIZOPHRENIA,
SCHIZOTYPAL DELUSIONAL
DISORDER AND ACUTE AND
TRANSIENT PSYCHOTIC
DISORDERS
10.1
Principles of treatment
Drugs used to treat disorders included
in ICD-10 category F20-F29 include a
number of compounds, belonging to
different chemical classes which induce in
animals and in men similar biochemical,
pharmacological and behavioural effects.
The most important classes of
antipsychotic drugs used in the treatment of
schizophrenic disorders are:
phenothiazines (e.g. chlorpromazine);
butyrophenones (e.g.z haloperidol);
diphenyl butylpiperidine (e.g.,
pimozide)3;
thioxanthens (e.g., flupentixol);3
benzamides (e.g., sulpiride);3
atypical and "new" neuroleptics,
including clozapine, piquidone and
risperidone.3
It is maintained that their therapeutic
effect in schizophrenia is exerted through a
block of D2 dopamine receptors in limbic
areas. Some of these medicaments also
exert a sedative action, due to their alphaadrenolytic and anti-histaminic properties.
No important differences in
effectiveness have been demonstrated
among the various antipsychotic drugs
mentioned above. The differences reported
in clinical practice are related to the
different incidences of adverse effects.
10.1.1
Acute phase treatment
The antipsychotic medicaments reduce
or eliminate 'positive' symptoms of
schizophrenic disorders, e.g. delusions,
hallucinations and psychomotor
disturbances. In as many as 80 to 90% of all
patients, they seem also to reduce the
impact of acute and chronic stress in the
every-day living environment. Although
these drugs reduce florid symptoms
particularly
in
acute
phases of
56
schizophrenia, some 10 percent of acutely ill
patients will show little response to these
drugs. Some of these patients whose
symptoms fail to respond to one of the
antipsychotic drugs will respond to another.
The reasons for this are obscure, since all of
them are believed to act by blocking D-2
dopamine receptors. 'Negative' symptoms,
(e.g. lack of motivation and interest,
inactivity, lack of emotional display, and
restricted speech) do not seem to respond as
well to treatment with classical neuroleptic
drugs. There are however some reports
showing that clozapine (a drug not
discussed in this document) might be
effective for negative symptoms. The
interaction and reinforcement between
negative symptoms and sedation caused by
maintenance drug treatment is insufficiently
explored.
The general strategy for acute treatment
involves the administration of an
antipsychotic drug such as chlorpromazine
or haloperidol. In the acute phase
chlorpromazine may be administered by an
intra muscular injection in a dose of 100-200
mg which can be repeated while observing
the patient for a possible hypotension. In
most cases, however, the intra-muscular
administration is not needed and the
patients can be treated with a simple oral
dose. A maximum daily dose of up to 1,2001,600 mg may be necessary, although doses
above 800 mg per day are rarely required.
Regarding haloperidol, the dosage
generally used for the management of acute
cases ranges between 3.0 and 10 mg per
day. There is often the need for an upward
titration in the acute phase. Combinations of
two or more antipsychotic drugs should not
be administered.
Treatment strategies centred on the use
of very high dosages of antipsychotic drugs
(up to 100 mg of haloperidol a day),
administered at very short intervals, called
'rapid neuroleptization', have not proved to
be more effective than more conservative
and gradual treatment strategies, while they
seem to increase the overall risks associated
with the administration of neuroleptics.
10.1.2
Maintenance treatment
The effectiveness of antipsychotic drugs
in maintenance therapy of schizophrenia has
WHO/MNH/MND/93.27
been established by numerous studies.
However, protection against relapse is
incomplete, with about 30-40 percent of
patients relapsing by the end of a year after
commencing treatment. Exacerbations of
illness in patients on maintenance drug
therapy is often precipitated by acute stress,
(e.g. stressful life events), and chronic stress
occasioned by living circumstances. The
addition to the drug regime of stress
management procedures can reduce this
relapse rate. Reported success rates of
rehabilitation programmes for long-term
schizophrenic patients show remarkable
variation from one third to three quarters of
all patients according to different authors,
techniques and populations.
Optimum long-term drug management
appears to be maintenance on the lowest
possible dose of neuroleptics that will
prevent major exacerbations of florid
symptoms. Controlled studies in countries
with well-developed services, over a period
of one year after a florid acute episode,
comparing oral with intramuscular depot
preparations used for maintenance, have not
demonstrated any significant advantages for
the depot preparation. However, in
individual, non-compliant cases depot
medications may have some advantages
over oral medications. On the other hand,
prevention of relapse by reintroducing drug
treatment when prodromal symptoms of the
relapse appear, (so-called "targeted
medication") has also been reported as an
effective strategy useful in particular to
reduce side effects likely to be more
frequent in long-term maintenance therapy.
However, recent studies have failed to
confirm the effectiveness of this medication
strategy.
In all cases, it has been recommended to
foster the education of patients and
immediate caregivers, about the illness;
about factors that promote relapse; about
the costs and benefits of drug therapy; as
well as about the early recognition of signs
of major exacerbations.
The main disadvantage of antipsychotic
drugs is their adverse effects involving
movements, autonomic nervous functions,
haematopoiesis and other vital functions.
Among the most serious of these
irreversible side effects is tardive dyskinesia,
which can be extremely disabling and
disfiguring.
A substantial proportion of patients with
schizophrenia will recover completely after
a first episode and remain well. The
proportion of these patients seems to be
significantly higher in developing countries,
as shown by two major WHO international
collaborative studies (12, 13). There are no
clinically useful predictors of good
prognosis for individual patients; for groups
of patients features associated with a good
outcome include female sex, married status,
acute onset, nutritional deficiencies,
puerperal status, significant co-existing
affective symptoms, a good premorbid
personality, a preceding life event, and
living in low stress households. In this
group of patients many clinicians
recommend the interruption of long-term
medication, especially in order to prevent
adverse, possibly irreversible effects (e.g.,
tardive dyskinesia), with the prevention of
relapse by reintroducing drug treatment
when prodromal symptoms of the relapse
appear.
All patients receiving long-term
treatment require periodic evaluation and
documentation of continued need and
benefit. The benefits and risks of long-term
neuroleptic treatment should be discussed
with patients and families and their
informed consent to treatment, documented.
Patients should also be routinely examined
for signs of tardive dyskinesia.
10.1.3
Special problems: Tardive dyskinesia
Tardive dyskinesia (TD) is a syndrome
of choreoathetoid and/or other involuntary
movements that may affect mouth, lips,
tongue, arms, legs or trunk; TD is associated
with the long-term (usually greater than 6
months) use of neuroleptics. There is a wide
variation in reports of the incidence of
tardive dyskinesia in patients on long-term
neuroleptic therapy (0.5 to 56%), with an
average prevalence rate of 20% among
patients continuously exposed to neuroleptic
treatment for at least one year. It is likely
that part of this variation can be attributed
to the differences among criteria used for
assessing abnormal involuntary movements,
ranging from minimal sinuous movements
57
WHO/MNH/MND/93.27
of the lips to a gross motor disability
impeding breathing and swallowing.
The proportion of patients developing
abnormal involuntary movements is
believed to increase with increasing length
of treatment or total exposure to
neuroleptics. The syndrome can develop
after relatively brief (3 to 6 months)
treatment periods at low dosages.
However, it is impossible at present to
identify which patients are at risk.
In cross-sectional studies, the majority of
cases are judged to be mild (i.e., not
obvious to the untrained observer or
subjectively troublesome to the patient).
Identification and diagnosis are complicated
by the fact that neuroleptic drugs may mask
TD symptoms. Drug discontinuation or
dosage reduction may reveal previously
masked symptoms.
Although there are few long-term
follow-up studies, the condition does not
appear to be generally progressive. The
incidence of tardive dyskinesia does
increase with age.
58
The course of the condition is difficult to
predict in individual patients. In a
substantial proportion of cases symptoms
will disappear within 2 to 5 years, if the
neuroleptic medication is discontinued.
However, a proportion of patients (in the
range of about 30%) will show persistent
dyskinesias even after drug discontinuation.
There is no established treatment for
tardive dyskinesia. Antiparkinsonian drugs
are ineffective for tardive dyskinesia and
there have been reports that giving them in
the absence of extrapyramidal signs to
prevent their occurrence in fact facilitates
the occurrence of tardive dyskinesia.
Antiparkinsonian drugs are advised only for
the treatment of extrapyramidal side effects
when they actually appear. They should be
gradually discontinued over time.
Appendix V reports the WHO Consensus
Statement on the prophylactic use of
anticholinergics in patients on long-term
neuroleptic treatment.
t
WHO/MNH/MND/93.27
11.
11.1
F30 - F39 MOOD
(AFFECTIVE) DISORDERS
Principles of treatment
The current ICD 10 classification of
affective disorders includes:
a) Manic episode
b) Depressive episode:
severe depressive episode
mild depressive episode
c) Bipolar affective disorder
d) Recurrent depressive disorders
e) Persistent affective states
f) Other mood (affective) episodes
These conditions occur with high
prevalence and cause remarkable morbidity
in all ethnic groups and cultures so far
studied. Prevalence varies somewhat from
place to place, but not as much as was once
believed. Regardless of the cut-off point
(symptom severity) chosen, depressive
disorders affect a large proportion of the
population at some stage of their lives.
Mood disorders are very often recurrent
and chronic (50% relapse after a first
episode, and 20% develop a chronic course
after a first episode). They are under
diagnosed and under-treated world-wide.
Because of their guises, and particularly
because of the frequency with which
sufferers complain of fatigue, weakness and
anergia, with multiple somatic and painful
complaints, they are most commonly first
encountered by primary care workers,
general practitioners, and physicians.
Studies suggest that depressive episodes
may comprise 10% -15% of illnesses seen in
general medical practice and these figures
may be an underestimate. Many cases are
not initially diagnosed, or are misdiagnosed
as anxiety states in primary care practice.
All too frequently, they are treated with
tranquillizers - drugs which may provide
some initial symptomatic relief of agitation
and insomnia. A depressive illness is a
major risk factor for suicide.
Appendix VI shows the WHO
Consensus Statement on pharmacotherapy
of depressive disorders.
11.2
Depressive episodes
11.2.1
Treatment options
Tricyclic and allied antidepressants
(imipramine, amitriptyline, doxepin3,
dothiepin3) are the most widely used drugs
in the treatment of depressive disorders.
Controlled clinical trials have established
their effectiveness in these states, but have
not demonstrated significant differences in
efficacy between individual drugs.
Administration in adequate dosage is
essential for a good response in patients
with a severe depressive episode. Non
psychiatrist physicians often employ too
low a dosage. Although it has been claimed
that the dose level needed varies from
culture to culture, there is no firm evidence
on this point. Response to antidepressant
drugs is usually delayed, with a lag up to 38 weeks, although the sedative and
anxiolytic properties of some (especially
doxepin and dothiepin) may provide partial
relief of insomnia and anxiety from the
beginning - to the encouragement of the
patient in many cases.
The use of more than one tricyclic drug
has not been shown to enhance
effectiveness, nor is the delay in onset of
action shortened by parenteral
administration.
Anticholinergic side-effects occur with all
the tricyclic drugs, dryness of the mouth,
blurring of vision (cave glaucoma which can
be worsened), difficulty in micturition (cave
retention of urine, particularly in males with
prostatic disease), constipation (cave faecal
impaction and intestinal obstruction,
especially in the elderly), and partial
impotence and anorgasmia are common.
The patient's compliance with therapy is
usually much better if he/she (and the
family) is informed of these possible effects
- in detail. Toxic effects on cardiac
conduction (slowing)
and myocardial
contractility (increased irritability with
enhanced potential for dysrhythmias) are a
feature of all the tricyclics. These effects are
not troublesome in normal dosage, except in
persons with myocardial disease, where
dysrhythmias and cardiac arrest can occur.
In overdosage, intended or accidental, these
toxic effects make tricyclic drugs potentially
lethal.
59
WHO/MNH/MND/93.27
11.2.2
Acute phase treatment
ii.
The pharmacologic treatment of a
depressive episode should involve the
administration of an antidepressant.
Practitioners should become familiar with
the properties of two or three compounds,
particularly with regard to the effective
dose. The effective dose may vary from one
population to another, and in general older
patients need lower doses than younger
ones. If a patient does not respond within
3 weeks, increasing the dosage or changing
to an alternative medication should be
considered. Side effects, which may be
particularly pronounced with higher doses,
should always be discussed with the
patient. In prescribing, it should always be
borne in mind that depressed patients,
especially those with severe depression,
may be at risk of suicide and the total
amount of medication prescribed or given
to the patients at one time should not be
high.
As regards the optimal dose, in the case
of clomipramine it is advised to start with a
lower dose (25-50 mg/day) on the first day
and increase the dose gradually up to a
maximum of 300 mg within 2-3 weeks.
11.2.3
Maintenance treatment
Antidepressant medication should be
continued up to 6 months after recovery. It
should then be discontinued gradually and
the patient should always be seen about 3
weeks after cessation of all antidepressant
medication to assess the psychological state.
If well, the patient should then be seen at
no more than 2-month intervals for up to a
6-month period. From the beginning, the
patient and the family should be involved
in the treatment and it should be explained
that the best time to end treatment can only
be ascertained through trial discontinuation
of the medication.
11.3
Special issue:
resistance in depression
Treatment
Assessing the issue of treatment
resistance in these episodic disorders
requires the study of such questions as:
i.
60
Is treatment being delivered efficiently
and with skill?
Is treatment at this stage of the natural
history of an affective episode being
given at the wrong time? There is
evidence for differing efficacy of
treatments at different points in the
waxing and waning of an affective
cycle. Might not the same treatment
work if given later?
iii Is apparent response of a "resistant
case" to a special regime, an
observational artefact; i.e., a
spontaneous improvement occurring at
this point in time?
iv. Is "resistant depression" in some cases
the results of adverse effects of the
drug, plus emotional reactions to such
side-effects (e.g. impotence), worsened
by marital discord resulting from
enforced celibacy, continuing day-time
sedation, hypersomnia, and excessive
drug-induced weight-gain etc.? Might
not recovery occur simply as a result of
stopping medication?
v . When this occurs, might not some "new"
treatment which has been introduced in
the meantime, and which lacks both
efficacy and side-effects, be given
undeserved credit, and written up as a
useful method of dealing with treatment
"resistance"?
Lithium carbonate, MAOIs, ECT,
carbamazepine3, regular physical exercise,
and various psychotherapies have all been
considered worthy of a trial in treatmentresistant depression, as well as treatment
by the combination of lithium with an
antidepressant which some consider as a
treatment of choice in these situations. It is
important to be aware that stopping all
treatment is sometimes effective.
11.4
Prevention of depressive episodes
If a depressed patient has had more
than one severe episode of depressive
illness, (especially if there has been one or
more episodes in the last five years), long
term prophylactic therapy should be
considered. This can take the form of long
term treatments with antidepressants or
lithium salts. Some experts advocate the
use of carbamazepine as a prophylactic
treatment with those patients for whom, for
WHO/MNH/MND/93.27
various reasons, lithium administration is
unfeasible.
11.5
Manic episodes
Lithium salts are effective in the acute
management of manic episodes.
Haloperidol, as well as other neuroleptics,
are also effective in controlling these acute
states and act faster than lithium salts,
especially for the control of agitation and
hyperactivity, but cause more side-effects
(confusion, over-sedation, slurring of
speech, ataxia, extra-pyramidal symptoms,
etc).
For patients with affective disorders, who
are particularly likely to suffer recurrences,
extensive studies support the efficacy of
lithium in preventing such recurrences,
whether depressive or manic. Some experts
advocate the use of carbamazepine as a
prophylactic treatment with those patients
for whom, for various reasons, lithium
administration is unfeasible. The tricyclic
antidepressants have been shown to be
effective as long-term preventive treatments
for recurrent unipolar disorder.
61
WHO/MNH/MND/93.27
12.
F40 - F48 TREATMENT OF
NEUROTIC, STRESS-RELATED
AND SOMATOFORM
DISORDERS
12.1
Principles of treatment: panic,
agoraphobia, generalized anxiety
disorders and obsessive-compulsive
disorder
The main disorders which will be
discussed in this section are panic and
agoraphobia, generalized anxiety disorders
and obsessive compulsive disorders.
Agoraphobia without panic is rare and,
like specific phobias, seldom produces
sufficient disability to warrant medical
attention. Panic disorder, with or without
agoraphobia, is a potent reason for seeking
medical attention simply because of the fear
that panic may end in a medical emergency.
Despite medical attention, avoidance of
situations for fear of panic frequently
follows a chronic course simply because of
the absence of avoidance learning.
There has been extensive research on the
drug treatment of this disorder,
demonstrating that imipramine,
clomipramine and alprazolam3 will produce
improvement. Antidepressant drugs are
recommended as the treatment of choice in
panic disorder. Some tolerance to high
doses seems to develop so that after a few
weeks on the drug the dose can be raised
further if the therapeutic effect is
inadequate. It may take four to six weeks on
a full dose before suppression of panic
attacks occurs. Maintenance therapy should
be continued for a minimum of six months
(at an usual dosage of 100-125 mg at night)
for the tricyclics, and the drug should then
be withdrawn. Should symptoms recur
treatment can be re-instituted. Drug therapy
should only rarely be continued beyond 18
months. If symptoms recur after this period
one should consider a more systematic
application of alternative approaches (e.g.,
behaviour therapy techniques) and family,
interpersonal, or dynamic factors that may
be perpetuating the panic disorder should
be investigated.
62
About 20% of panic disorder patients
experience a reaction after one or two
tablets of imipramine, causing increased
anxiety, unsteadiness, and feeling very ill in
some unspecifiable way. Even those who
persist with the drug need a clear waning
about the side effects like dry mouth,
hypotension, or tremor if they are not to
misinterpret these symptoms as evidence of
a worsening of panic. It is usual to begin
with a 50 mg dose of imipramine,
increasing by one 25 or 50 mg tablet every
few days until the patient is taking 150-200
mg in divided doses in the early evening
and before retiring.
Regarding the management of
generalised anxiety disorders, the efficacy
and safety of benzodiazepines has led them
to become the dominant anxiolytic drug
group. They should, however, preferably be
used for short-term management, that is for
less than four weeks, because of the
tolerance and dependence that often
develops with longer use. In terms of
withdrawal symptoms, short-acting
benzodiazepines are more problematic than
the long-acting compounds. However, if
they are slowly tapered, there is no
difference between long and short-acting
compounds.
Benzodiazepines may be used in two
ways in the short-term management of
uncomplicated generalised anxiety disorder.
First, short-acting compounds may be
prescribed either for occasional and
intermittent treatment of acute symptoms or
in specified situations where an individual
is subject to a particularly potent stressor.
Second, where the patient suffers severe
anxiety over a substantial part of the day,
low doses of the long-acting compounds
may be employed adjunctively with both
behaviour therapy and psychotherapy. The
use of anxiolytic drugs in larger doses may
impair the ability of the patient to benefit
from the behavioural or dynamic
psychotherapies.
There is no evidence to suggest any
significant role for beta-blockers in this
condition. Similarly, the use of major
tranquillizers in otherwise uncomplicated
generalised anxiety disorder is
not
indicated. A few elderly patients taking
benzodiazepines
may show excessive
sedation and confusion. If drug therapy
WHO/MNH/MND/93.27
appears obligatory in such cases, then there
may be a limited role for low and
intermittent doses of major tranquillizers
otherwise not indicated in this condition.
Regarding obsessive-compulsive
disorders, tricyclic antidepressants,
especially clomipramine, have been reported
to have a specific effect in their
management and a therapeutic trial of a
tricyclic antidepressant is worthy of
consideration in patients with significant
compulsions. Resistance to drug taking is
high in this group of patients and may
reflect a predominant personality conflict
over self control versus control by others.
These patients do not tolerate changes in
state easily, and even patients who have
benefited from the drug often discontinue
voluntarily, then relapse and have to begin
taking the drug again. Some patients may
have difficulty in tolerating the adverse
effects of tricyclic antidepressants; in some
cases non-tricyclic antidepressants (e.g.,
MAOI, SSRI, or others) can be better
tolerated. The demand for or refusal of a
prescribed drug can become a focus for
debate in therapy, the issues of domination
and submission becoming the main topics.
Prescribing therefore has to be done with a
high level of psychological sensitivity.
Obviously, the combination of drug and
psychological therapy is frequently
indicated, especially when there is evidence
of depression.
Anxiolytic drugs have a very limited
role in the treatment of
obsessive-compulsive disorders. These
drugs can produce suppression of the
anxiety associated with the disorder, but
this may rapidly lead to dependence so that
even though patients obtain no lasting
benefit, they may have great difficulty in
discontinuing benzodiazepines.
Clomipramine has also been shown to
be effective in the management of social
phobia.
Principles of treatment:
Post12.2
traumatic stress disorder (PTSD),
adjustment disorder, dissociative
disorder, somatization disorder
A small number of recently controlled
trials seem to indicate that tricyclic
antidepressant
(imipramine or
amitriptyline) may be effective in the
management of PTSD; antidepressants have
been employed for eight-week treatment
periods, with doses up to 300 mg. It is
worth noting the lack of any placebo
response in PTSD:
The use of benzodiazepines in
adjustment disorders is not supported by
the results of well controlled trials;
moreover, drug treatment may involve risks
because prescription of a drug (or of
another intervention) can 'legitimize' the
symptoms as illness, convincing the patient
of the seriousness of the state and may
present an obstacle to recovery.
There is to date no adequate scientific
information about the pharmacological
treatment of dissociative disorders.
Medication should generally be avoided in
somatization disorder.
63
WHO/MNH/MND/93.27
13.
F51.0 NON-ORGANIC
INSOMNIA
In many cases a disturbance of sleep is
one of the symptoms of another disorder,
either mental or physical. Even when a
specific sleep disorder appears to be
clinically independent, a number of
associated psychiatric and/or physical
factors may contribute to its occurrence.
Whether a sleep disorder is an independent
condition or simply one of the features of
another disorder should be determined on
the basis of a careful assessment by the
clinician.
It should also be noted that the actual
amount of hours of sleep is not necessarily
related to the patient's complaints, as there
are so-called short sleepers who do not
consider themselves as insomniacs while
there are people who suffer greatly from the
poor quality of their sleep, and yet their
sleep quantity is considered subjectively
and/or objectively within normal limits.
Treatment of nonorganic insomnia
should be highly individualized, as it is in
any disorder in which lifestyle and learning
patterns interact with different physiological
parameters.
64
Before starting any pharmacological
treatment, the patient should be carefully
educated for a proper sleep hygiene.
Appendix VII lists twelve rules for a better
sleep hygiene (16). It is surprising how
frequently some, or most of these simple
rules are violated, and nevertheless the
patient complains of a poor sleep. These
rules should also serve as a guide for the
clinician to explore the behavioral patterns
of the patient concerned and find ways to
improve them.
A chronic, nightly use of hypnotics and
sedatives is hardly justified, because of the
risk of withdrawal and rebound symptoms
when the patient stops taking the medicine.
However, in selected circumstances the
prescription of an hypnotic is justified,
especially when sleeping is a primary need
for the patient, for instance because of a
very important upcoming day or other
selected situations. For temazepam, the
usual dosage is in the range of 10-50 mg.
In these cases, temazepam (and similar
short-acting benzodiazepines) are to be
preferred, since they are rapidly
metabolized and there are smaller hang
over symptoms the day after.
WHO/MNH/MND/93.27
14.
■
14.1
F60.0-F60.7 TREATMENT OF
DISORDERS OF ADULT
PERSONALITY AND
BEHAVIOUR
Principles of Treatment
Personality disorders (PD) are usually
present from adolescence onwards. They
often lead to (chronic) difficulty maintaining
employment or meaningful relationships.
Despite the shortage of randomised
controlled trials, it is becoming apparent
that the treatment to be preferred differs
between the various personality disorders.
Given the chronic, long-term course of
these disorders, it is difficult to think in
terms of acute treatment as opposed to
maintenance treatment. However, patients
suffering from PDs can have acute
decompensation which may require the
administration of targeted pharmacotherapy.
The choice of the drug, its dosage, and the
length of the administration will depend on
the specific nature and characteristics of the
disorder and of the acute decompensation.
F60.0 Paranoid Personality Disorder: There
are no controlled studies about the
pharmacological treatment of this condition
but clinical wisdom suggests that
neuroleptics at low dosage may lead to
increased trust and decreased
suspiciousness that may improve the social
and occupational functioning of some of
these individuals, at least in periods of
worsened social adaptation.
F60.2 Dyssocial Personality Disorder:
There is a large amount of literature on this
disorder that points out its relationship to
behavioural disorder in childhood, and to
criminality and drug and alcohol abuse in
adulthood. There is no acceptable evidence
that the disorder can be ameliorated by
drug treatment.
F60.3 Borderline Personality Disorder:
There are three double-blind drug studies
from which one might conclude that
benzodiazepines are not to be recommended
because they can lead to difficulties in
emotional and behavioural control. There
are suggestions from some controlled
clinical trials that low dose neuroleptics
may have some short-term limited
usefulness in selected severely ill patients,
notably those with transient psychotic
ideation, anxiety and somatization. Major
depressive episodes may complicate the
disorder and may necessitate an adequate
treatment using tricyclic antidepressant
drugs.
F60.4 Histrionic Personality Disorder:
There is no research-based information
available about the drug treatment of this
disorder.
F60.5 Anancastic personality disorder:
There is no evidence about the effectiveness
of current pharmacological treatments.
F60.6 and F60.7 Anxious and Dependent
Personality Disorders: Also for these
personality disorders, there are very few
data concerning effective pharmacological
treatment approaches. In dependent
personality disorders, the need to avoid
drug dependence has been stressed.
F60.1 Schizoid Personality Disorder: There
are no studies of effective treatment in this
condition but especially case reports suggest
that neuroleptics at low dosage can help in
the management of acute decompensations;
acute anxiety or depressive episodes can
also be treated pharmacologically, using
benzodiazepines at low dosage.
65
WHO/MNH/MND/93.27
15.
F70-F79
RETARDATION
MENTAL
*
Mental retardation (MR) as such is not
amenable to drug treatment: however,
psychiatric disorders often associated with
mental retardation can be treated
pharmacologically. Neuroleptics are used in
schizophrenia and schizophrenia-like states;
and in severe behaviour disorder. Tardive
dyskinesia is a common toxic effect,
particularly in persons over the age of 50
years. The neuroleptic malignant syndrome
has also been reported. Care is necessary to
avoid excessive dosage, particularly in this
population. These patients are frequently
not of sufficient competence to be involved
in treatment decisions about themselves,
and are usually compliant with treatment
instructions.
Antidepressants are used in affective
disorders; lithium carbonate in manic and
depressive disorders; and more recently to
reduce aggression in MR. Stimulant drugs
(e.g., methyl amphetamine3) are used for
hyperactivity, and anticonvulsants for the
treatment of epilepsy, often associated with
MR. Consent to treatment with medication
should be sought from a person authorized
to give it, when the patient is unable to give
informed consent. Such treatment should be
reviewed on a regular basis with special
attention to adverse effects since these
patients are often poor informants.
66
WHO/MNH/MND/93.27
16.
*
F80 - F99 BEHAVIOURAL
AND EMOTIONAL
DISORDERS WITH ONSET
USUALLY OCCURRING IN
CHILDHOOD
This section will deal with only a few
behavioural and emotional disorders with
onset usually in childhood
(e.g.
hyperactivity, conduct disorders, and
enuresis) (ICD F80-99).
16.1
Current treatments
Dietary approaches for hyperactivity have
been popularized, but evidence as to their
efficacy is conflicting; they may be of some
value in cases of hyperactivity due to
sensitivity to specific food substances.
However, it is not clear how to identify
such patients. With regard to the treatment
of hyperactivity with stimulants, however,
effectiveness in reducing some of its
associated symptoms, such as attention
deficits, has been well established, as are
rational indicators for the selection and
timing of this treatment approach.
In the management of enuresis, although
tricyclics have been shown in randomized
control trials to be effective, relapse after
termination is common and drug side
effects may be significant.
Little attention has been given to
childhood psychiatric disorders in
developing countries, particularly with
regard to the evaluation of the effectiveness
and the appropriateness of various therapies
used in different cultural and ethnic setting.
This is particularly important in child
psychiatry because of the extent to which
disorders and treatments are influenced by
cultural, developmental, and ambient
disease variables.
67
WHO/MNH/MND/93.27
*
PART VI
APPENDICES
69
WHO/MNH/MND/93.27
APPENDIX I
CLASSIFICATION OF PSYCHOACTIVE DRUGS
1. ANXIOLYTICS
2. ANTIDEPRESSANTS
1.1 Benzodiazepines
2.1 Tricyclic antidepressants
1.1.1 1,4 Benzodiazepines
Pro- and Nor-diazepam derivatives
Bromazepam
Clorazepate
Chlordiazepoxide
Diazepam4
Flurazepam
Ketazolam
Medazepam
Prazepam
Nitro-derivatives
Flunitrazepam
Nitrazepam
3-hydroxy substituted derivatives
Lorazepam
Lormetazepam
Oxazepam
Temazepam4
1.1.2 1,5 Benzodiazepines
Clobazam
1.1.3 Triazolo-benzodiazepines
Alprazolam
Midazolam
Triazolam
Brotizolam
1.1.4 Thiodiazepines
Clothiazepam
2.1.1 Iminodibenzilic
Clomipramine4
Desipramine
Imipramine4
Lofepramine
2.1.2 Dibenzocicloheptadienic
Amitriptyline4
Nortriptyline
2.1.3 Dibenzocicloheptatrienic
Butriptyline
Protriptyline
2.1.4 Other
Amineptine
Amoxapine
Dibenzepine
Dothiepin
Doxepin
Dosulepine
Melitracen
1.2 With a different chemical structure
Buspirone
Meprobamate
Zoplicone
Zolpidem
2.2 Mono-Amine Oxidase Inhibitors
2.2.1 Irreversible
Phenelzine
Isocarboxazid
Nialamid
Tranylcypromine
2.2.2 Reversible (RIMA)
Moclobemide
Toloxatone
2.3 With a different chemical structure
Bu propione
Maprotiline
Mianserine
Minaprine
Trazodone
2.4 Serotoninergic selective re-uptake inhibitors
Fluoxetine
Fluvoxamine
Paroxetine
Citaprolam
Sertraline
71
WHO/MNH/MND/93.27
3
ANTIPSYCHOTICS
3.1 Phenothiazines
Aliphatic phenothiazines
Chlorpromazine4
Levomepramazine
Promazine
Trifluopromazine
Piperidine phenothiazines
Pipotiazine
Thioridazine
Piperazine phenothiazines
Fluphenazine4
Perphenazine
Trifluoperazine
3.2 Thioxanthenes
Clopenthixol
Clorprothixene
Flupen th ixole
Tioxanthene
3.3 Dibenzoxazepines
Clothiapine
Loxapine
3.4 Butyrophenones
Haloperidol4
Droperidol
Trifl uoperidol
3.5 Biphenylbutylpiperidines
Pimozide
3.6 Benzamides
Sulpiride
3.7 Dibenzodiazepine
Clozapine
3.8 With different chemical structure
Molindone
Risperidone
9
4
72
WHO/MNH/MND/93.27
APPENDIX II
Tables of equivalency of selected psychiatric drugs
TABLE 1.
EQUIVALENCY OF SELECTED ANTISPYCHOTIC DRUGS
DRUG
Relative potency
Chlorpromazine
Droperidol
Fluphenazine
Haloperidol
Levomeproma zine
Perphenazine
Pimozide
Pipothiazine
Promazine
Thioridazine
Trifluoperazine
TABLE 2.
100
2
4
2
120
12
2
2
100
120
5
COMPARATIVE FEATURES OF THREE ANTIPSYCHOTIC DRUGS
CHLORPROMA
ZINE
HALOPERIDOL
FLUPHENAZINE
DECANOATE
Dose equivalency
100 mg
2 mg
2 mg
Half life
15-30 hrs
24 hrs
7-10 days
Steady state
5-7 days
several days
several days
Acute phase doses
300-800 mg/day
3-10 mg/day
25-50 mg every
2-4 days
Maintenance treatment doses
100-500 mg/day
2-6 mg/day
12.5-25 mg every
2-4 days
73
WHO/MNH/MND/93.27
r
TABLE 3.
EQUIVALENT AVERAGE DOSES OF SELECTED ANTIDEPRESSANT DRUGS
Average dose (mg)
Drug
150
150
100
150
140
100
20
200
90
150
Amitriptyline
Clomipramine
Dothiepin
Imipramine
Lofepramine
Nortriptyline
Fluoxetine
Fluvoxamine
Mianserin
Trazodone
Isocarboxazid
Phenelzine
Moclobemide
30
45
300
TABLE 4. THERAPEUTIC AVERAGE DOSES OF SELECTED BENZODIAZEPINES
Drug
Alprazolam
Bromazepam
Chlordesmethyldiazepam
Chlord iazepoxide
Desmethyldiazepam
Diazepam
Flunitrazepam
Flurazepam
Lorazepam
Oxazepam
Temazepam
Triazolam
Anxiolytic effect
0.50
2
1
15
2.5
5
1
15
6
Hypnotic effect
6
5
75
10
20
4
30
5
60
25
0.25
V
74
WHO/MNH/MND/93.27
TABLE 5.
APPROXIMATE COMPARATIVE COST OF SOME ESSENTIAL DRUGS*
US$/FOB
(approx.)
Unit quantity
supplied for
quoted price
Average cost of 4
weeks maintenance
treatment
Amitriptyline HO
tabs 25 mg
7
per 1,000
2.10
Biperiden HC1 **
tabs 2 mg
4
per 50
4.80
2
per 5
Chlorpromazine HC1
tabs 100 mg
inj. 50 mg/2 ml
11
6
per 1,000
per 100
1.15
Diazepam
tabs 5 mg
inj. 10 mg/2 ml
3
6
per 1,000
per 100
0.18
8
per 10 vials
of 1 ml
0.80
Haloperidol
tabs 1.5 mg
7
per 1,000
0.63
Imipramine HC1
tabs 25 mg
7
per 1,000
2.10
Lithium carbonate
tabs 300 mg
4
per 60
6.00
5
per 100
Drug
Biperiden lactate
inj. 5mg/ml
Fluphenazine decanoate
inj. 25 mg/ml
Disposable 5 ml syringes
with needles
*
* Average prices quoted by several WHO suppliers, whose addresses are available on request.
** Other anticholinergic antiparkinson drugs are available more cheaply, e.g.
benzihexol/trihexyphenoxyl 5 mg: US$ 6.00 per 1,000.
75
WHO/MNH/MND/93.27
APPENDIX III
PSYCHOACTIVE DRUGS IN PREGNANCY
Special precautions should be used
whenever a psychotropic drug is prescribed
during pregnancy. The first point to be
considered is to what extent the pregnant
woman needs a pharmacologic treatment,
and whether it is possible to use alternative
non-pharmacologic treatments. Should the
drug prescription be absolutely needed, it is
necessary to know the following data
concerning psychotropic drugs in
pregnancy; they will dealt with under four
headings: hypnotic and anxiolytic drugs,
neuroleptic drugs, antidepressants, and
lithium carbonate.
1. Hypnotic and anxiolytic drugs
Benzodiazepines, the most widely used
anxiolytic drugs, cross the placenta and may
cause hypotonia, respiratory depression and
hypothermia in the newborn. These drugs,
owing to their pharmacological effects, have
caused, or may be suspected of causing,
harmful effects on the human fetus or
neonate without causing malformations.
These effects may be reversible.
Long-term treatment and administration
of high dosages in connection with the
delivery should be avoided. Withdrawal
symptoms in newborn infants have been
reported with this class of drugs.
2. Neuroleptic (anti-psychotic) drugs
2.1 Phenothiazines
These drugs, owing to their
pharmacological effects, have caused, or
may be suspected of causing, harmful
effects on the human fetus or neonate
without causing malformations. These
effects may be reversible.
In some cases in which they have been
administered in high dosages during late
pregnancy, pheno thia zines have caused
prolonged extrapyramidal symptoms in the
newborn.
76
c
2.2 Butyrophenones
Although there have been isolated case
reports of birth defects following fetal
exposure to haloperidol and droperidol in
combination with other drugs, no definite
cause and effect relationship can be
confirmed for the butyrophenones. In some
cases in which they have been administered
in high dosages during late pregnancy,
butyrophenones have caused prolonged
extra pyramidal symptoms in the newborn.
3.
Antidepressant drugs
Tricyclic antidepressants have not been
shown to be associated with an increased
incidence of birth defects. However, there
is evidence of interference with central
monoamine neurotransmission in rats.
Therefore these drugs should be taken only
in selected cases needing an urgent
pharmacologic treatment.
As regards other antidepressants
including MAOIs, the evidence available
about their safety is scanty, and therefore
they are best avoided in pregnancy.
4. Lithium carbonate
Several studies have shown the
teratogenic effect of lithium taken in the
first months of pregnancy. The
cardiovascular system is especially affected,
in particular the tricuspid valve. Other
studies have shown other teratogenic effects
possibly due to lithium.
Moreover lithium enters the fetal
circulation and cases of disturbance of
thyroid function of the newborn infant have
been reported. For all these reasons, lithium
should be avoided during pregnancy.
For more detailed information on this
very sensitive and specific issue, the reader
should to consult up-to-date textbooks of
pharmacology.
I
WHO/MNH/MND/93.27
APPENDIX IV
a
T
PSYCHOACTIVE MEDICINES IN OLD AGE
There are no psychiatric disorders that
are absolutely specific to old age. The
various syndromes that are discussed in this
document, except age specific conditions of
childhood, adolescence, and the
reproductive period of life, are all found in
the elderly. However old age is a period of
life in which diseases and disorders occur
more frequently than in younger age
groups. These conditions not only interact
with one another, but also with
environmental and treatment variables to
produce a group of characteristic
management and drug treatment problems
which deserve attention.
Psychiatric conditions which show
increased rates in the elderly include
organic psycho-syndromes and depressive
illness of all types. Paranoid, neurotic and
hypochondriacal disorders are also frequent,
and often complicate the treatment of
somatic illnesses, themselves prevalent in
the elderly.
The pharmacological
management of these states does not differ
greatly from those dealt with elsewhere in
this report. However, mental disorders in
the elderly do have certain unique features
affecting drug treatment.
Mental disorders in the elderly are
superimposed on diminishing physiological
capacities and functions. Cerebral neuronal
reserve is diminished, making the
emergence of organic psycho-syndromes
more likely when minimal additional insult
occurs; hence the elderly are more at risk
for minor states of illness, toxicity, or
deprivation to set off a delirium or other
acute organic state. Reduced renal clearance
and diminished efficiency of hepatic and
other detoxification mechanisms, make them
peculiarly vulnerable to the consequences of
high blood levels of drugs, and also to
interactions between drugs; this is further
influenced by the fact that their numerous
ills lead to the accumulation of prescriptions
for different types of medications. Drugs are
added to this list more often than they are
removed;
removal is often stubbornly
resisted by patients because of the false
security medicaments may provide.
Polypharmacy thus constitutes a major
source of secondary mental disorder. Added
to this, infectious or toxic states, themselves
of minor consequence, are common, and
cerebral oxygenation is often compromised
by inefficient cardiopulmonary and oxygen
transport systems. Neglect of adequate
nutrition because of (a) reduced appetite,
(b) the effect of living alone and on a
reduced income, and (c) less efficient
intestinal absorptive mechanisms,
contributes to this overall picture of cerebral
vulnerability.
The net result is an increase in the rate
of occurrence of organic psycho-syndromes.
These are frequently mild; unfortunately,
their manifestations are often dismissed as
simply those of old-age and senescence.
These mild states of cerebral dysfunction are
typically characterised by organic affective
symptoms, resembling personality features
(particularly paranoia, anxiety, irritability
and querulousness, low frustration toleran
ce, affective disinhibition and lability, and
hypochondriacal preoccupation with minor
discomforts). More frank states of delirium
can emerge with suddenness. Management
requires that the practitioner be sensitive to
these circumstances, and tailor his drug
prescribing, and his dosages, accordingly.
As with other diseases in the elderly,
depressive illness may respond well to
lower doses of anti-depressants; but there is
a risk of side effects due to anticholinergic
properties of many of the currently used
antidepressants.
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WHO/MNH/MND/93.27
APPENDIX V
Prophylactic Use of Anticholinergics in Patients on Long-Term Neuroleptic
Treatment: a Consensus Statement (14)
The heads of centres collaborating with
the WHO in biological research on mental
disorders decided to develop a series of
consensus statements on key issues in
biological research and treatment of
psychiatric problems, The statement on
prophylactic use of anticholinergics in
patients on neuroleptic treatment is the
second of the proposed series.
Anticholinergics (that is, agents which
antagonise the action of acetylcholine at
muscarinic receptor sites) are not only
commonly used for the treatment of early
neuroleptic-induced extrapyramidal side
effects (Parkinsonism, dystonia), but are also
sometimes administered from the onset of
antipsychotic therapy, with the aim of
preventing the occurrence of such effects.
The prophylactic use of anticholinergics
has been claimed to be particularly useful in
order: (a) to avoid the appearance of
neurological manifestations (such as
akinesia and akathisia) which may mimic
psycho pathological symptoms and therefore,
may lead to an inappropriate increase of the
neuroleptic dosage; and (b) to improve the
patient's compliance, since patients who
experience neurological adverse reactions
are more prone to become non-compliant.
Nevertheless, several arguments against
the prescription of anti-Parkinsonian
preventive medication can be advanced:
i
(a) The long-term use of anticholinergics
may predispose to tardive dyskinesia (in
fact, the administration of these agents
exacerbates the syndrome in affected
patients and has been used as an aid to
its early detection).
(b) Anticholinergic medication may induce
autonomic side-effects, which may be
sometimes serious (urinary retention,
paralytic ileus).
78
c
(c) The long-term use of anticholinergics
is likely to affect memory functions,
thus further compromising the already
impaired cognitive performance of
schizophrenic patients.
(d) It has been suggested that
anticholinergics may contribute to the
development of hyperthermic episodes,
some of which may be fatal.
(e) The consumption of an excessive dose
of anticholinergics may produce an
acute toxic state, with agitation,
disorientation in time and space,
delusions and hallucinations.
(f) In some cases, anticholinergics may be
abused as euphoriants, so that their
discontinuation may be difficult.
(g) There are some indications that
anticholinergics can decrease
the
therapeutic activity of neuroleptics,
although early reports of
pharmacokinetic interactions between
the two classes of drugs have not been
confirmed by more recent studies.
(h) Many patients on antipsychotic therapy
do not develop Parkinsonism, so that
anti-Parkinsonian preventive treatment
is sometimes unnecessary.
On the basis of these considerations, the
prophylactic use of anticholinergics in
patients on neuroleptic treatment is not
recommended, and may be justified only
early in treatment (after which it should be
discontinued and its need should be re
evaluated. As a rule, these components
should be used only when Parkinsonism
has actually developed, and when other
measures, such as the reduction of
neuroleptic dosage or the substitution of the
administered drug by another less prone to
induce Parkinsonism, have proven
ineffective.
V
WHO/MNH/MND/93.27
7
APPENDIX VI
Pharmacotherapy of depressive
disorders: a consensus statement
(15)
WHO Mental Health Collaborating
Centres
The heads of centres collaborating with
WHO in biological psychiatry and
psychopharmacology decided to develop a
series of consensus statements on key issues
in biological research and treatment of
psychiatric problems. This statement on
Pharmacotherapy of Depressive Disorders is
the first of the proposed series.
Acute treatment.
Treatment of
depressive disorders will be initiated with
antidepressants.
Practitioners should
become familiar with the properties of two
or three compounds, particularly with
regard to the effective dose. The effective
dose may vary from one population to
another. In general, older patients need
lower doses than younger ones. If a patient
does not respond within 3 weeks, changing
dosage or alternative medication should be
considered. Electroconvulsive therapy may
be considered in some cases of severe
depressive illness and those not responding
to treatment with antidepressant drugs and
psychotherapy. Potential side-effects should
always be discussed with the patient. In
prescribing, it should always be borne in
mind that depressed patients may have
suicidal thoughts and the total amount of
medication prescribed or given to the
patients should not be too large.
For all patients suffering from
depressive disorders psychotherapy may be
useful in conjunction with
pharmacotherapy.
1
Continuation treatment Antidepressant
medication should be continued for at least
six months after recovery. It should then be
discontinued gradually and the patient
should always be seen about 3 weeks after
cessation of all antidepressant medication to
check the mental state. If well, the patient
should then be seen at no more than 2month intervals for up to a 6-month period.
From the beginning the patient and the
family should be involved in the treatment
and it should be explained that the best
time to end treatment can only be
ascertained through trial discontinuation of
the medication.
Prophylaxis. If the patient has had more
than one severe episode of depressive
illness and especially if there has been one
or several other episodes (apart from the
present one) in the last 5 years, long-term
prophylactic therapy should be considered.
This can take the form of long-term
treatment with antidepressants (particularly
with an antidepressant the patient is known
to have responded to) or with lithium salts.
Lithium has the advantage of also
preventing manic attacks and is known to
be effective in lower doses than previously
used (a plasma lithium concentration 12 h
after the last dose of 0.5-0.7 mmol/I is
sufficient). It is useful to check plasma
levels every 2 months after the patient has
been stabilised on the appropriate dose.
Whenever possible long-term lithium or
antidepressants should be given in a single
dose (usually at bedtime) so as to ensure
maximum compliance.
All long-term
therapy should be accompanied by regular
check-up visits at least once every 2 months.
A special facility for systematic and
regular follow-up of patients and for
monitoring plasma lithium (e.g. an affective
disorder clinic) can greatly assist the
management of these patients.
Prophylactic medication should always
be carefully discussed with the patient and
family. If the patient does not wish to
receive long-term medication, it is
particularly important to make clear to the
patient and the family that they should seek
help at the first sign of a recurrence of the
illness.
Patients maintained on long-term
medication will often request (especially
after a period of good health) to discontinue
treatment.
If the patient presses to
discontinue prophylactic medication after
appearing well for 2 years or more, it is
reasonable to undertake a trial
discontinuation of treatment. In these cases
the patient should still be followed up as
before, i.e., at 2-month intervals, and
warned of the danger of future episodes
and the need to return immediately for
treatment if the symptoms return.
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APPENDIX VII
Rules for Better Sleep Hygiene
(16)
1.
Lie down intending to go to sleep only
when you are sleepy. But have a
consistent time when you plan to go to
sleep.
2.
Never use the bedroom for anything but
sleep or sex. No activities in bed like
reading, watching television, eating,
talking on the telephone or discussing
problems.
3. Set your alarm and get up at the same
time every morning, regardless of how
much sleep you get during the day.
4. Do not nap during the day.
5. Do not drink alcohol within several
hours of bedtime.
6. Do not consume caffeine beverages or
medications that contain caffeine within
several hours of bedtime.
7. Do not smoke within several hours of
bedtime.
8. Exercise in the late afternoon or early
evening. Light stretching or a short
walk may be sufficient .
9. Allow yourself a transition period.
During the hour before you go to bed,
gradually decrease your activity level.
Do things that are quiet and relaxing
10. Develop a routine before going to bed.
Include activities like personal hygiene,
checking lights, and locked doors. Do
things that make you feel safe and
secure.
11. Make sure no excessive light or sound
will disturb you, and that your room is
at a comfortable temperature.
r
12. Going to bed hungry or after a large
meal can inhibit sleep. However, if you
feel hungry, a light snack or a glass of
warm milk is appropriate.
80
4
WHO/MNH/MND/93.27
18.
NOTES
>
i
For instance: WHO, The selection of
essential drugs. Geneva, WHO, 1977;
WHO, The selection of essential drugs.
Geneva, WHO 1992; Ghodse H. & Khan
I. Psychoactive drugs: improving
prescribing practices. Geneva, WHO,
1988; WHO, Benzodiazepines and
therapeutic counselling.
Geneva,
WHO, 1988; WHO, The introduction of
a mental health component into
primary health care. Geneva, WHO,
1990; WHO, Evaluation of methods for
the treatment of mental disorders.
Geneva, WHO, 1991.
2
This section is adapted from WHO
Scientific Group on the Treatment of
Psychiatric Disorders. Evaluation of
methods for the treatment of mental
disorders (TRS 812). Geneva, WHO,
1991.
3
Not discussed in this document.
4
Described in some detail
document.
in
this
81
■2
WHO/MNH/MND/93.27
19.
REFERENCES
<
<
1.
WHO. The selection of essential drugs.
Geneva, World Health Organization,
1977.
2. WHO. Evaluation of methods for the
treatment of mental disorders ( TRS
No. 812). Geneva, World Health
Organization, 1991.
3.
Harding T & Chrusciel TL. The use of
psychotropic drugs in developing
countries. Bulletin of the World Health
Organization, 52: 357-367, 1975.
Essential Treatments in
4. WHO.
Psychiatry.
(Doc.
WHO/MNH/MND/93.26).
Geneva,
World Health Organization, 1993.
5. American Medical Association. Council
Report: Quality of Care. Journal of the
American Medical Asociation,
256(8):1032-1034, 1988.
6. Ghodse H & Khan 1. Psychoactive
drugs:
improving prescribing
practices.
Geneva, World Health
Organization, 1988.
I
7. Gutheil TG. Drug therapy: alliance and
compliance. Psychosomatics, 19: 219225, 1978.
8. Smith GT. Keep on taking the tablets?
Office of Health Economics Briefing,
21, 1-6, 1983.
9.
WHO. The selection of essential drugs.
Geneva, World Health Organization,
1992.
10. Mallett P. Anticholinergic drugs in
psychiatry. International Journal of
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11. WHO. The introduction of a mental
health component into primary health
care.
Geneva, World Health
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12. WHO. The International Pilot Study
of Schizophrenia. Chichester, Wiley,
1979.
13. Jablensky A, Sartorius N, Emberg G et
al.
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14. WHO Mental Health Collaborating
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Consensus Statement British Journal of
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