Chapter 6.

15: Depression in Young People and the Elderly

Priority Medicines for Europe and the World

"A Public Health Approach to Innovation"

Background Paper

Depression in Young People and the Elderly

By Eduardo Sabaté

7 October 2004

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 Chapter 6.15: Depression in Young People and the Elderly

Table of Contents

Abbreviations Used in this Report......................................................................................................3

Summary...............................................................................................................................................4
1. Introduction.................................................................................................................................5
Definition and Classifications.......................................................................................................5
Natural History.............................................................................................................................6
Depression in Young People.........................................................................................................7
Depression in the Elderly..............................................................................................................7
2. Epidemiology and Burden of Depression...................................................................................8
Epidemiology of Depression in the General Population...............................................................8
Epidemiology of Depression in Youth........................................................................................10
Epidemiology of Depression in the Elderly................................................................................10
Epidemiology of Depression as a Comorbidity..........................................................................11
Economic Impact of Depression.................................................................................................12
3. Control Strategy.........................................................................................................................12
Antidepressants in Young People...............................................................................................15
Antidepressants in the Elderly....................................................................................................15
Side-Effects of Antidepressants..................................................................................................16
4. Major Problems and Challenges for Disease Control: Why Does the Disease Burden
Persist?......................................................................................................................................20
5. Past and Current Research into Pharmaceutical Interventions with Antidepressants........21
6. What Are the Opportunities for Research into New Pharmaceutical Interventions?..........25
6. What Are the Opportunities for Research into New Pharmaceutical Interventions?..........26
7. Gaps Between Current Research and Potential Research Issues that Could Make a
Difference..................................................................................................................................26
8. Conclusions................................................................................................................................27
9. References:.................................................................................................................................27

Annex

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 Chapter 6.15: Depression in Young People and the Elderly

Abbreviations Used in this Report

5HT: 5-hydroxytryptamine
AD: Alzheimer disease
ADHD: attention deficit with hyperactivity disorder
CRF: corticotropin-releasing factor
CT: computerized tomography
CVD: cardiovascular disease
DALY: disability-adjusted life year
EU10: European union new accession countries
EU15: European union countries
EU25: Expanded European union
ECT: electroconvulsive therapy
FDA: United States’ Food and Drug Administration
fMRI: functional magnetic resonance imaging
GABA: gamma-aminobutyric acid
GDP: gross domestic product
GnRH: gonadotropin releasing hormone
GP: general practitioner
Obs & Gyn: obstetrics and gynaecology
HMO: health management organization
IHD: ischaemic heart disease
IP: interpersonal psychotherapy
CM-IPT: clinician-managed interpersonal psychotherapy
MAO: monoamine oxidase
MAOI: monoamine oxidase inhibitors
MRI: magnetic resonance imaging
NK: neurokinin
NMDA: N-methyl-D-aspartate
PD: Parkinson disease
PET: positron emission tomography
PTSD: post-traumatic stress disorder
PUFA: polyunsaturated fatty acids
RCT: randomized clinical trial
SNSRI: serotonin and noradrenaline-selective reuptake inhibitor
SSRI: serotonin-selective reuptake inhibitor
TCA: tricyclic antidepressant
TMS: transcranial magnetic stimulation
YLD: years lived with disability

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 Chapter 6.15: Depression in Young People and the Elderly

Summary
Depression is a common mental disorder that presents with depressed mood and/or loss of
interest. It is mainly due to adverse life events, disease or medications. It affects important
mental and social functions, which depending on the severity might substantially impair a
patient’s abilities to carry out simple daily activities. Episodes might last for 1 year, be
recurrent or become chronic. Fifteen per cent of patient will commit suicide if not treated.

Depression accounted for 4.5% of the global and 7.6% of the European burden of disease in
the year 2002. Depression affects 3–15% of the general population; 0.4–5% of cases are severe.
It affects mainly adults, women, and low-income groups. In young people, the prevalence of
depression is 0.3% in preschool children; 2% in schoolchildren; and 4 –8% in adolescents.
Children of both sexes are equally affected, but in adolescents, females are affected twice as
often as males. The symptoms may include behavioural problems, social isolation and
difficulties at school; thus depression is frequently misdiagnosed as “growing pains ”.
Depression in adolescents is risk factor for depression and bipolar disorder during
adulthood; drug or alcohol abuse; and suicide. Suicide is one of the major causes of
adolescent mortality.

The percentage of the elderly affected by depression ranges from 2.5% to 53% depending on
the setting. Concurrence of other chronic diseases, polymedication, and behavioural
symptoms, might mask the psychological symptoms of depression (“depression without
sadness”). The suicide rate in the elderly is greater than that for any other segment of the
population.

Depressed patients incur higher medical costs, perform worse at work and have a higher
level of absenteeism than those who are not depressed. In the general population, depression
is often undiagnosed or misdiagnosed and even more frequently untreated. In general, fewer
than 40% of cases are diagnosed at the primary care level; fewer than 40% of these are
treated; and around 40% of treated patients take their medicines as indicated. Assuming
100% treatment efficacy, the effectiveness of health systems in managing depression at the
population level is less than 6.4%.

There are three main forms of treatment for depression:

(1) counselling and/or psychotherapy;

(2) electroconvulsive therapy (ECT); and
(3) antidepressant medications.

The biology of depression and its treatments are poorly understood, especially in adolescents
and in the elderly who have been systematically excluded from studies. Antidepressants
have been reported as highly efficacious, but recently, their risks and benefits have been
publicly discussed. Withholding of safety data by the pharmaceutical industry may have
distorted the real assessment of these drugs. Lack of efficacy data and a growing number of
drug-related suicides preclude their use in young people. There is no first-line drug for
treatment of the elderly, but due to their side-effect profile, selective serotonin re-uptake
inhibitors (SSRIs) are the preferred choice of many physicians.
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 Chapter 6.15: Depression in Young People and the Elderly

In a market worth US$ 16.6 billion, with 7.6% annual growth, the research on antidepressants
is intensive, accounting for approximately 16–20% of annual revenues (US$ 5.6 –3.2 billion).
The current basic research focuses on understanding the relationship between depression
and the circadian rhythms, the hormonal system (hypothalamus regulation), genetics and the
characterization of neuronal receptors and circuits, using PET scan and functional MRI.
Products in the pipeline mainly target new mechanisms, such as NK, 5HT, and CRF
receptors, alone or in combination with known mechanisms, such as selective serotonin,
noradrenalin and dopamine reuptake inhibitors.

Recommendations for narrowing the therapeutic gaps are as follows:

a) include adolescents and the elderly in basic research studies and in RCTs of both new and
old drugs;
b) improve our understanding of the biology of depression and its treatments, which should
be considered together with better clinical diagnostic protocols and robust psychological
models; and
c) improve the effectiveness of models of care for mental health.

1. Introduction
Definition and Classifications

Depression is a common mental disorder that presents with depressed mood, loss of interest
or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy, and
poor concentration. It usually occurs as a result of adverse life events, such as: losses of a
significant person, object, relationship or health, but can also occur due to no apparent cause.
These problems can become chronic or recurrent and lead to substantial impairments in an
individual's ability to take care of his or her every day responsibilities. 1

Despite significant improvements in understanding the biological basis of mental conditions,

information on genetics, neuroendocrine and functional imaging has not been found valid
enough to be included in the diagnostic criteria listed in international classification reports
such as DSM-IV or CIE-10.

Currently, depression is included in the category of mood disorders, which is divided into
bipolar depression, unipolar depression and dysthymic disorders. The relationship between
psychological stress, adverse life events, and the onset of depressive episodes remains
unclear. The distinction between these conditions and anxiety disorders (general anxiety
disorder, panic, post-traumatic stress syndrome, and obsessive–compulsive disorder), has no
physiopathological support. They usually present together in clinical practice. Certainly,
adverse life events can precipitate and contribute to depression, but depression itself can also
be the source of stressful experiences.

New evidence suggests the need for a different classification, based on clusters with
significant comorbidities, common neurophysiopathology, and clinical commonalities.
Under this classification, the bipolar conditions would include bipolar depression, rapid mood
cycling, dysphoric mania, cyclothymiacs and others.2 The obsessive cluster would include
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 Chapter 6.15: Depression in Young People and the Elderly

obsessive–compulsive disorder, obsessive personality and other neurological syndromes

with obsessive movement such as Tourette syndrome. The affective cluster would include
the stress-related mental conditions, bringing together major depression, dysthymia, general
anxiety, panic, post-traumatic stress, adaptation disorders, and evasion-prone personalities.
The less well understood cluster is the non-affective psychosis cluster, which would include
several types of schizophrenia, delirium, type A personality disorders (paronoid and
schizoid), and some genetic syndromes such as fragile X and Asperger’s syndromes.

“Late-onset depression” has been proposed, but has not yet been widely accepted, as an
additional item in the classification of depression, based on common physiopathological
findings in the elderly, such as changes in cognitive function, frontal cortical atrophy seen on
a CT-scan, and other associated conditions.

The most common clinical classification for mood disorders divides them into three groups:

(1) depressive disorders;

(2) bipolar disorders; and
(3) depression associated with medical illness or alcohol and substance abuse.

Among depressive disorders (unipolar), the most used clinical classifications are major
depression, mild/moderate depression and dysthymic disorders.3

Natural History

Depression, as a disorder, usually starts in early adulthood, with likely recurrences. An

episode may be characterized by sadness, indifference or apathy, or irritability. It is usually
associated with change in a number of neurovegetative functions, including sleep patterns
and appetite and weight, motor agitation or retardation, fatigue, impaired concentration and
decision-making, feelings of shame or guilt, and thoughts of death or dying. 1;3-6 A small
proportion of patients will experience psychotic symptoms. The duration of an untreated
crisis ranges from 9 months to several years. Fifty to sixty per cent of patients will have at
least one more episode in their lifetime.

The nature of depression is such that affected persons are unlikely to realize that they are
depressed and therefore unlikely to seek help for themselves. They are also incapable of
appropriately taking their treatment as directed by health care professionals. In all chronic
conditions, the concurrence of depression, highly affects the quality of care provided by
themselves and received by others. When present with other chronic conditions, outcomes
are usually poorer and health care considerably more expensive than expected. 5;7

Major depression is diagnosed when depressed mood or anhedonia (lack of ability to enjoy
or experience pleasure) has been present for more than 2 weeks and is associated with at
least five of the following symptoms: loss of interest, fatigue or loss of energy, insomnia or
hypersomnia, feelings of worthlessness or excessive guilt, decreased concentration,
significant weight loss or gain, and recurrent suicidal ideation.8

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A diagnosis of dysthymic disorder is founded on a patient having suffered from mild but
constant depressive symptoms for at least 2 years, which are not clearly related to any
specific cause. It might concur with a more intensive depressive crisis; this is what is known
as “double depression”.3

Depression in Young People

Depression in young people may be expressed differently from that in adults, with manifest
behavioural disorders (e.g. irritability, verbal aggression and misconduct), substance abuse
and/or concurrent psychiatric problems. Between the ages of 6 and 12 years, the most
common signs and symptoms are somatic (generalized bodily) complaints, school
difficulties, fatigue, boredom/apathy, disturbed eating, lack of motivation, decreased
concentration and anxiety. It is common for young, schoolchildren to present with
irritability, restlessness and hyperactivity, which frequently lead professionals to suspect
attention deficit with hyperactivity disorder (ADHD) instead of depression. 9 Also they might
be wrongly taken to be "typical adolescent mood swings." Between the ages of 12 and 18
years, the most common signs and symptoms are suicidal thoughts, hopelessness, social
isolation, drug or alcohol use, overeating and oversleeping, and rage.10

Risk factors for suicide in young people are: previous suicide attempts; a close family
member who has committed suicide; past psychiatric hospitalization; recent loss of a
significant figure (through death, divorce or separation); social isolation; drug or alcohol
abuse; exposure to violence in the home or the social environment; and handguns in the
home. Early warnings for suicide are talking about it, preoccupation with death and dying,
giving away special possessions, and making arrangements to take care of unfinished
business.6

Depression in the Elderly

Depression in the elderly progresses slowly. Somatic and behavioural symptoms are usually
so intense that they mask the psychological ones, up to the point that they may seem to
suffer “depression without sadness”. The concurrence of several chronic conditions highly
complicates the diagnosis: in these cases depressive symptomatology may reflect the
psychological stress of coping with disease, may be caused by the disease process itself or by
the medications used to treat it, or may simply coexist in time with the medical diagnosis.11
The elderly are also highly likely to be taking many medications concurrently. Virtually
every class of medication includes some agent that can induce depression. Antihypertensive
drugs, anticholesterolemic agents and antiarrhythmic agents are commonly used classes of
medication that can trigger depressive symptoms.

In the general population, depression is often undiagnosed or misdiagnosed and, even more
frequently, it is untreated.12-18 Some studies show that only 30% of parents will share their
children’s psychosocial concerns with their paediatricians, and only 40% of them will
respond to these concerns.19 In an HMO, primary care providers referred only 19% of
patients with a diagnosis of depression, prescribed antidepressants to 25% of them, 49% of
patients who had been prescribed antidepressants made at least one follow-up visit. 20;21
When depression is diagnosed in the elderly, this is usually after years of delay. 22 At least

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 Chapter 6.15: Depression in Young People and the Elderly

15% of patients whose depressive illness goes untreated will commit suicide. Some studies
show that most elderly people who commit suicide visited their physician within 1 month
Graph # 2.1 : Mental
Burden (DALYs per 1000,illness
of mental All regions, 2002)
(DALYs/1000, 2002)
70.00

60.00

50.00

EU25-M
EU25-F
DALYs per 1,000

40.00
EU15-M
EU15-F
EU10-M
30.00 EU10-F
W-M
W-F

20.00

10.00

-
0-4 5-14 15-29 30-44 45-59 60-69 70-79 80+
Age groups

prior to the event, but symptoms were not recognized or treatment was not adequate. 23

2. Epidemiology and Burden of Depression

Epidemiology of Depression in the General Population

Depression is common, affecting about 121 million people worldwide. An estimated 3–15%
of the general population will experience a depressive episode in any given year; 0.4–5% will
experience major depression.1;15;24 In Europe, 58 out of every 1000 adults, or 33.4 million people,
suffer from major depression.25

The burden of mental ill health is the second major cause of the burden of disease at a global
level (12.5%) and major cause in Europe (25.26%). When evaluated as disability-adjusted life
years (DALYs)/ 1.000, it has a common pattern in all regions in the world. Beginning in the
age group 5–14 years, it peaks in the age group 15–29 years, then declines until the age group
60–69 years at which point it increases again almost to the level of the 15 –26-year age group.
Between the ages of 70 and 79 years, a difference appears between sexes and regions; it is
higher in women than men, and EU15 and EU10 (see Fig. # 2.1).

Depression is the leading cause of disability as measured by years lived with disability
(YLDs) and the fourth leading contributor to the global burden of disease (in DALYs) in
2000.

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 Chapter 6.15: Depression in Young People and the Elderly

The burden of depression contributes at least 30% of the overall burden of mental illnesses.
Its distribution is the same for all regions, significantly affecting the younger and older age
groups. A gender difference exists, the burden being twice as high for females than males. In
females the peak is in the age group 30–44 years, whereas in males the peak is in the age
group 15–29 years. These gender differences were previously believed to reflect sociocultural
factors, but recent studies show that genes are largely responsible for major depression in
adult women, and that the environmental factors have a transitory effect which does not
affect lifetime prevalence. Additional sociocultural studies have shown that external
manifestations of depression differ between cultures but the core symptoms are the same. 3

When considered as a percentage of the total burden, males in the age group 5 –15 years and
females aged 30–44 years, account for the highest proportion. There are apparently regional
differences; depression contributes less to the overall burden of diseases when evaluated at
the global level. This is mainly due to the epidemics of HIV/AIDS, malaria and TB in less
developed countries, especially in Africa.

Mortality due to depression is low and increases exponentially with age. Mortality due to
“self-inflicted injuries” is accounted for separately in vital statistics, and accounts for a total
of 850 000 lives every year.1 Among the elderly, deaths caused by self-inflicted injuries
represents an extra 50% and 8% the deaths caused by depression, in males and females
respectively. Depression is suspected to be the cause of the majority of self-inflicted deaths. 26
In many European countries, suicides now exceed traffic deaths, and in countries with a

Depression (DALYs per 1,000, All regions, 2002)

Graph # 2.2 : Burden of Depression (DALYs/1000, 2002)
25.00

20.00

EU25-M
15.00 EU25-F
DALYs per 1,000

EU15-M
EU15-F
EU-10-M
EU-10-F
10.00 W-M
W-F

5.00

0.00
0-4 5-14 15-29 30-44 45-59 60-69 70-79 80+
Age groups

medium-to-high suicide rate, their costs amount to 1.5% of annual GDP.25

Epidemiological studies lack standardized instruments for the evaluation of depression in

zoung people and and in the elderly. Currently, the Pediatric Symptom Checklist, 27;28
Children's Depression Inventory,29;30 the Reynolds Child Depression Scale, 31 and other
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 Chapter 6.15: Depression in Young People and the Elderly

structured interviews are useful in determining the existence of depression in a child or

adolescent. Instruments validated for general populations are not useful in the elderly as the
threshold of objective and subjective functional status changes with age. Several instruments
such as the Zung questionnaire and CES-D have been fairly well adapted for the elderly. 10
Some specific tools for the elderly has been successfully been developed, such as the
Geriatric Scales of Yesavage and Brink.32 Some additional tools have been developed for
evaluating depression in patients with dementia, i.e. the Cornell scale for depression in
dementia33 and the Dementia Mood Assessment Scale.34;35

Epidemiology of Depression in Youth

Depression is an important psychiatric disorder in children and adolescents, but it is

frequently unrecognized or dismissed as “growing pains”. The prevalence of depression is
0.3% in preschool children; 2% in schoolchildren; and 4–8% in adolescents. Dysthymia is
present in 0.6–1.7% of children and 1.6–8.0% of adolescents. Children of both sexes are
equally affected, but in adolescents, females are twice as likely to be affected as males. 19;36 The
average recovery time from a depressive episode is 9 months, but 10% of those having a
major episode may have chronic illness. The average duration of dysthymic disorder is 3
years.19 Childhood–onset depression has a 60–70% risk of continuing into adulthood and
20–40% develop bipolar disorder within 5 years. 36;37 After a recovery from a major depressive
episode, children might experience sequelae, such as poor self-esteem, increased risk-taking
behaviour, subclinical depressive symptoms, and impairment of interpersonal relations and
global functioning.38

Thirty to 50% of children with major depressive disorder have comorbid dysthymic or
anxiety disorder, and substance use disorder occurs in 20–30%. 36 Depressed youngsters often
have problems at home, and in many cases, the parents are depressed too, as depression
tends to run in families. 39 Four out of every five runaway youths suffer from depression.
Studies have shown that depression in young people is a risk factor for suicide, increased
risk-taking behaviour (e.g. substance abuse, early onset sexual experimentation), teenage
pregnancy, adult depression, conduct disorder, and delinquency. 38;40 Suicide is one of the
major causes of adolescent mortality in developed countries. 41 In the United States, suicide
rates in adolescents have increased threefold during the last 40 years, being the third leading
cause of death in those aged 15–24 years, accounting for 13.7% of deaths in this age group. 42

Epidemiology of Depression in the Elderly

Although most psychiatric disorders occur less frequently in the elderly than in younger
adults, more than 10% of the elderly have at least one mental disorder, and they frequently
experience depressive symptoms that significantly affect their lives but that do not meet the
criteria for a specific disorder.43

Minor depression affects from 2.5 to 9.4% of the community, but from 47% to 53% in clinical
settings.15 Fifteen per cent to 25% of patients with minor depression develop major
depression within 2 years. One per cent to 5% of the elderly in the community, 6 –9% in
primary care and 5–40% in nursing homes suffer from major depression. 18;36;44;45 In the elderly,
depression is also a major cause of morbidity and mortality.

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 Chapter 6.15: Depression in Young People and the Elderly

Dysthymic disorder occurs in approximately 20% of elderly outpatients. 21;46 Ten to fifteen
per cent of all cases are secondary to general medical illness or medicines. Depression is 1.5
to two times more prevalent among the low-income groups of a population, therefore
poverty could be considered a significant contributor to mental disorders, and vice versa. 5

The suicide rate among the elderly is greater than of any other segment of the population.
Fifteen per cent of all untreated cases will commit suicide. 41 The rate of suicide completion
(those attempts that result in death) among the elderly is 1 in 4 as compared to 1 in 100 in the
general population.47 Treatable contributing factors for suicide in the elderly are pain, grief,
loneliness, alcoholism and career stress.26

Risk factors for depression in the elderly include a past history of depression, female sex,
single status, alcohol abuse, chronic stress and stressful events (e.g. loss of a spouse),
hospitalization, lack of social support and concurrent chronic diseases. 15

Epidemiology of Depression as a Comorbidity

Twenty to fifty per cent of patients with cardiac disease manifest a depressive disorder. An
even higher percentage report depressive symptomatology when self-reporting scales are
used. Depressive symptoms following myocardial infarction have a negative effect on
rehabilitation and are predictive of a higher rate of mortality and medical morbidity.48;49

Depression occurs frequently in patients with neurological disorders, particularly

cerebrovascular disorders, Parkinson disease, multiple sclerosis, and traumatic brain injury. 5
(See Figure # 2.3) At least 30% of stroke patients experience depression, both early and late
after stroke; such depression is mostly undetected and untreated. 50 Post-stroke depression
(PSD) is associated with poorer recovery from stroke and increased mortality. 51;52
Over 80% of patients with Alzheimer disease (AD) develop “noncognitive ” neuropsychiatric
symptoms at some point
Graph # 2.3:Prevalence of major
Prevalence depression
of major in patients
depression with physical
in patients withillnesses
physical illnesses
during the course of their
illness, depression affect General Population

20–40% of AD patients.15 TB

Depression in AD patients
HIV/AIDS

leads to mental suffering,

Cancer
behavioural disturbances
Diseases

Diabetes
(such as aggression), poor
cognition, poor self-care, Stroke

caregiver burden, and early Epilepsy

entry into a nursing home. MI

Depression is associated with Hypertension

severe, but avoidable,

0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 50%

negative consequences for Max Reported Prevalence (%)

patients and caregivers: half Source: World Health Organization. Investing in Mental Health. Geneva: World Health
Organization, 2003
of them suffer a major
depression themselves.53

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 Chapter 6.15: Depression in Young People and the Elderly

The prevalence of depression in cancer patients depends on tumour site, severity of illness,
and type of medical or surgical intervention. Depression occurs in 25% of patients, but it can
be present in 40–50% of patients with certain cancers. Initiation of antidepressant medication
in cancer patients has been shown to improve mood and quality of life.

In patients with diabetes mellitus, a common comorbidity in the elderly, the prevalence of
depression varies from 8 to 27%, showing a high correlation between the mood state and the
physical symptoms of illness and the degree of hyperglycaemia.

Economic Impact of Depression

The economic impact of depression on patients and society is well documented. The average
annual health costs for depressed patients, including medical, pharmaceutical and disability
costs, may be 4.2 times higher than those incurred by the general population. 5;54 These
patients make frequent visits to the doctor, use more medications, incur more expenses and
outpatient charges, and stay longer in hospital, than those patients without depression. 18;24
They also perform less well at work and have more short-term disability days.55 The cost of
treatment is often completely offset by a reduction in the number of days of absenteeism and
productivity lost while not at work.5

Together with the treatment of adult mental disorders, chemical dependency, paediatric
behavioural problems and family conflict, treatment for depression accounts for 10% of the
expenditure on health care in the United States. 20 The total cost was estimated as US$ 83.1
billion in 2000, of which US$ 26.1 billion (31%) were direct medical costs, US$ 5.4 billion (7%)
were suicide-related mortality costs and US$ 51.5 billion (62%) were workplace costs.
Despite an increase in treatment of over 50% in the last 10 years, the economic burden
increased by only 7%, suggesting an increase in the efficiency of the management of
depression.56

3. Control Strategy
There are three main forms of treatment for depression:57

(1) counselling and/or psychotherapy;

(2) electroconvulsive therapy (ECT); and
(3) antidepressant medications.

Other effective interventions include setting up supportive networks for vulnerable

individuals, families and groups. The evidence regarding prevention of depression is
inconclusive, only a few isolated studies show that interventions proposed for the
prevention of depression are effective.4

Psychotherapy can be used when a specific loss can be identified about which the depressed
person can talk with a psychotherapist. Evidence-based treatment guidelines from the
literature are limited for most psychological interventions. Those that have been shown to be
effective in treating depression are: cognitive therapy (especially in young people), 19
problem-solving interventions, and interpersonal therapy (especially in the elderly).
Psychotherapeutic interventions in severely ill patients are more effective when provided in
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conjunction with antidepressant medication. In patients with mild or moderate illness,

combined therapy is better than any of which two alone.58

Electroconvulsive therapy (ECT) is used rarely, in only the most severe cases, i.e. in patients
with acute severe depression, those who have not responded to the above-mentioned
options, or when medication cannot be used for a specific medical reason. The efficacy of
ECT in improving acute depression is high, but its effects do not persist over a long period of
time.

Antidepressants have been reported in the scientific literature to be highly efficacious, alone
or in combination with psychotherapy, in improving depressive symptoms and the quality
of life of adult patients.
Antidepressants are classified based on their mechanism of action, as

a) monoamine oxidase inhibitors (MAOI);

b) norepinephrine reuptake inhibitors or tricyclic antidepressants (tertiary and
secondary);
c) selective serotonin reuptake inhibitors; and
d) atypical antidepressants.

Antidepressant therapy is based on the poorly known neurobiology of unipolar depression.

It has been suggested that neural networks involving the prefrontal cortex and the basal
ganglia may be primary sites of neurological deficit. Studies have shown altered
noradrenergic activity, including increased binding to alpha-1-, alpha-2-, and beta-
adrenergic receptors in the cerebral cortex and a decreased total number and density of
noradrenergic neurons in the locus coeruleus in patients with depression. Involvement of the
serotonin system has also been suggested, as an increase in brain 5-HT receptors and pre- or
postsynaptic dysfunction in the serotonin neuron. Reduced serotonergic activity in the
central nervous system has been found to correlate with temperament, impulsivity and
aggression better than it does with mood state or clinical diagnosis. Although antidepressant
drugs result in a blockade of neurotransmitter uptake within hours, their therapeutic effects
typically emerge over several weeks, implicating neuroadaptive changes in secondary
messenger systems, such as the G proteins, as a possible mechanism of action. 41

Monoamine oxidase (MAO) causes the oxidative deamination of norephinephrine, serotonin,

and other amines. This oxidation is the method of reducing the concentration of the
neurotransmitter after it has sent the signal at the receptor site. Monoamine oxidase
inhibitors acts as antidepressant agents by preventing the breakdown and inactivation of
norepinephrine at the neurons, thus increasing the concentration of the neurotransmitter at
the receptor site. Other mechanisms used to increase the level of norepinephrine are the use
of norepinephrine-mimetics (amphetamines and cocaine), ECT and inhibitors of the
norepinephrine reuptake.22

The first antidepressant, iproniazid, was discovered in the 1950s; it was a TB drug with a
strong monoamine oxidase inhibition effect. The monoamine oxidase enzyme is present in
central and peripheral tissues. Current examples of this type of drug are Phenelzine,

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Tranylcypromine, and Selegiline. These drugs have proven antidepressant effects but have
serious side-effects, and potentially fatal interactions with many substances.

The tricyclic antidepressants increase the level of neurotransmitters, especially serotonin, by

blocking its reuptake at nerve terminals. However, the potency and selectivity for the
inhibition of the uptake of norepinephrine, serotonin and dopamine vary greatly between
the agents. The tertiary amine tricyclics seem to inhibit the serotonin uptake pump, whereas
the secondary amine tricyclics seem better at switching off the norepinephrine. These drugs
affect the peripheral noradrenergic systems and, to a lesser degree, the serotonin systems.
This produces undesirable side-effects in a significant proportion of patients. Due to the
interaction with other medications and conditions in the elderly, the side-effects might
decrease patients’ quality of life and even cause death.22

Examples of tertiary amine tricyclic antidepressants are amitriptiline, clomipramine,

doxepin, imipramine, and trimipramine. Secondary amine tricyclics are amoxapine,
desipramine, maprotiline, nortriptyline and protriptyline.

Major autonomic side-effects related to their strong antimuscarinic effects have been
reported. Tricyclic antidepressants are contraindicated in acute myocardial infarction,
bundle-branch conduction blockage or when another antidepressant is being administered.
In children, there is a risk of cardiotoxicity and seizure-inducing effects in patients treated
with high doses, including accidental and unexplained sudden death. The risk –benefit
balance of treating this population is uncertain as trials have failed to show that these drugs
lead to better outcomes than treatment with a placebo. 59 In the elderly, dizziness, postural
hypotension, constipation and tremor are very common. A risk of toxicity exists if
metabolism is affected or in cases of overdose.

Although some of the serotonin is metabolized by monoamine oxidase, most of the serotonin
released into the post-synaptic space is removed by the neurons through a reuptake
mechanism inhibited by the tricyclic antidepressants and SSRIs (clomiprimine, fluoxetine,
sertraline and paroxetine). SSRIs are more selective to serotonin receptors in the central
nervous system, producing less peripheral side-effects, therefore are expected to be safer for
use in young people and the elderly. Examples of SSRIs are citalopram, fluoxetine,
fluvoxamine, paroxetine, sertraline and venlafaxine.

Atypical antidepressants are drugs with significant norepinephrine and dopamine-uptake

inhibiting actions. The drugs in this groups are bupropion, nefazodone and trazodone.

Published systematic reviews show that all types of antidepressants are more efficacious in
improving acute depressive symptoms than treatment with a placebo (see table 3.1). In
general, there is no major difference in efficacy between different types of antidepressants,
but they do differ in their side-effect profiles.58

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 Chapter 6.15: Depression in Young People and the Elderly

Table # 3.1: Comparison of efficacy of antidepressants

Author Avg AD MAOI TAC SSRI Placebo Obs
Gill & Hatcher (2002)60 52% 30%
Wilson et al (2002) 61 49% 25% Elderly
Wilson et al (2002) 61 28% 17% Elderly
Wilson et al (2002) 61 41% 10% Elderly
Mulrow et al (2000)62 60% 63% 35%

Antidepressants in Young People

Despite the lack of evidence for the efficacy of SSRIs in children and adolescents, they have
been prescribed increasingly over the last few years. The current knowledge on the efficacy
and safety of antidepressants in adults may not be appropriate for extrapolation to young
people. New drugs need to be tested in RCTs with children and adolescent before they are
used.63

A recent survey suggested that 40% of new prescriptions for children and adolescents issued
by psychiatrists in the United Kingdom were either for unapproved medicines or for
approved medicines to be used for unapproved indictations. 63 Only fluoxetine (Prozac) is
approved by the FDA for use in children and adolescents for the treatment of major
depressive disorder. Fluoxetine (Prozac ), sertraline (Zoloft), and fluvoxamine (Luvox) are
approved for use in children and adolescents for the treatment of obsessive –compulsive
disorder.

Tricyclic antidepressants are unlikely to be efficacious in prepubertal children, but there is

some evidence to support their use in adolescents. 63 Kirsch et al. found that only 12 efficacy
trials of antidepressants have been conducted in children. Of the antidepressants studied,
only four (all SSRIs) showed a statistically significant difference from the control group, but
only in physician-reported indicators. All trials have failed to provide evidence of efficacy
based on patient-reported indicators.64;65

Antidepressants in the Elderly

Seventy five per cent of the elderly people with depression can be successfully treated, but if
left untreated is fatal in 15% of cases.66 No one class of antidepressant has been found to be
more efficacious than another in the treatment of acute episodes of major depression. There is
no one “first-line” antidepressant for the treatment of elderly patients with depression, and
selection should be made on a case-by-case basis, taking into account each patient's
characteristics and drugs’ side effects profile67 (Table # 3.2). Recovery from a severe
depressive episode takes from 6–12 months if treated.15

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 Chapter 6.15: Depression in Young People and the Elderly

Table # 3.2: Antidepressant treatment for elderly patients with various medical conditions 15
Medical condition Antidepressant of choice Drugs to avoid
Endocrine disorders None favored None
Cardiac disease SSRIs, bupropion, TCAs, venlafaxine, (if patient has high
nefazodone blood pressure), SSRIs (if patient takes
antiarrhythmics)
Cancer
- with severe pain TCAs MAOIs
- with cachexia Sertaline, paroxitine, Fluoetine
trazodone, nefazodone,
- with nausea TCAs, venlafaxine Buproprion, SSRIs, venlafaxine
None
Neurologic disorders
Parkinson Disease Buproprion, venlafaxine TCAs, MAOIs, buproprion
Stroke SSRIs TCAs, MAOIs, buproprion
Alzheimer’s dementia SSRIs, nefadone, venlafaxine TCAs, buproprion, fluoxetine
SSRI: serotonin-selective reuptake inhibitor; TCA: tricyclic antidepressant; MAOI: monoamine oxidase
inhibitors

Side-Effects of Antidepressants

The side-effects of antidepressants are dosage-related. 68 Many patients have a first-dose

reaction due to the prescription of a higher dose than that necessary for that particular
patient. For example, the original studies on fluoxetine showed that at 5 mg (25% of the
recommended dose), the drug was effective in most patients (56%). 68 Higher doses increase
the number of patients responding to the treatment, but might also produce, even in healthy
subjects, mental confusion, disorganized thinking and severe agitation (akathisia). 68
Personality might be severely affected, changing usually peaceful personalities into irritable
and aggressive ones. Some experts complain that unnecessarily high dosages are promoted
to increase sales volume and profits.69 Some of reported side-effects are summarized in
Table 3.3 and a full list is given in Table # 3.4.

Table # 3.3: Summary of side-effects of antidepressants by class 24

Drug Mode of action Anticholinergic Antihistamini -adrenergic
Class
c blocker
Tricyclic Amitriptiline Noradrenaline (++) +++ ++++ ++++
antidepressant Imipramine 5-HT (+) ++ ++ +++
Dothiepin ++ ++ ++
Reverse inhibitors Moclobemide MAO 0/+ 0 0
of MAO-a
SSRI Fluvoxamine 5HT 0/+ 0/+ 0
Fluoxetine 0/+ 0 0
Sertraline 0/+ 0 0
Citalopram 0/+ 0 0
Paroxetine 0/+ 0 0
Noradrenaline + Mirtazepine 2, 5HT2 0 ++ 0
SSRI
SNSRI Velafaxine Noradrenaline (+) 0/+ 0 0/+
5HT (++)

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 Chapter 6.15: Depression in Young People and the Elderly

Table # 3.4: Details of side-effects of antidepressants by product 70

Component Side effects
MAOI
Isocarboxazid (Marplan) Dry mouth; dizziness; constipation; diarrhoea; sleeplessness; tremor; involuntary jerks or twitching;
numbness; impotence; urinary changes (increased frequency and hesitation); anxiety; forgetfulness;
hyperactivity; fatigue; feeling of heaviness in muscles; sleepiness; sensitivity to light
Phenelzine (Nardil) Upset stomach; drowsiness; weakness or tiredness; excitement or anxiety; insomnia; nightmares; dry
mouth; skin more sensitive to sunlight than usual; changes in appetite or weight
Tranylcypromine Upset stomach; drowsiness; weakness or tiredness; excitement or anxiety; insomnia; nightmares; dry
(Parnate) mouth; skin more sensitive to sunlight than usual; changes in appetite or weight
Tricyclic
Amitriptyline (Elavil, Upset stomach; drowsiness; weakness or tiredness; excitement or anxiety; insomnia; nightmares; dry
Endep, Vanatrip) mouth; skin more sensitive to sunlight than usual; changes in appetite or weight
Amoxapine (Asendin) Upset stomach; drowsiness; weakness or tiredness; excitement or anxiety; insomnia; nightmares; dry
mouth; skin more sensitive to sunlight than usual; changes in appetite or weight
Clomipramine Drowsiness; dry mouth; upset stomach; vomiting; diarrhoea; constipation; nervousness; decreased sexual ability;
(Anafranil) decreased memory or concentration; headache; stuffy nose; change in appetite or weight
Desipramine Upset stomach; drowsiness; weakness or tiredness; excitement or anxiety; insomnia; nightmares; dry
(Norpramin) mouth; skin more sensitive to sunlight than usual; changes in appetite or weight
Doxepin (Adapin, Upset stomach; drowsiness; weakness or tiredness; excitement or anxiety; insomnia; nightmares; dry mouth; skin
Sinequan) more sensitive to sunlight than usual; changes in appetite or weight
Imipramine (Tofranil) Upset stomach; drowsiness; weakness or tiredness; excitement or anxiety; insomnia; nightmares; dry
mouth; skin more sensitive to sunlight than usual; changes in appetite or weight
Nortriptyline (Aventyl, Upset stomach; drowsiness; weakness or tiredness; excitement or anxiety; insomnia; nightmares; dry
Pamelor) mouth; skin more sensitive to sunlight than usual; changes in appetite or weight
Protriptyline (Vivactil) Drowsiness, dizziness; increased sensitivity to sunlight or blurred vision; heartburn; loss of appetite;
dry mouth; strange taste in mouth, anxiety; restlessness or sweating
Trimipramine Upset stomach; vomiting; diarrhoea; stomach pain; drowsiness; weakness or tiredness; excitement or
(Surmontil) anxiety; confusion; dizziness; headache; difficulty falling asleep or staying asleep; nightmares; dry
mouth; changes in appetite or weight; constipation; difficulty urinating; frequent urination; blurred
vision; changes in sex drive or ability; excessive sweating; ringing in the ears; painful, burning or
tingling feeling in the hands or feet

Table # 3.4: Details of side-effects of antidepressants by product (Continued)

SSRIs
Citalopram (celexa) Joint pain 1.0%; confusion 1.0%; diarrhoea 3.0%; dizziness 1.0%; drowsiness 8.0%; dry mouth 6.0%;
fatigue 2.0%; fever 1.0%; gas 1.0%; insomnia 1.0%; nausea 7.0%; nervousness 2.0%; palpitations 1.0%;
rash 1.0%; sexual dysfunction 8.0%; urinary retention 0.1–1.0%; vomiting 1.0%; heartburn 1.0%; loss of
appetite 2.0%; visual disturbances 1.0%; numbness/tingling 1.0%; increased sweating 2.0%; respiratory
infections 1.0–2.0%;
Escitalopram (Lexapro) Nausea 8.0%; insomnia 5.0%; drowsiness 4.0%; diarrhoea 3.0%; fatigue 3.0%; increased sweating 3.0%;
decreased sex drive 2.0%; constipation 2.0%; dizziness 2.0%; indigestion 2.0%; sexual dysfunction 2.0%;
loss of appetite 2.0%; dry mouth 1.0%
Fluoxetine (Prozac) Nausea 11.0%; loss of appetite 7.2%; sexual dysfunction 7.0%; respiratory infections 5.8%; diarrhoea
5.3%; increased sweating 5.0%; dry mouth 3.5%; heartburn 2.1%; vomiting 2.0%; increased frequency of
urination 1.6%; constipation 1.2%; gas 1.0%; rash 0.9%; palpitations > 0.1%; numbness/tingling 0.0–0.3%
Fluvoxamine (Luvox) Nausea 25.6%; drowsiness 17.2%; constipation 11.2%; loss of appetite 8.6%; fatigue 6.2%; increased
sweating 4.0%; respiratory infections 4.0%; heartburn 3.2%; headache 2.9%; sexual dysfunction 2.0%;
dry mouth 1.8%; dizziness 1.3%; gas 1.0%; palpitation 1.0%; urinary retention 1.0%; vomiting > 1.0%;
increased frequency of urination 0.6%; diarrhoea > 0.1%
Paroxetine (Paxil) Joint pain 1.0%; confusion 1.0%; constipation 5.2%; diarrhoea 4.0%; dizziness 7.8%; drowsiness 14.3%;
Paroxetine CR (Paxil dry mouth 6.0%; fatigue 10.3%; fever 2.0%; gas 1.0%; headache 0.3%; insomnia 7.1%; nausea 16.4%;
CR) nervousness 4.9%; palpitation 1.5%; increased frequency of urination 2.4%; rash 1.0%; sexual
dysfunction 10.0%; tremor 6.4%; urinary retention 2.7%; heartburn 0.9%; loss of appetite 4.5%; visual
disturbances 2.2%; numbness/tingling 2.1%; increased sweating 9.0%
Sertraline (Zoloft) Nausea 14.3%; diarrhoea 8.4%; tremor 8.0%; drowsiness 7.5%; insomnia 7.5%; dry mouth 7.0%;
increased sweating 5.5%; dizziness 5.0%; nervousness 4.4%; heartburn 3.2%; fatigue 2.5%; constipation
2.1%; visual disturbances 2.1%; palpitations 1.9%; headache 1.3%; numbness/tingling 1.3%; loss of
appetite 1.2%; gas 1.0%; vomiting 1.0%; confusion 0.8%; increased frequency of urination 0.8%;
respiratory infections 0.8%; rash 0.6%; joint pain 0.2%; fever 0.1%; sexual dysfunction 1.5–13.3%

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 Chapter 6.15: Depression in Young People and the Elderly

Atypical
Bupropion (Wellbutrin) Tremor 13.5%; agitation 9.7%; dry mouth 9.2%; constipation 8.7%; sweating 7.7%; dizziness 6.1%;
hearing disturbance 4.3%; nausea/vomiting 4.0%; menstrual complaints 3.6%; confusion 3.5%;
headache 3.5%; insomnia 2.9%; high blood pressure 2.7%; rash 2.5–7.7%; itching 2.2%; increased heart
rate (rate >100 beats per minute) 2.2%; blurred vision 2.1%; anxiety 2.0%; taste disturbance 2.0%;
hostility 1.8%; increased appetite 1.5%; decreased sex drive 1.5%; palpitations 1.5%; impaired sleep
quality 1.2%; irregular heart rate 1.0%; stomach upset 0.9%; euphoria 0.7%; fever 0.7%; fainting 0.7%;
inability to sit still 0.4%; arthritis 0.4%; low blood pressure 0.3%; impotence 0.3%; increased
frequency of urination 0.3%; sedation 0.3%; delusions 0.1%; loss of appetite 0.1
Maprotiline (Ludiomil) Dry mouth 22.0 %; constipation 8.0 %; dizziness 8.0 %; nervousness 6.0 %; blurred vision 4.0 %;
fatigue 4.0 %; headache 4.0 %; anxiety 3.0 %; tremor 3.0 %; agitation 2.0 %; nausea/vomiting 2.0 %;
insomnia 2.0 %
Mirtazapine (Remeron) Abnormal drowsiness or laziness 54.0%; dry mouth 25.0%; increased appetite 17.0%; constipation
13.0%; weight gain 12.0%; dizziness 7.0%; impaired sleep quality 4.0%; confusion 2.0%; increased
frequency of urination 2.0%; tremor 2.0%; nausea/vomiting 1.5%; euphoria > 1.0%; hostility > 1.0%;
menstrual complaints > 1.0%; arthritis > 1.0%; delusions > 1.0%; fever > 1.0%; hearing disturbance >
1.0%; low blood pressure > 1.0%; impotence > 1.0%; fainting > 1.0%; urinary retention > 1.0%; weight
loss > 1.0%; agitation 1.0%; anxiety 1.0%; high blood pressure 1.0%; itching 1.0%; rash 1.0%; loss of
appetite 1.0%
Nefazodone (Serzone) Dizziness 12.0%; dry mouth 12.0%; abnormal drowsiness or laziness 11.0%; blurred vision 6.0%;
constipation 6.0%; headache 3.0%; increased appetite 2.0%; stomach upset 2.0%; insomnia 2.0%;
decreased sex drive 1.0%; anxiety < 1.0%; confusion < 1.0%; diarrhoea 1.0%; fever 1.0%; impotence
1.0%; increased frequency of urination 1.0%; rash 1.0%; taste disturbance 1.0%; ringing of the ears
1.0%; tremor 1.0%; urinary retention 1.0%; impaired sleep quality 1.0%; increased saliva in mouth >
0.1%; hearing disturbance > 0.1%; euphoria 0.1–1.0%; hostility 0.1–1.0%; menstrual complaints
0.1–1.0%; arthritis 0.1–1.0%; high blood pressure 0.1–1.0%; dilation of the pupils 0.1–1.0%; light
sensitivity 0.1–1.0%; sexual dysfunction 0.1–1.0%; fainting 0.1–1.0%; increased heart rate (>100 beats
per minute) 0.1–1.0%; weight loss 0.1–1.0%; slow movements and reflexes 1.0–2.0%; low blood
pressure 1.0–3.0%; nausea/vomiting 1.0–10.0%
Trazodone (Desyrel) Decreased sex drive < 1.0%; hostility < 1.0%; blurred vision < 1.0%; constipation < 1.0%; diarrhoea <
1.0%; dry mouth < 1.0%; fatigue < 1.0%; nausea/vomiting < 1.0%; headache > 1.0%; high blood
pressure < 1.0%; low blood pressure < 1.0%; insomnia < 1.0%; nervousness < 1.0%; palpitation < 1.0%;
sweating < 1.0%; fainting < 1.0%; increased heart rate (>100 beats per minute) < 1.0%; taste
disturbance < 1.0%; ringing in the ears < 1.0%; tremor < 1.0%; weight gain < 1.0%; weight loss < 1.0%;
loss of appetite < 1.0%; impaired sleep quality < 1.0%; **increased appetite; **inability to sit still;
**menstrual complaints; **increased saliva in mouth; **delusions; **irregular heart rate; **gas;
**impotence; **muscle spasm; **increased frequency of urination; **itching; **rash; **sexual
dysfunction; **urinary retention
Venlafaxine (Effexor) Abnormal drowsiness or laziness 14.0%; dizziness 12.0%; sexual dysfunction 12.0%; dry mouth
11.0%; sweating 9.0%; loss of appetite 9.0%; constipation 8.0%; insomnia 8.0%; nervousness 7.0%;
impotence 6.0%; nausea/vomiting 4.0–26.0%; blurred vision 4.0%; tremor 4.0%; anxiety 3.0%; fever
3.0%; decreased sex drive 2.0%; agitation 2.0%; high blood pressure 2.0%; dilation of the pupils 2.0%;
increased heart rate (rate >100 beats per minute) 2.0%; taste disturbance 2.0%; ringing in the ears
2.0%; euphoria 0.1–1.0%; hostility 0.1–1.0%; arthritis 0.1–1.0%; light sensitivity 0.1–1.0%; fainting
0.1–1.0%; inability to sit still > 0.1%; menstrual complaints 1.0%; increased saliva in mouth > 0.1%;
slow movements and reflexes > 1.0%; confusion 1.0%; delusions > 0.1%; diarrhoea 1.0%; irregular
heart rate > 0.1%; gas 1.0%; stomach upset 1.0%; headache 1.0%; low blood pressure 1.0%; muscle
spasm > 0.1%; increased frequency of urination 1.0%; itching 1.0%; rash 1.0%; urinary retention 1.0%;
weight loss 1.0%; impaired sleep quality 1.0%
** Side-effect reported, but no figure given for its incidence.

Misuse of Antidepressants

A relation between suicide and use of SSRIs has been reported, especially among children
and adolescents. Negative changes in mood and judgement produced by SSRIs increase the
risk of suicide to 2–3 times that seen in subjects treated with placebo, mainly during the first
month of treatment or withdrawal.71

Due to the lack of evidence on benefits, and the increasing number of reports of suicides
among young patients treated with SSRIs, the UK Government Advisory Board on
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 Chapter 6.15: Depression in Young People and the Elderly

Antidepressants banned the use of SSRIs in children and adolescents last year and has issued
a warning about its use in adults. 72 The US FDA only issued a general warning on suicide as
a potential dangerous side-effect.73;74

For many years, experts have been issuing warnings about the low efficacy of these drugs,
their misuse, and their potentially dangerous side-effects, that have been under-reported in
the literature and in the reports of the US FDA.

One of the arguments supporting these claims is that part of the reported efficacy of
antidepressants is just a strong “placebo effect” seen in all RCTs on mental health, but
especially in the treatment of depression. 5 Others report a variety of methodological flaws,
such uncovered double-blind by side-effects, confounding effects caused by accepting
patients under treatment for anxiety and selection bias caused by excluding patients
responding to placebo, among many others.75

The “placebo effect” is the spontaneous improvement in health experienced by some patients
when “treated” with a pill known to be pharmacologically-inactive, also called a placebo.
Such a placebo is commonly used to “treat” control groups in single- or double-blinded
RCTs, to avoid the differences produced by patients being aware of the status of their
treatment. The extent of the placebo effect, is also called “placebo response ”, and is defined as
the proportion of patients in the control group (group not treated with a pharmacologically
active agent) that responds to treatment with the placebo. The extent of the placebo effect in
the intervention group is supposed to be the same than as in the control group; therefore the
clinical effect attributable to the drug under study is simply the difference between the
efficacy shown by the drug in the intervention group (drug response) and the placebo
response measured in the control group.

In studies on depression, the placebo effect may be up to 75% of the overall efficacy shown
by the intervention group.76 This means that the therapeutic effect attributable to the drug
under study could be as low as 25% of the overall efficacy shown by the drug. In RCTs, in
order to avoid the placebo effect as far as possible, all subjects are treated with a placebo for
the first month and subjects who respond to it are excluded ( “placebo wash-out ”). Thus, in
real clinical practice the percentage of patients responding to placebo might be higher than in
RCTs.

Stating that “75% of patients showed improvement in depressive symptoms after treatment
with drug X” might not be accurate, as a typical antidepressant with 75% efficacy and with a
placebo effect of 50%, will have 25% of patients who do not respond to the treatment at all,
37.5% who do respond to the treatment, and 37.5% respond to a placebo effect. As a result,
only about 37.5% of patients under treatment will benefit from the drug itself. 65

Additionally, some experts estimate that 50% of all patients on antidepressants experience
some kind of side-effect, some of which severely affect their quality of life and some others
that are potentially life-threatening.69 As all patients under treatment are at risk of
experiencing any side-effect, in the example given above, the percentage of patients suffering
any side-effect can be greater than those benefiting from the drug itself.

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Several authors claim that the results of studies failing to show efficacy and those that report
life-threatening side-effects have been systematically withheld from publication or
minimized in the scientific literature by the industry, in order to minimize the awareness of
side-effects that would have a potential negative impact to the very profitable U$ 16.6 billion
antidepressant pharmaceutical business.77 Chan et al. reported that published articles on
antidepressants are not only frequently incomplete, but also biased and inconsistent with
their protocols. In their study Chan et al. found that 50% of efficacy reports and 65% harm
outcomes reports per trial were incomplete.78

This year, the Attorney General of New York, filed a lawsuit against the pharmaceutical
company GlaxoSmithKline for “fraud to consumers by withholding safety information and
misrepresenting data in general prescribing its antidepressant Paroxetine (Paxil) to
children”.79 On one side, the Attorney argued that full access to information is required, and
that biased withholding of safety information might jeopardize the ability of physicians to
make the right decisions for their patients. On the other side, company representatives
answered that they had made available all data to the US FDA and country regulatory
bodies, although they were never published nor were they included in promotional
materials.

Based on biased or incomplete efficacy and safety reports, the promotion of SSRIs is still
being expanded to non-psychiatric physicians (internists, GPs and Gyn&Obs), new
indications (such as panic disorder, social phobia) and new age groups (young people and
the elderly).

4. Major Problems and Challenges for Disease Control: Why Does the
Disease Burden Persist?
The poor understanding of the neurophysiology of mental disorders affects our capacity
for producing highly efficacious and safe antidepressants, and our capacity to accurately
define clinical syndromes that correspond to each therapy. 80 “Treatment-resistant”
depression, a common clinical problem affecting up to one-third of older depressed patients,
might be the result of variables involving the diagnostic or treatment process, rather than
because these patients suffer from a depression that is truly unresponsive to treatment. 81;82

Another important reason why the burden of depression still exist in the community is the
low diagnosis and treatment rate at all levels of care, but in particular at the primary care
level. A striking 60% of depressed patients go undetected at the primary care level and when
detected, only 30% are treated.45;83-86 It has been reported that it is especially difficult to
promote and implement the use of new knowledge on depression by clinicians. 87

In Europe the treatment gap is still considerable, 50% of cases of depression in primary
health care settings are unrecognized, although 30% of consultations with general
practitioners are for mental health problems. 25 Only 10–40% of depressed elderly patients in
developed countries receive treatment. 15 Co-payments for the provision of health care
services has been shown to have a high impact on access to care, but very little on those
already using the services (Table 4.1).

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 Chapter 6.15: Depression in Young People and the Elderly

Table 4.1: Mental health department usage in a large HMO 20

Co-payment Percentage using* Visit per user**
U$ 5 3.38 4.85
U$ 10 2.78 4.78
50% 1.49 4.44
* Fraction of enrolees using specialty mental health services in 1986.
** Visits to mental health department per psychiatric patient.

Several studies are under way to test the effectiveness of new integrated care and
collaborative models designed for improving the provision of care to patients with chronic
conditions.88-90

Poor adherence to pharmacological and psychosocial treatments for depression in the

elderly is an additional barrier to effective clinical care. Rates of adherence may be as low as
40% in older adults. Factors associated with nonadherence include lack of information and
misperceptions about mental illness and its treatment, stigma, lack of family support,
cognitive impairment, adverse events, side-effects, cost of treatments, and poor
physician–patient communication. Effective interventions for improving adherence must be
tailored to the patient and set within an integrated model of care. 7;17

In addition to all the above-mentioned barriers, the effectiveness of the health system in
managing depression in the overall population, assuming 100% drug efficacy, is not higher
than 6.4% (40% diagnosed × 40% treated × 40% adherent).

5. Past and Current Research into Pharmaceutical Interventions with

Antidepressants
The estimated size of the antidepressant market is US$ 16.6 billion with an annual growth
rate of 7.6%; the research on antidepressants is highly intensive, approximately 16 –20% of
the estimated market (US$ 2.5–3.2 billion).

Several research paths are being developed to look into the mechanisms through which
several non-psychiatric conditions produce depression, how depression comorbidity affects
other conditions (e.g. IHD and stroke), and their treatments and common biological
mechanisms of depression and anxiety-related conditions, such as obsessive –compulsive
disorder, panic attacks, social phobia, and post-traumatic shock disorder.

The current basic research focuses on understanding the relationship between depression
and the circadian rhythm, the hormonal system (hypothalamus regulation), genetics and the
characterization of neuronal receptors and circuits, using PET scan and functional MRI.

Research on drugs based on already proven mechanisms, looking to simultaneously target

several noradrenergic, serotonergic, and dopaminergic systems, and having improved side-
effect profiles. These agents might have stronger antidepressant effects, better side-effect
profiles and they might be used in other concomitant diseases, such as Parkinson disease,
Alzheimer disease, bipolar depression and certain psychoses. A new generation of MAOIs
have shown less toxicity and multiple effects (antipsychotic, antidepressant and anti-
parkinsonian) due to their dopaminergic activity.22

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Alternative therapies, such as herbal remedies Hypericum perforatum (St. John's wort) and
Ginkgo biloba, transcranial magnetic brain stimulation (a magnetically-induced ECT),
massage, electroacupuncture, and use of light, have been reported.

The US National Institutes of Health’s Clinical Trials Database 91 show that research during
the past ten years has mainly focused on functional brain imaging to explore the link
between biological, sensorial and cognitive processes with areas of the brain, neuronetworks
and even specific neuronal receptors. Also intensive research is being done on the
epidemiology of risk factors for depression, including morbidity, mortality and other
socioeconomic aspects. A substantial amount of work on the endocrine basis of depression
has also been done. Together these areas represent about 75% of the reported research. A
summary is presented in Table # 5.1 and a complete list of trials in Annex 6.15.1.

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Table # 5.1: Summary of trials on depression

Area of research Mechanism of action Freq
Basic biological Functional brain imaging PETs 13
research
Risk factors epidemiology 13
Endocrine Leptin, hydrocortisone, progestin, circadian 10
rhythm
Traditional medicine Various unknown 3
Brain neurotransmitters and 3
receptor characterization
Genetics Genetic mapping 2
Electroconvulsive therapy- Transcranial magnetic stimulation 1
related
Others Various 2
Basic psychological Child development 2
research
Risk factors 1
HIV-related 1
Applied clinical SSRIs and atypical Serotonin reuptake inhibitors 27
research
Comparative Various 17
Others traditional Massages, PUFA, light therapy, hypericum, 13
acupunture, yohimbe
Undisclosed Unknown 7
Endocrine-based therapies 17 beta-estradiol 5
Magnetic brain stimulation and 5
ECT
Other compounds Lamotrigine, dutastaride, pramixole, 5
propanolol
TCAs 4
Felbamate and others Glutamatergic system 3
Soya bean Phytoestrogen and protein tyrosine kinase 2
MAOIs Monoamine-oxidase inhibitors 2
Other compounds Lamotrigine, dutastaride, pramixole, 5
propanolol
Psychological clinical Cognitive therapy 8
research
Behavioural change 5
Problem-solving therapy 3
Interpersonal therapy 3
Other psychotherapy 12
Heath care research Protocols 4
Integrated models 2
Teamwork 1

Over the last ten years federal funding in the USA has substantially increased for all mental
health conditions reaching nearly US$ 288 million in 2003. 74 Currently the US National
Institute of Health is funding intensive research on mental health, as shown in Table 5.2.

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 Chapter 6.15: Depression in Young People and the Elderly

Table # .5.2: US National Institute of Health Research funding for mental conditions 74
Research/disease areas* FY 2003 FY 2004 FY 2005
(Million US$) (actual) (estimate) (estimate)
Alzheimer disease 658 680 699

Attention deficit disorder (ADD) 103 106 109

Behavioural and social science 2684 2762 2831

Biotechnology research 9893 10418 10716
Brain disorders 4740 4887 5023
Clinical research 8028 8383 8678
Depression research 288 296 304
Neuroscience research 4711 4859 4995
*The table is not additive. Clinical research includes all other conditions.

In Europe NEWMOOD’s partners from 13 laboratories across Europe — including three

from new Member States Estonia, Hungary and Poland— received €7.3 million through one
of EU’s Framework Programme, under the "life sciences, genomics and biotechnology for
health" thematic priority.92

The company IMS Health reports a closer look into the industry ’s product development. 93
About 89 new products under development were reported in May 2004 (not yet on the
market). Of these almost 30% did not disclose the compound under study. Of those
disclosed, 65% exploited new mechanisms alone (mainly NK antagonists, 5-HT
antagonist/agonist, and CRF antagonists) and 30% in combination with old mechanisms
(selective noradrenaline and dopamine reuptake inhibitors). There was only one new version
of an MAOI and no products targeting serotonin receptors were disclosed. Forty-three per
cent of these compounds are at the pre-clinical stage, 53% in clinical trials (phases I, II, and
III) and 4% are in the registration process.

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 Chapter 6.15: Depression in Young People and the Elderly

A wider spectrum of indications are mentioned for these products. The primary indications
(those conditions for which these products might be used as first-line treatment) include:
depression (72%), anxiety (10%), schizophrenia (3%), psychosis (2%), Parkinson disease (2%)
and psychosis (2%) (Fig. # 6.X.5.1). The secondary indications (those conditions for which
these products might be used as second-line treatment) included: anxiety (30%), bipolar
disorder (7%), emesis (5%), cognitive defect (2%), schizophrenia (2%) and many others (Fig. #
6.X.5.2)

Graph # 5.1: Antidepressants

Antidepressants R&D Pipeline
R&D Pipeline 2004,
2004, byindication
by first first indication
(Source: IMS Health May 2004 report on Antidepressant Pipeline)
(Source: IMS Health report on antidepressant R&D pipeline, May 2004)
35%

30%
Schizophrenia
Psychosis
25%
Parkinson
Obesity
20% Irritable Vowel Syndrome
% of total

Epilepsy
Depression
15% Cognitive Defect
Bipolar
Anxiety
10% AlzhDis
ADD

5%

0%
Phosphodiesterasa Inh

5HT Inv Ago

5TH Ago

Dopa Ago

Peptide

Undisclosed

b-adren Ago

Dopa Ago + 5HT Ago

Adenosine A2 Ant

MAOI

S5HTNRI

S5HTRI

SPNRI

Vasopresine Ant
5TH Ant

CRF Ant

GABA Ant

Glucocort Ant

Glutamate Ant

S5HTDNRI

SDNRI

a-adren Ant

NK Ant

Sigma + 5HT Ago + S5HTRI

Active compound

Antidepressants R&D Pipeline 2004, by second indication

Graph # 5.2: Antidepressants R&D
(Source: IMS Health Pipeline
May 2004 2004, byPipeline)
report on Antidepressant second indication
(Source: IMS Health report on antidepressant R&D pipeline, May 2004)
35%

30%

Urinary Incontinence
25%
SexDis
Schizophrenia
Nicotine Withdrawal
20%
% of Total

Emesis
Depression
COPD
15%
Cognitive Defect
Bipolar
Asthma
10%
Anxiety

5%

0%
5HT Inv Ago
MAOI
5TH Ago

Phosphodiesterasa Inh

Undisclosed

Dopa Ago + 5HT Ago

5TH Ant

Adenosine A2 Ant

CRF Ant

S5HTDNRI

SPNRI

Vasopresine Ant
S5HTNRI

S5HTRI

SDNRI

a-adren Ant

NK Ant

Active compound

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 Chapter 6.15: Depression in Young People and the Elderly

6. What Are the Opportunities for Research into New Pharmaceutical

Interventions?
New opportunities for research aim to further understand the function of the brain through
an understanding of the brain’s cellular and molecular mechanisms, and their relationship
with mental functions such as cognition, memory and attention.

Currently the most promising developments are being made in the understanding of the
functioning of 2-adrenergic receptor antagonists, several 5-HT receptors, alone and in
combination with known agents; amino-acid neurotransmission systems targeting GABA-
receptors, N-methyl-D-aspartate (NMDA) receptors, cerebral sigma receptors, neurokinin-1
receptors (NK), substance P, and corticotropin (ACTH)-releasing peptide (CRF). 22

7. Gaps Between Current Research and Potential Research Issues that

Could Make a Difference
Although there has been significant progress in understanding mood disorders over the last
two decades,94 our understanding of the treatment of depression in young people and the
elderly is still poor, mainly due to their systematic exclusion from the clinical trials testing
the drugs. When the elderly are considered, only medically stable patients with no
significant comorbidities (particularly dementia or other neurological problems) are included
in trials. Exclusive clinical research in youth and in the elderly is needed to evaluate the
efficacy of current drugs in these groups and the best way to use them.

For young people, who are living through crucial stages of their own psychological
development, it is important to understand the neurophysiological basis of the psychiatric
conditions they suffer. Although early clinical data have suggested that selective serotonin
reuptake inhibitors (SSRIs) may provide effective treatment, and they are actively used in
daily clinical practice, there is no strong evidence to support this practice. Thus further
clinical trials are urgently required.95;96

In the elderly, the natural loss of psychomotor capacity, the concurrence of several chronic
conditions, and changes in the pharmacokinetics of medicines, make it inappropriate to use
medicines designed for younger adults. Clinical trials are needed to adapt the available
psychopharmacological management to the altered metabolism of drugs in the elderly. 48

There are remarkably high levels of underdiagnosis and misdiagnosis, undertreatment and
mistreatment and of lack of follow-up and adherent behaviour in the management of
depression in the general population, but especially among youth and the elderly. More
effective and safer drugs will have very little impact at the population level if the
effectiveness of mental health care services at all levels of care is not substantially improved.
Therefore, research on the biology of mental diseases needs to be conducted along with the
research on more efficient and effective models of mental health care. 97

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 Chapter 6.15: Depression in Young People and the Elderly

8. Conclusions
It is clear that depression is a condition that affects the quality of life of a considerable
proportion of young people and the elderly. From an individual perspective, depression
might lead to social underperformance, violence, drug abuse and suicide in adolescents. For
the elderly, it might bring undesirable suffering during their last years of life. From a societal
perspective, the costs associated with depression (especially with the fast ageing of our
societies which is making them more dependent on fewer healthy young people) and the
recognition that existing treatment might be cost-saving, make depression in young people
and in the elderly a condition worthy of further research.

Efficacious treatments and a number of promising new drugs do exist, but they have not
been appropriately tested in young people and the elderly. The extrapolation of findings
from RCTs in adults might be misleading, doing more harm than good.

Major efforts to improve the effectiveness of health systems in diagnosing and treating
depression are required. A 6.8% effectiveness for treating a highly disabling condition
representing 7.6% of the burden of disease is unacceptable. The availability of effective drugs
will achieve very little if patients are not diagnosed, treated and appropriately supported.

Further basic research into the biology of depression in youth and in the elderly, and the
operationalization of this knowledge into better clinical diagnostic protocols and robust
psychological models is needed.

9. References:

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