depression in the youth and adolescent - world health...

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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Table of Contents

Abbreviations Used in this Report.............................................................3Summary....................................................................................................41. Introduction.........................................................................................5

Definition and Classifications.........................................................................5Natural History..............................................................................................6Depression in Young People...........................................................................7Depression in the Elderly...............................................................................7

2. Epidemiology and Burden of Depression............................................8Epidemiology of Depression in the General Population.................................8Epidemiology of Depression in Youth..........................................................10Epidemiology of Depression in the Elderly..................................................10Epidemiology of Depression as a Comorbidity............................................11Economic Impact of Depression...................................................................12

3. Control Strategy................................................................................12Antidepressants in Young People.................................................................15Antidepressants in the Elderly.....................................................................15Side-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........................................................................................279. References:........................................................................................27

Annex

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http://mednet3.who.int/prioritymeds/report/annexes/depression_listanx.htm


Abbreviations Used in this Report5HT: 5-hydroxytryptamineAD: Alzheimer diseaseADHD: attention deficit with hyperactivity disorderCRF: corticotropin-releasing factorCT: computerized tomographyCVD: cardiovascular diseaseDALY: disability-adjusted life yearEU10: European union new accession countriesEU15: European union countriesEU25: Expanded European unionECT: electroconvulsive therapyFDA: United States’ Food and Drug AdministrationfMRI: functional magnetic resonance imagingGABA: gamma-aminobutyric acidGDP: gross domestic productGnRH: gonadotropin releasing hormone GP: general practitionerObs & Gyn: obstetrics and gynaecology HMO: health management organizationIHD: ischaemic heart diseaseIP: interpersonal psychotherapyCM-IPT: clinician-managed interpersonal psychotherapy MAO: monoamine oxidaseMAOI: monoamine oxidase inhibitorsMRI: magnetic resonance imagingNK: neurokininNMDA: N-methyl-D-aspartatePD: Parkinson diseasePET: positron emission tomographyPTSD: post-traumatic stress disorderPUFA: polyunsaturated fatty acidsRCT: randomized clinical trialSNSRI: serotonin and noradrenaline-selective reuptake inhibitorSSRI: serotonin-selective reuptake inhibitorTCA: tricyclic antidepressantTMS: transcranial magnetic stimulationYLD: years lived with disability

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SummaryDepression 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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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. IntroductionDefinition 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 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,

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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

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

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

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Mental (DALYs per 1000, All regions, 2002)

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Graph # 2.1 : Burden of mental illness (DALYs/1000, 2002)


2. Epidemiology and Burden of DepressionEpidemiology 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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Depression (DALYs per 1,000, All regions, 2002)

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


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

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

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


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 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

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suffer from major depression.18;36;44;45 In the elderly, depression is also a major cause of morbidity and mortality.

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 during the course of their illness, depression affect 20–40% of AD patients.15

Depression in AD patients leads to mental suffering, behavioural disturbances (such as aggression), poor cognition, poor self-care, caregiver burden, and early entry into a nursing home. Depression is associated with severe, but avoidable, negative

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Prevalence of major depression in patients with physical illnesses

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Graph # 2.3: Prevalence of major depression in patients with physical illnesses

Source: World Health Organization. Investing in Mental Health. Geneva: World Health Organization, 2003


consequences for patients and caregivers: half of them suffer a major depression themselves.53

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 StrategyThere 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

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interpersonal therapy (especially in the elderly). Psychotherapeutic interventions in severely ill patients are more effective when provided in 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, Tranylcypromine, and Selegiline. These drugs have proven antidepressant effects but have serious side-effects, and potentially fatal interactions with many substances.

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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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Table # 3.1: Comparison of efficacy of antidepressants Author Avg AD MAOI TAC SSRI Placeb

oObs

Gill & Hatcher (2002)60 52% 30%Wilson et al (2002) 61 49% 25% ElderlyWilson et al (2002) 61 28% 17% ElderlyWilson et al (2002) 61 41% 10% ElderlyMulrow 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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Table # 3.2: Antidepressant treatment for elderly patients with various medical conditions15

Medical condition Antidepressant of choice

Drugs to avoid

Endocrine disorders None favored NoneCardiac disease SSRIs, bupropion,

nefazodoneTCAs, venlafaxine, (if patient has high blood pressure), SSRIs (if patient takes antiarrhythmics)

Cancer - with severe pain- with cachexia

- with nausea

TCAsSertaline, paroxitine, trazodone, nefazodone, TCAs, venlafaxineNone

MAOIsFluoetine

Buproprion, SSRIs, venlafaxine

Neurologic disordersParkinson DiseaseStrokeAlzheimer’s dementia

Buproprion, venlafaxineSSRIsSSRIs, nefadone, venlafaxine

TCAs, MAOIs, buproprionTCAs, MAOIs, buproprionTCAs, 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 class24

ClassDrug Mode of

actionAnticholiner

gicAntihistam

inic-

adrenergic blocker

Tricyclic antidepressant

AmitriptilineImipramineDothiepin

Noradrenaline (++) 5-HT (+)

+++++++

++++++++

+++++++++

Reverse inhibitors of MAO-a

Moclobemide

MAO 0/+ 0 0

SSRI FluvoxamineFluoxetineSertralineCitalopramParoxetine

5HT 0/+0/+0/+0/+0/+

0/+0000

00000

Noradrenaline + SSRI

Mirtazepine 2, 5HT2 0 ++ 0

SNSRI Velafaxine Noradrenaline (+) 5HT (++)

0/+ 0 0/+

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Table # 3.4: Details of side-effects of antidepressants by product70

Component Side effectsMAOIIsocarboxazid (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 (Parnate)

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

Tricyclic Amitriptyline (Elavil, Endep, Vanatrip)


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 (Anafranil)

Drowsiness; dry mouth; upset stomach; vomiting; diarrhoea; constipation; nervousness; decreased sexual ability; decreased memory or concentration; headache; stuffy nose; change in appetite or weight

Desipramine (Norpramin)


Doxepin (Adapin, Sinequan)


Imipramine (Tofranil)


Nortriptyline (Aventyl, Pamelor)


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 (Surmontil)

Upset stomach; vomiting; diarrhoea; stomach pain; drowsiness; weakness or tiredness; excitement or 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)SSRIsCitalopram (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) Paroxetine CR (Paxil CR)

Joint pain 1.0%; confusion 1.0%; constipation 5.2%; diarrhoea 4.0%; dizziness 7.8%; drowsiness 14.3%; dry mouth 6.0%; fatigue 10.3%; fever 2.0%; gas 1.0%; headache 0.3%; insomnia 7.1%; nausea 16.4%; 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%

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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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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

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Board on 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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Table 4.1: Mental health department usage in a large HMO20

Co-payment Percentage using* Visit per user**U$ 5 3.38 4.85U$ 10 2.78 4.7850% 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 AntidepressantsThe 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 Database91 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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http://mednet3.who.int/prioritymeds/report/annexes/depression_anx1.doc


Table # 5.1: Summary of trials on depressionArea of research Mechanism of action Freq

Basic biological research

Functional brain imaging PETs 13

Risk factors epidemiology 13Endocrine Leptin, hydrocortisone, progestin,

circadian rhythm10

Traditional medicine Various unknown 3Brain neurotransmitters and receptor characterization

3

Genetics Genetic mapping 2Electroconvulsive therapy-related

Transcranial magnetic stimulation 1

Others Various 2Basic psychological research

Child development 2

Risk factors 1HIV-related 1

Applied clinical research

SSRIs and atypical Serotonin reuptake inhibitors 27

Comparative Various 17Others traditional Massages, PUFA, light therapy,

hypericum, acupunture, yohimbe13

Undisclosed Unknown 7Endocrine-based therapies 17 beta-estradiol 5Magnetic brain stimulation and ECT

5

Other compounds Lamotrigine, dutastaride, pramixole, propanolol

5

TCAs 4Felbamate and others Glutamatergic system 3Soya bean Phytoestrogen and protein tyrosine

kinase2

MAOIs Monoamine-oxidase inhibitors 2Other compounds Lamotrigine, dutastaride, pramixole,

propanolol5

Psychological clinical research

Cognitive therapy 8

Behavioural change 5Problem-solving therapy 3Interpersonal therapy 3Other psychotherapy 12

Heath care research

Protocols 4

Integrated models 2Teamwork 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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Table # .5.2: US National Institute of Health Research funding for mental conditions74

Research/disease areas*(Million US$)

FY 2003(actual)

FY 2004(estimate)

FY 2005(estimate)

Alzheimer disease 658 680 699

Attention deficit disorder (ADD) 103 106 109

Behavioural and social science 2684 2762 2831Biotechnology research 9893 10418 10716Brain disorders 4740 4887 5023Clinical research 8028 8383 8678Depression research 288 296 304Neuroscience 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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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)

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

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SchizophreniaPsychosisParkinsonObesityIrritable Vowel SyndromeEpilepsyDepressionCognitive DefectBipolarAnxietyAlzhDisADD

Graph # 5.1: Antidepressants R&D Pipeline 2004, by first indication

(Source: IMS Health report on antidepressant R&D pipeline, May 2004)

Antidepressants R&D Pipeline 2004, by second indication(Source: IMS Health May 2004 report on Antidepressant Pipeline)

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Urinary IncontinenceSexDisSchizophreniaNicotine WithdrawalEmesisDepressionCOPDCognitive DefectBipolarAsthmaAnxiety

Graph # 5.2: Antidepressants R&D Pipeline 2004, by second indication

(Source: IMS Health report on antidepressant R&D pipeline, May 2004)


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 DifferenceAlthough 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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8. ConclusionsIt 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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depression in the youth and adolescent - world health...

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