Professor and BC Leadership Chair in Depression Research Department of Psychiatry, University of British Columbia Vancouver, British Columbia, Canada
1
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Preface to the Third Edition
Despite some initial controversy, DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edn) has been accepted and adopted by most clinicians as an incremental advance for the field. This new edition now incorporates DSM-5 as well as recent revisions in treatment guidelines for depression. The CANMAT 206 Clinical Guidelines for the Management of Adults with Major Depressive Disorder were published as a theme issue in the Canadian Journal of Psychiatry, and are available for free download at http://www.canmat.org, accessed October 207. The CANMAT guidelines provide much of the reference material used to summarize new evidence and recommendations for the dizzying array of available treatments for depression, ranging from mindfulness-based psychotherapies to novel antidepressant medications, to neurostimulation and exercise. All the key references in this edition have been updated to reflect the latest evidence. I want to thank, again, my CANMAT colleagues (nearly 50 strong) for their dedicated leadership in producing these internationally used guidelines, especially my guidelines’ co-lead, Dr Sidney Kennedy. Their efforts contribute to making this book clinically useful.
Progress usually advances incrementally, but medicine is at the tipping point for the next great revolution—a digital personalized one. The emergence of data science with ‘big data’ artificial intelligence and machine learning algorithms heralds a real promise of precision medicine. Biomarker studies have given way to biosignature research incorporating panels of integrated clinical, neuroimaging, and molecular markers. Predicting individual response to treatment using crowdsourced EEG (electroencephalographic) and clinical information; personalized alerts for relapse with apps that analyze voice modulation, text messages, and geographic location patterns; reprogramming neural circuits with individualized brain games; adapting the lighting at home to optimize sleep and circadian rhythms—these possibilities are no longer science fiction even if, for now, they are not yet ready for prime-time clinical use. I have no doubt that this innovative research will soon transform the diagnosis, management, and treatment of depression. I look forward to incorporating these discoveries in a major rewrite for the next edition of this book.
Raymond W. Lam, MD, FRCPC
Preface to the Second Edition
Progress is inevitable. In the 3 years since publication of the first edition, a number of advances have occurred in the management of depression. Several new antidepressants have entered the clinical market. Second generation antipsychotic medications are now clearly beneficial as adjunctive therapy (and, for one, as monotherapy) for major depressive disorder. Mindfulness-based cognitive therapy has strengthened its evidence base for prevention of depressive relapse. Technology-assisted psychotherapy has come of age and transcranial magnetic stimulation has become clinically available in many centres. The ketamine story may herald a new frontier for understanding the pathophysiology of depression as well as offering the promise of a truly rapid acting antidepressant. It is because of these advances that a revision and second edition of this book was necessary. Several new sections have been added and the key references have been updated throughout. Some of these developments were summarized in the CANMAT Clinical Guidelines for Management of Major Depressive Disorder, published in 2009 and widely distributed and accessed all over the world.
The next revision will likely be necessary after the upcoming publication and dissemination of the DSM-5 in 203 (www.dsm5.org). Although the section on mood disorders will not undergo major modification, there are many planned changes in other diagnoses and in the overall structure and ‘look and feel’ of DSM-5. Many of the proposed revisions remain controversial. It will be important to update clinical management in response to these changes. In the meantime, I dedicate the second edition of this book to the patients and families who are our partners in the recovery process from major depressive disorder.
Raymond W. Lam, MD, FRCPC
Preface to the First Edition
All the recent new research and knowledge about depression makes it a daunting task to summarize the vast amounts of information into manageable, yet still relevant, portions. Much of the work of this volume arose from my involvement with the Canadian Network for Mood and Anxiety Treatments (CANMAT) in developing Canadian clinical practice guidelines for depression. I am indebted to my expert CANMAT colleagues for their many hours of thought-provoking discussion about all aspects of depression and its treatment. I especially want to thank Dr Sidney H. Kennedy, Professor of Psychiatry at the University of Toronto and Chief of Psychiatry at the University Health Network, for his support and collaboration over many years.
Throughout this book we have tried to simplify the diagnosis and management of what is a complex disorder, to make the evidence relevant, and to illustrate the art and the science. Our intent is to provide a practical reference to help ‘at the bedside’ (or, at least, at the nursing station). We hope that clinicians will find this book useful.
Raymond W. Lam, MD, FRCPC
Abbreviations
5-HT 5-hydroxytryptamine (serotonin)
ACTH adrenocorticotropic hormone
AIDS acquired immune deficiency syndrome
ASRI allosteric serotonin reuptake inhibitor
BA behavioural activation
BDNF brain-derived neurotrophic factor
BT behaviour therapy
CAM complementary and alternative medicine
cAMP cyclic adenosine monophosphate
CANMAT Canadian Network for Mood and Anxiety Treatments
CANTAB Cambridge Neuropsychological Test Automated Battery
CBASP cognitive behavioural-analysis system of psychotherapy
CBT cognitive–behavioural therapy
CDM chronic disease management
CNS central nervous system
CNS-VS CNS Vital Signs
CREATE Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (trial)
CRF/CRH corticotropin-releasing factor/hormone
CT cognitive therapy
DBS deep brain stimulation
Dex/CRH dexamethasone suppression test in combination with the CRH-stimulation test
DLPFC dorsolateral prefrontal cortex
DSM-5 Diagnostic and Statistical Manual of Mental Disorders, 5th edn
DSM-IV Diagnostic and Statistical Manual of Mental Disorders, 4th edn
DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders, 4th edn (text revision)
ECT electroconvulsive therapy
EEG electroencephalograph
ENRICHD Enhancing Recovery in Coronary Heart Disease (study)
EPDS Edinburgh Postnatal Depression Scale
FDA US Food and Drug Administration
GI gastrointestinal
G×E gene by environment
HADS Hospital Anxiety and Depression Scale
HAM-D Hamilton Depression Rating Scale
HPA hypothalamic-pituitary-adrenal
5-HTTLPR 5-hydroxytryptamine (serotonin) transporter linked polymorphic region
ICD-0 International Classification of Diseases (version 0)
INR international normalized ratio
IPT interpersonal psychotherapy
K-DEPACS Korean Depression in Acute Coronary Syndrome (study)
LEAPS Lam Employment Absence and Productivity Scale
LED light-emitting diode
MADRS Montgomery–Åsberg Depression Rating Scale
MAO monoamine oxidase
MAOI monoamine oxidase inhibitor
MBCT mindfulness-based cognitive therapy
MDD major depressive disorder
MDE major depressive episode
MI myocardial infarction
MINI Mini International Neuropsychiatric Interview
SIGMA structured interview guide for the Montgomery–Åsberg Depression
Rating Scale
SNRI serotonin and noradrenaline reuptake inhibitor
SRI serotonin reuptake inhibitor
SSRI selective serotonin reuptake inhibitor
STAR*D Sequenced Treatment Alternatives to Relieve Depression (study)
SWA slow-wave activity
SWS slow-wave sleep
TADS Treatment for Adolescents with Depression Study
TCA tricyclic antidepressant
TRD treatment-resistant depression
TSD total sleep deprivation
VNS vagus nerve stimulation
WHO World Health Organization
Chapter 1
Introduction
Key points
• Depression is a common and disabling psychiatric condition that must be recognized by all physicians and health professionals.
• The principles of care for major depressive disorder include: thorough assessment and diagnosis, selection of appropriate and evidence-based treatments, and careful follow up using measurement-based care.
A 36 year old janitor who has insomnia and is fatigued all the time. A 24 year old with diabetes who has stopped taking her insulin. A 40 year old homemaker who cries and cannot cope at home. A 69 year old seen in the emergency room with his second heart attack within 3 months. A 32 year old executive who is procrastinating about making decisions at work. A 7 year old high-school student who cannot stop thinking about ending her life. What do all these various people have in common? They are all suffering from depression, one of the most common of all medical conditions, yet one of the most difficult to recognize.
Depression is ubiquitous, but the number and range of physical and cognitive symptoms associated with major depressive disorder (MDD) means that many people do not present with emotional symptoms. Although one in seven people will suffer psychosocial impairment from MDD, many will not be diagnosed despite repeated healthcare visits. And, it is not only family physicians, psychiatrists and mental health clinicians that need to diagnose depression. The high prevalence of MDD with other medical illnesses means that other health professionals and physicians, whether internists or oncologists or surgeons or cardiologists or neurologists or any other specialist, must also recognize and manage clinical depression in their patients. After all, as some authors have noted, there is ‘no health without mental health’.
Governments and healthcare payers are now finally appreciating the hidden socioeconomic burden that results from MDD. Depression is a huge drain on the economy, with exceedingly high rates of disability and reduced productivity. The World Health Organization announced in 207 that depression had become the leading medical cause of functional disability worldwide. The concentration, memory, and decision-making problems associated with depression are particularly damaging to workforces in knowledge-based industries, a major issue for many countries trying to convert from resource-based economies.
But, recognizing depression is not enough. The good news is that there are very effective treatments for depression. Evidence-based psychotherapies abound, there are many effective antidepressant medications, and several non-invasive somatic treatments also are available. With appropriate treatment, most patients are able to promptly recover from a depressive episode and return to their usual functioning. And, there is an explosion of new research and new methodologies to expand our understanding of the pathophysiology of depression, with the promise of new, more effective, and better tolerated treatments to come.
The bad news, however, is that many patients with depression are still not able to access these treatments, whether psychotherapy or new medications or new technologies. Even when available, the current systems of health care often do not achieve best practices for treating MDD, so that the ‘usual care’ of depression is not good enough. For those patients whose depression can be regarded as a chronic or persistent condition, collaborative disease management programmes that include a focus on self-management and functional improvement, instead of symptom resolution, will further engage patients and clinicians to optimize care. Mobile and internet technologies also herald promise in terms of access to both educational information and evidence-based treatments. And, we are getting closer to identifying clinically useful biomarkers to personalize treatment recommendations for patients with MDD.
This book seeks to succinctly address the diagnostic and treatment issues that clinicians will encounter when dealing with patients with MDD. The principles of care for depression can be quite simple. Attention to early recognition, careful assessment, selection of appropriate evidence-based treatments, and measurement-based follow up will help our patients get the best care possible.
Further r eading
Lam RW, Kennedy SH, Parikh SV, et al. (206) Canadian Network for Mood and Anxiety Treatments (CANMAT) 206 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Introduction and methods. Can J Psychiatry 61: 506–9. Prince M, Patel V, Saxena S, et al. (2007) No health without mental health. Lancet 370: 859–77.
Summergrad P (206) Investing in global mental health: the time for action is now. Lancet Psychiatry 3: 390–.
World Health Organization (207) Depression and Other Common Mental Disorders Geneva: WHO Document Production Services.
Epidemiology and burden
Key points
• Depression is a highly prevalent condition—about one in seven people will experience a depressive episode during their lifetime.
• Many people with depression will have a recurrent or chronic course, leading to substantial impairment in psychosocial function.
• Depression is now the leading cause of years lived with disability worldwide.
• The economic costs of depression are staggering, both in direct medical costs of treating depression and in indirect costs of work absence and loss of productivity.
• Depression remains severely undertreated, but scaling up depression treatment brings US$5 of economic return for every US$ spent.
2.1 Prevalence
2.. Current trends
Depressive disorders are very common conditions as the lifetime risk for experiencing major depressive disorder (MDD) is approximately 5% (Table 2.). Depression also contributes significantly to disability, with estimates that depression accounts for .3–4.4% of all disability and premature deaths worldwide. Two major epidemiological trends are occurring with respect to depressive disorders. First, the lifetime risk of developing depression in those born after the Second World War is increasing, although some studies suggest this increase began as far back as 925. Second, in both women and men, the age of onset for depression is becoming increasingly younger, which corresponds to the rise in psychiatric hospitalizations amongst adolescents.
2..2 Sex
The lifetime prevalence of MDD is .6–3. times more common in women than men, with a greater disparity found in the USA and Western Europe. The disparity begins at the age of puberty and it is common to find worsening of depressive symptoms in women coinciding with the onset of menses. Other hypothesized causes of increased depressive episodes in women include hormonal differences, psychosocial stressors, and childbirth. The disparity between the sexes appears to be narrowing in studies involving younger cohorts, and the gap also decreases after the age of 50–55 years as women enter menopause.
Table 2.
Prevalence of DSM-IV MDD in general populations
Pâulo)
Source data from: BMC Medicine, 9, Bromet E, Andrade LH, Hwang I et al., Cross-national epidemiology of DSM-IV major depressive episode, 20; Canadian Journal of Psychiatry, 60, Patten SB, Williams J, Lavorato DH, et al., Descriptive epidemiology of major depressive disorder in Canada in 202, 205, pp. 23–30.
* Data on Canada is from the Canadian Community Health Survey.
2..3 Age
In worldwide population samples aged 8–64 years, the average age for the onset of depression varies from 24 to 35 years, with a mean age of 27 years. There is currently a trend of an increasingly younger age of depression onset. For example, 40% of depressed individuals have their first depressive episode prior to the age of 20, 50% have their first episode between the ages of 20–50, and the remaining 0% after 50 years of age.
Depressive symptoms also vary with age. Childhood depression tends to involve more somatic complaints combined with irritability and social withdrawal, and adolescents experience more ‘atypical’ features of depression (e.g. overeating, hypersomnia), while elderly depressed patients are most likely to have depressive features of melancholia (e.g. loss of interest or pleasure, lack of reactivity, insomnia).
2.2 Course and prognosis
2.2. Course
About half of individuals with first-episode depression experience a prodromal period during which significant depressive symptoms are present. These
symptoms, which can be present for weeks to years prior to diagnosis, include anxiety and other mild depressive symptoms. The length of an untreated depressive episode varies from 4 to 30 weeks for a mild–moderate depression, while severe episodes have an average length of 6–8 months. Nearly 25% of individuals with severe depressive episodes will endure symptoms for more than 2 months. Treated depressive episodes last on average 3 months; however, stopping antidepressants prior to 3 full months of use almost always results in the return of symptoms.
2.2.2 Prognosis
For many patients, MDD can be a chronic, relapsing illness. Relapse within the first 6 months of recovery occurs in 25% of patients, 58% will relapse within the first 5 years, and 85% will relapse within 5 years of initial recovery. Moreover, those individuals that have had two previous depressive episodes have a 70% probability of a third, and having three previous depressive episodes incurs a 90% likelihood of relapse. As the disease progresses, the interval between depressive episodes becomes shorter and the severity of each episode becomes greater. Over a 20-year span, depressive recurrences occur on average five to six times. A significant proportion of depressed individuals remain chronically ill with varying levels of symptoms. About two-thirds of patients with a major depressive episode will fully recover, while one-third of depressed patients will either only partially recover or remain chronically ill. In a study of patients at year postMDD diagnosis, 40% had recovered with no symptoms of depression, 20% continued to have residual symptoms but did not meet the criteria for MDD, while 40% remained in a major depressive episode. Those individuals that continue to have residual depressive symptoms are at a high risk of relapse, suicide, poor psychosocial functioning, and higher mortality from other medical conditions. In addition to depression, 5–0% of individuals who have experienced a major depressive episode will subsequently have a manic or mixed episode indicative of bipolar disorder.
Numerous studies have focused on prognostic indicators which have a predictive value in terms of the recovery rate and relapse probability in depressed individuals (Box 2.).
2.3 Burden of illness
2.3. Disability and death
Depression causes substantial impairment in daily functioning. Social functioning decreases in correlation with increasing depressive severity as 8% of patients with minor depression were found to have major problems with daily interactions, compared to 52% of patients with seven to nine symptoms of a major depressive episode. In general, depression has been found to increase the risk of social disability 23-fold over the general population.
Box 2. Prognostic indicators of a prolonged recovery in patients with MDD
• Severe depressive episode
• Long duration of depressive episode (>6 months)
• Presence of comorbid illness
• Presence of psychotic features
• Early age of onset
• Alcohol or drug abuse
• History of prior psychiatric illness (e.g. previous depressions or anxiety disorder)
• Three or more prior hospitalizations
• Poor social support, poor family functioning, and low family income
• Low level of functioning for 5 years prior to illness
Similarly, depressed patients have almost two times greater overall mortality risk than the general population owing to direct causes (e.g. suicide) and indirect causes (e.g. medical illness). The risk of death by suicide increases 26-fold in depressed individuals. However, the lifetime prevalence of suicide for depressed individuals is 2.2% and suicide represents only % of reported deaths related to depression. Depressed patients are at a .8 times greater risk of developing a medical illness year post-diagnosis. In particular, hospitalized depressed patients with comorbid cardiovascular disease are at a significantly increased risk for myocardial infarct and death for 0 years post-hospitalization. For example, depressed patients with unstable angina are at a three times greater risk of death than nondepressed individuals. The increased risk of cardiovascular death likely is due to both direct physiological effects (e.g. reduced heart rate variability, increased platelet aggregation) and indirect effects (e.g. poor compliance with medications, drug and alcohol abuse, etc.) of depression (see Chapter 0).
2.3.2
Socioeconomic costs
As of 2000, depression was the fourth leading cause (of over 300 causes) of disability worldwide, representing 2% of all years lived with disability. By 203, depression had risen to the second leading medical cause of years lived with disability, behind only low back pain (Figure 2.). In April 207, the World Health Organization announced that depression had become the first-ranked leading cause of health-related disability. An estimated 322+ million people were estimated to have depression, representing 4.4% of the world population, leading to 50+ million years lived with disability in 205.
In terms of work productivity, those suffering with depression are three to four times more likely to take sick days off work than non-depressed individuals. In a U.S. survey, the salary-equivalent productivity loss attributed to depressive absenteeism (average US$82–US$395) approached the estimated cost of
2. The Global Burden of Disease Study. In 203, depression ranked second in total health-related disability worldwide.
treating depression. Studies have also found that employers, on the whole, have negative beliefs about mental illness and are less likely to hire depressed individuals based on expectations of sub-standard work performance. In fact, depressed individuals have a perceived increase in self-rated productivity when they experience fewer and less severe depressive symptoms, suggesting that early treatment of depression would economically benefit employers.
The astounding economic costs of depression are due to a combination of direct treatment of depression, premature mortality (e.g. by suicide), and reduced productivity and absenteeism. The total annual costs of depression in the United States are estimated at US$44 billion: US$2.4 billion in direct costs of treatment (hospitals, medications, doctors’ fees), US$8 billion in premature death, and US$24 billion in absenteeism and reduced productivity in the workplace. In Canada, the indirect costs of depression (premature mortality and reduced productivity) are estimated at C$5 billion, and represent 58% of the overall economic cost of depression. These approximations, however, underestimate the overall cost of depression because they do not include out-of-pocket family expenses, and costs of minor and untreated depression, excessive hospitalization, general medical services, and diagnostic tests.
2.3.3 Costs of untreated depression
Depression increases the risk for both social and physical disability, and as a result, increases the costs for other medical services. Nevertheless, an even greater strain on the medical system originates from the cost of undiagnosed and untreated depression. Individuals with depressive symptoms, who have not been diagnosed with a depressive disorder, utilize more medical services and attempt Mean years lived with disability (x1,000,000) Hearing
Figure
suicide more often than MDD-diagnosed patients. In a U.S. study, patients diagnosed with depression recovering from surgery stay on average 0 days longer in hospital than non-depressed patients. However, those individuals with untreated depressive symptoms stayed 26 days longer than non-depressed patients. In fact, individuals with untreated depression account for the majority of ‘high utilizers’ of general medical services. Thus, diagnosing and treating these individuals should lessen the burden on the medical system.
2.3.4 Costs of treatment
Depression remains severely undertreated worldwide, but especially so in lower income countries, where there are also very low rates of perceived need for treatment (Figure 2.2). Effective treatment of depression has been found to improve patient social functioning, lower risks of other medical illnesses, decrease lost and unproductive work days, and consequently reduce disability costs. Moreover, the use of pharmacotherapy and psychotherapy in the treatment of depression reduces the overall cost to the entire healthcare system. In primary care settings, the implementation of collaborative care and chronic disease management programmes also has been shown to cost-effectively improve outcomes of depressed patients. Unfortunately, even higher income countries have low rates of adequate treatment for depression (Figure 2.2). The economic savings for
Perceived need for treatment Received any treatment Received adequate treatment
* Data from individual city surveys for Brazil (Sao Pâulo) and China (Beijing /Shanghai) Percentages below country label indicate the 12-month prevalence rate of MDD.
Figure 2.2 Proportion of people with MDD who perceived a need for treatment, received any treatment, and received adequate treatment in the WHO World Mental Health Survey.
Source data from The WHO World Mental Health Surveys: Global Perspectives on the Epidemiology of Mental Disorders, Kessler R.C and Ustun T.B (eds.), 2008.
scaling up treatment services for depression are considerable, with a global study estimating a US$5 return on investment for every US$ spent.
Further r eading
Bromet E, Andrade LH, Hwang I, et al. (20) Cross-national epidemiology of DSM-IV major depressive episode. BMC Medicine 9: 90.
Chesney E, Goodwin GM, Fazel S (204) Risks of all-cause and suicide mortality in mental disorders: a meta-review. World Psychiatry Rep 13: 53–60.
Chisolm D, Sweeny K, Sheehan P, et al (206) Scaling-up treatment of depression and anxiety: a global return on investment analysis. Lancet Psychiatry 3: 45–24.
Coventry PA, Hudson JL, Kontopantelis E, et al. (204) Characteristics of effective collaborative care for treatment of depression: a systematic review and meta-regression of 74 randomised controlled trials. PLoS One 9: e084.
Donohue JM, Pincus HA (2007) Reducing the societal burden of depression: a review of economic costs, quality of care and effects of treatment. Pharmacoeconomics 25: 7–24.
Global Burden of Disease Study 203 Collaborators (205) Global, regional, and national incidence, prevalence, and years lived with disability for 30 acute and chronic diseases and injuries in 88 countries, 990–203: a systematic analysis for the Global Burden of Disease Study 203. Lancet 386: 743–800.
Kessler RC (202) The costs of depression. Psychiatr Clin North Am 35: –4.
Lam RW, McIntosh D, Wang JL, et al. (206) Canadian Network for Mood and Anxiety Treatments (CANMAT) 206 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section . Disease burden and principles of care. Can J Psychiatry 61: 50–23.
Thornicroft G, Chatterji S, Evans-Lacko S, et al. (207) Undertreatment of people with major depressive disorder in 2 countries. Br J Psychiatry 210: 9–24.
World Health Organization (207) Depression and Other Common Mental Disorders. Geneva: WHO Document Production Services.
Chapter 3
Pathogenesis
Key points
• There are likely multiple processes to explain the aetiology and pathophysiology of depression, with involvement of biological, psychological, and social factors.
• Circadian rhythmicity, stressful life events, and stress reactivity can modify genetic and biological processes (gene–environment interactions) to contribute to depression.
• Endophenotypes, or genetic expressions of neural systems involved in depression, are important in the study of the pathogenesis of depression and the development of novel treatments.
3.1 Introduction
The exact pathophysiology of major depressive disorder (MDD) remains unknown, but the aetiology has always been presumed to be heterogeneous since the diagnosis of MDD is only descriptive and likely consists of a number of syndromes with related symptoms. Biological, psychological, and social factors all influence MDD, and each has reciprocal relationships with the others (Figure 3.). New research in genetics, neuroimaging, and molecular biology has clarified some of the relationships between these broad forces, particularly in the modulation of stress and life events on genetic and neurobiological processes. There is increasing emphasis on endophenotypes, defined as endogenous phenotypes that are not evident to the unaided eye that fill the gap between genes and a complex disease, to advance our classification of depressive disorders and to guide treatment selection (Figures 3.2 and 3.3). This chapter will highlight some of these recent advances.
3.2 Genetics
3.2. Family, twin, and adoption studies
Family studies indicate at least two or three times increased relative risk (5–25%) for MDD in first-degree relatives of MDD probands, with early age of onset and recurrent depression conferring greater risk. Adoption studies, most from Scandinavia, found that biological relatives of depressed adoptees were much more likely to have depression than the adoptive relatives. Twin studies, by comparing monozygotic to dizygotic twins, allow the dissection of genetic from
chapter 3
Biological
Genetics
Circadian Rhythms
Neurohormones, Neurochemicals, Neuroin ammation
Psychological
Personality
Person with depression
Social
Relationships, Work/Leisure
Physical illnesses, Medications/drugs
Life experiences, Life stresses
Figure 3. Relationships between biological, psychological, and social factors in the pathophysiology of depression.
environmental influences on disease risk. Estimates from twin studies of genetic heritability of depression range from 33% to 70%, independent of gender. The consistent results from these varied studies indicate a substantial genetic basis for MDD.
3.2.2 Linkage and association studies
Linkage analysis studies have not produced replicated results, mainly because complex disorders such as MDD are not likely to be due to abnormalities in a single gene locus. Large samples (at least ,000 affected sibling pairs) are needed to reliably detect a locus that causes even a 30% increase in risk. Genome scanning is a powerful new tool used to detect genetic associations, but results from genome scans are prone to false-positive errors and need to be replicated in other large samples.
Candidate gene strategies involving association analysis to genes coding for particular elements of neurotransmitter function have been more informative (Figures 3. and 3.2). Particular attention has been focused on functional polymorphisms, which are variations in DNA sequences that alter expression and/or functioning of gene products. Initial enthusiasm was generated for an association of MDD with the polymorphism involving the short allele of the promoter region of the serotonin transporter gene, 5-HTTLPR (5-hydroxytryptamine (serotonin) transporter linked polymorphic region), and with response to SSRIs (selective serotonin reuptake inhibitors), but subsequent studies and meta-analyses have not replicated these findings. However, other evidence suggests that 5-HTTLPR polymorphisms are associated with neurotic traits and response to stressful life
Figure 3.2 Example of how neurochemical abnormalities may relate to candidate genes and to key components of major depression. Not all functional directions are indicated for the sake of clarity for the figure. Abbreviations: 5-HTTLPR, 5HT (serotonin) transporter promoter region gene; ACC, anterior cingulate cortex; bcl-2, B-cell lymphoma-2 gene; BDNF, brain-derived neurotrophic factor; CREB, cAMP response element binding protein; MR, mineralocorticoid receptor; NMDAR, NMDA receptor; PFC, prefrontal cortex.
Reprinted by permission from Macmillan Publishers LTD: Hasler G, Drevets WC, Manji HK, et al. Discovering endophenotypes for depression. Neuropsychopharmacology 2004; 29:765–8, copyright 2004.
events, suggesting that this transporter gene modifies stress reactivity rather than causing MDD, per se. Other candidate genes being investigated in MDD include tryptophan hydroxylase-2, brain-derived neurotrophic factor (BDNF), cAMP-responsive element-binding protein (CREB)-, and genes involved in the circadian clock.
3.3 Neurobiology
3.3.
Monoamines
The monoamine hypothesis has been the foundation of neurobiological theories for depression for the past half century. Initially based upon observations of the mechanism of action of antidepressants, this hypothesis postulates that depression results from deficits in key brain areas in serotonin (5-HT) or noradrenaline synaptic neurotransmission. Antidepressants were thought to act by blocking the
Figure 3.3 Example of how neurochemical abnormalities may relate to candidate genes and to key components of major depression. Not all functional directions are indicated for the sake of clarity for the figure. Abbreviations: 5-HTAR, 5-HT (serotonin) A receptor; 5-HT2AR, 5-HT (serotonin)-2A receptor; 5-HTTLPR, 5-HT (serotonin) transporter promoter region gene; CHRM2, cholinergic muscarinic-2 receptor; COMT, catechol-O-methyltransferase; CREB, cAMP response element binding protein; CRH, corticotropin-releasing hormone; CRH-R, CRH receptor; DBH, dopamine-beta-hydroxylase; GR, glucocorticoid receptor; HPA, hypothalamic-pituitary-adrenal axis; MAO-A, monoamine oxidase-A; MR, mineralocorticoid receptor; REM, rapid eye movement; SERT, serotonin transporter; TPH2, tryptophan hydoxylase-2.
Reprinted by permission from Macmillan Publishers LTD: Hasler G, Drevets WC, Manji HK, et al. Discovering endophenotypes for depression. Neuropsychopharmacology 2004; 29:765–8, copyright 2004.
serotonin transporter (SERT), leading to increased availability of neurotransmitter within the synaptic cleft. However, this theory did not account for the lag time for onset of therapeutic effects of antidepressants, given that increases in synaptic neurotransmitters occur immediately with reuptake inhibitors. Tryptophan and catecholamine depletion studies also have not produced any evidence in support of a simple deficit of neurotransmitter levels or function in MDD.
Newer models, incorporating various interdisciplinary neuroscience approaches, have extended past the synapse to focus on the importance of presynaptic and postsynaptic receptors and processes (Figure 3.4). For example,
Figure 3.4 Characterization of antidepressant effects using an interdisciplinary approach. Abbreviations: 5-HT, serotonin; GPCR, G-protein coupled receptor; HPLC, high-performance liquid chromatography; IC, ion channel; SERT, serotonin transporter.
Adapted from: Millan MJ. The role of monoamines in the actions of established and “novel” antidepressive agents: a critical review. European Journal of Pharmacology 2004; 500:37–84.
delayed desensitization of presynaptic 5-HTA autoreceptors and downregulation of postsynaptic α2-adrenergic receptors and/or 5-HT2 receptors have been proposed to explain the delayed response to antidepressants.
3.3.2 Beyond monoamines
There is increasing evidence that non- monoamine neurotransmitters are involved in the pathophysiology of depression. For example, glutamate is a major excitatory neurotransmitter that acts via N-methyl-D-aspartate (NMDA) and other receptors to help regulate neurotrophic factors and neuroplasticity, including BDNF-mediated synaptogenesis (Figure 3.5). Ketamine, an NMDA antagonist used primarily as an intravenous anaesthetic agent, has been shown to induce rapid relief of depressive symptoms in people with treatment-resistant depression. The mechanism of rapid ketamine action involves a glutaminergic cascade that results in synaptogenesis and synaptic potentiation. A novel melatonergic antidepressant, agomelatine, acts as an agonist at melatonin- and -2 receptors and as an antagonist at 5-HT2C receptors. The chronobiotic effects of agomelatine may be integral to its antidepressant mechanism of action.
Figure 3.5 Mechanisms for cellular plasticity and neurogenesis and therapeutic effects of standard and novel antidepressants. Abbreviations: α2AR, α2 adrenergic receptor; 5-HT, serotonin; AC, adenyl cyclase; AMPAR, α-amino-3-hydroxy-5-methyl-4isoxazole propionic acid (AMPA) receptor; Bcl-2, B-cell lymphoma 2 protein; BDNF, brain-derived neurotrophic factor; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element binding; CRH, corticotropin-releasing hormone; GC, glucocorticoids; Glu, glutamate; GR, glucocorticoid receptor; HPA, hypothalamic pituitary adrenal; MAPK, mitogen-activated protein kinase; NE, norepinephrine; NMDAR, N-methyl-D-aspartate (NMDA) receptor; PKA, protein kinase A; TrkB, receptor tyrosine kinase B.
This figure depicts the multiple targets by which neuroplasticity and cellular resilience can be increased in mood disorders. (a) Phosphodiesterase inhibitors increase the levels of pCREB; (b) MAP kinase modulators increase the expression of the major neurotrophic protein Bcl-2; (c) mGluR II/III agonists modulate the release of excessive levels of glutamate; (d) drugs such as lamotrigine and riluzole act on Na+ channels to attenuate glutamate release; (e) AMPA potentiators upregulate the expression of BDNF; (f) NMDA antagonists like ketamine and memantine enhance plasticity and cell survival; (g) novel drugs to enhance glial release of trophic factors and clear excessive glutamate may have utility for the treatment of depressive disorders; (h) CRF antagonists and (i) glucocorticoid antagonists attenuate the deleterious effects of hypercortisolemia, and CRF antagonists may exert other beneficial effects in the treatment of depression via non-HPA mechanisms; (j) agents which upregulate Bcl-2 (e.g., pramipexole, shown to be effective in bipolar depression). These distinct pathways have convergent effects on cellular processes such as bioenergetics (energy metabolism), neuroplasticity, neurogenesis, resilience, and survival.
Adapted from: Mathew SJ, Manji HK, Charney DS. Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology 2008; 33:2080–2092.
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