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O P L
OX F O R D PSYCH IATRY LIB RARY
Depression
O P L
OX F O RD P S YC HIATRY LIB RARY
Depression
THIRD EDITION
Raymond W. Lam
Professor and BC Leadership Chair in Depression Research
Department of Psychiatry, University of British Columbia
Vancouver, British Columbia, Canada
1
1
Great Clarendon Street, Oxford, OX2 6DP,
United Kingdom
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First Edition published in 2008
Second Edition published in 202
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Oxford University Press makes no representation, express or implied, that the
drug dosages in this book are correct. Readers must therefore always check
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contained in any third party website referenced in this work.
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
206 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 207. 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 psycho-
therapies to novel antidepressant medications, to neurostimulation and exercise.
All the key references in this edition have been updated to reflect the latest evi-
dence. 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, neuroimag-
ing, and molecular markers. Predicting individual response to treatment using
crowdsourced EEG (electroencephalographic) and clinical information; personal-
ized alerts for relapse with apps that analyze voice modulation, text messages,
and geographic location patterns; reprogramming neural circuits with individual-
ized 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 innova-
tive 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 num-
ber 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 ther-
apy 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 203 (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.

Preface to the First Edition
All the recent new research and knowledge about depression makes it a daunt-
ing 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 dis-
cussion 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.

Contents
Abbreviations x
. Introduction 1
2. Epidemiology and burden 3
3. Pathogenesis 11
4. Clinical features and diagnosis 23
5. Associated clinical features 35
6. Clinical management 45
7. Psychological treatments 53
8. Pharmacological treatments 63
9. Somatic treatments 85
0. Special populations 95
Appendix: Sample rating scales 3

Index 3
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
abbreviations • xi
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
MT melatonin
NDRI noradrenaline–dopamine reuptake inhibitor
NMDA N-methyl-D-aspartate
NNT number needed to treat
NRI noradrenaline reuptake inhibitor
NSAID non-steroidal anti-inflammatory drugs
OCD obsessive-compulsive disorder
PDQ-D-5 Perceived Deficits Questionnaire—Depression, 5 item
PHQ-9 Patient Health Questionnaire
PRIME-MD Primary Care Evaluation of Mental Disorders
PST problem-solving therapy
QIDS-SR Quick Inventory of Depressive Symptomatology (self-rated)
QTc corrected QT interval
RCT randomized controlled trial
RDoC Research Domain Criteria
REM rapid eye movement
RIMA reversible inhibitor of MAO-A
rTMS repetitive transcranial magnetic stimulation
SAD-HART Sertraline AntiDepressant Heart Attack Randomized Trial

xii • abbreviations
SAM-e S-adenosylmethionine
SCID Structured Clinical Interview for DSM-IV-TR
SERT serotonin transporter
SGA second-generation antipsychotic
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 procras-
tinating 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 des-
pite repeated healthcare visits. And, it is not only family physicians, psychiatrists
and mental health clinicians that need to diagnose depression. The high preva-
lence of MDD with other medical illnesses means that other health profession-
als 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 207 that depression had become
the leading medical cause of functional disability worldwide. The concentration,
memory, and decision-making problems associated with depression are particu-
larly damaging to workforces in knowledge-based industries, a major issue for
many countries trying to convert from resource-based economies.
chapter 1
2 • introduction
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 methodolo-
gies 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 recom-
mendations 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 princi-
ples 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 Reading
Lam RW, Kennedy SH, Parikh SV, et al. (206) Canadian Network for Mood and Anxiety
Treatments (CANMAT) 206 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 (206) Investing in global mental health: the time for action is now. Lancet
Psychiatry 3: 390–.
World Health Organization (207) Depression and Other Common Mental Disorders.
Geneva: WHO Document Production Services.
chapter 1
Chapter 2
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 expe-
riencing major depressive disorder (MDD) is approximately 5% (Table 2.).
Depression also contributes significantly to disability, with estimates that depres-
sion 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 dispar-
ity 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.
chapter 2
4 • epidemiology and burden
Table 2. Prevalence of DSM-IV MDD in general populations

Prevalence rates (%)
Location 2 month Lifetime

Brazil (Sao Pâulo) 0.4 8.4
USA 8.3 9.2
New Zealand 5.7 5.8
France 5.9 2.0
Netherlands 4.9 7.9
Australia 4.8 2.8
Spain 4.0 0.6
Mexico 4.0 8.0
Canada* 3.9 9.9
China (Shenzen) 3.8 6.5
Germany 3.0 9.9
Japan 2.2 6.6
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
202, 205, 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 ado-
lescents experience more ‘atypical’ features of depression (e.g. overeating, hyper-
somnia), 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 pro-
dromal period during which significant depressive symptoms are present. These
chapter 2
epidemiology and burden • 5
symptoms, which can be present for weeks to years prior to diagnosis, include
anxiety and other mild depressive symptoms. The length of an untreated depres-
sive 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 anti-
depressants 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 post-
MDD diagnosis, 40% had recovered with no symptoms of depression, 20% con-
tinued 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 pre-
dictive 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 interac-
tions, 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.
chapter 2
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 myocar-
dial 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 non-
depressed 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 203,
depression had risen to the second leading medical cause of years lived with dis-
ability, behind only low back pain (Figure 2.). In April 207, the World Health
Organization announced that depression had become the first-ranked leading
cause of health-related disability. An estimated 322+ million people were esti-
mated to have depression, representing 4.4% of the world population, leading to
50+ million years lived with disability in 205.
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 individu-
als. In a U.S. survey, the salary-equivalent productivity loss attributed to depres-
sive absenteeism (average US$82–US$395) approached the estimated cost of
chapter 2
Low back pain
Major
depression
Iron deficiency
anaemia
Neck pain
Hearing loss
0 20 40 60 80
Mean years lived with disability (x1,000,000)
Figure 2. The Global Burden of Disease Study. In 203, 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 individu-
als based on expectations of sub-standard work performance. In fact, depressed
individuals have a perceived increase in self-rated productivity when they experi-
ence 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 dir-
ect 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 treat-
ment (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 prod-
uctivity) 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
chapter 2
suicide more often than MDD-diagnosed patients. In a U.S. study, patients diag-
nosed 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 treat-
ment (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 depres-
sion reduces the overall cost to the entire healthcare system. In primary care
settings, the implementation of collaborative care and chronic disease manage-
ment 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
100
Perceived need for treatment Received any treatment Received adequate treatment
90
80
70
% of people with MDD
60
50
40
30
20
10
0
USA France Germany Spain Brazil* Mexico Bulgaria Iraq China* Columbia Peru
6.7% 5.6% 3.1% 3.8% 10.1% 3.7% 3.0% 3.9% 2.0% 5.3% 2.7%
Higher income Upper-middle income Lower-middle income
* 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.
chapter 2
scaling up treatment services for depression are considerable, with a global study
estimating a US$5 return on investment for every US$ spent.
Further Reading
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 (204) 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 (206) Scaling-up treatment of depression and
anxiety: a global return on investment analysis. Lancet Psychiatry 3: 45–24.
Coventry PA, Hudson JL, Kontopantelis E, et al. (204) Characteristics of effective
collaborative care for treatment of depression: a systematic review and meta-regression
of 74 randomised controlled trials. PLoS One 9: e084.
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 203 Collaborators (205) Global, regional, and national
incidence, prevalence, and years lived with disability for 30 acute and chronic diseases
and injuries in 88 countries, 990–203: a systematic analysis for the Global Burden of
Disease Study 203. Lancet 386: 743–800.
Kessler RC (202) The costs of depression. Psychiatr Clin North Am 35: –4.
Lam RW, McIntosh D, Wang JL, et al. (206) Canadian Network for Mood and Anxiety
Treatments (CANMAT) 206 Clinical Guidelines for the Management of Adults with
Major Depressive Disorder: Section . Disease burden and principles of care. Can J
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Thornicroft G, Chatterji S, Evans-Lacko S, et al. (207) Undertreatment of people with
major depressive disorder in 2 countries. Br J Psychiatry 210: 9–24.
World Health Organization (207) Depression and Other Common Mental Disorders.
Geneva: WHO Document Production Services.
chapter 2
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 modu-
lation 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 treat-
ment 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
12 • pathogenesis
Biological Psychological Social
Relationships,
Genetics Personality
Work/Leisure
Circadian
Rhythms
Neurohormones,
Neurochemicals,
Person
with depression
Neuroinflammation
Physical illnesses, Life experiences,

Medications/drugs 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 scan-
ning 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 poly-
morphisms, 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
chapter 3
pathogenesis • 13
Neuroanatomical abnormalities in major depression
Major depression
Increased stress
Depressed mood sensitivity (Gender
(Mood bias toward specific)
negative emotions)
Anhedonia
Impaired learning
(Impaired reward
and memory
Stress function)
Stress
Increased amygdala
activity/decreased Reduced Reduced Decreased
amygdala volume hippocampal ACC subgenual PFC
volume volume activity
CREB
NMDAR BDNF bcl-2 ?

5-HTTLPR MR
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, 5-
HT (serotonin) transporter promoter region gene; ACC, anterior cingulate cor-
tex; 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 depres-
sion results from deficits in key brain areas in serotonin (5-HT) or noradrenaline
synaptic neurotransmission. Antidepressants were thought to act by blocking the
chapter 3
14 • pathogenesis
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-HTAR, 5-HT
(serotonin) A receptor; 5- HT2AR, 5- HT (serotonin)-2A receptor; 5- HTTLPR,
5-
HT (serotonin) transporter promoter region gene; CHRM2, cholinergic mus-
carinic-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, mineralo-
corticoid 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 neurotransmit-

ter 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 pre-
synaptic and postsynaptic receptors and processes (Figure 3.4). For example,
chapter 3
pathogenesis • 15
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” antidepres-
sive agents: a critical review. European Journal of Pharmacology 2004; 500:37–84.
delayed desensitization of presynaptic 5-HTA autoreceptors and downregulation

of postsynaptic α2-adrenergic receptors and/or 5-HT2 receptors have been pro-
posed 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 neu-
roplasticity, 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 recep-
tors. The chronobiotic effects of agomelatine may be integral to its antidepres-
sant mechanism of action.
chapter 3
16 • pathogenesis
Figure 3.5 Mechanisms for cellular plasticity and neurogenesis and therapeutic effects
of standard and novel antidepressants. Abbreviations: α2AR, α2 adrenergic recep-
tor; 5-HT, serotonin; AC, adenyl cyclase; AMPAR, α-amino-3-hydroxy-5-methyl-4-
isoxazole 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, gluco-
corticoids; Glu, glutamate; GR, glucocorticoid receptor; HPA, hypothalamic pituit-
ary 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 modula-
tors increase the expression of the major neurotrophic protein Bcl-2; (c) mGluR II/III agonists modu-
late 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.
chapter 3
pathogenesis • 17
Other molecular biology studies have shifted attention from immediate pre-or
postsynaptic events to delayed post-receptor signalling pathways in the mech-
anism of action of antidepressants. The activation of postsynaptic receptors
initiates a cascade of biochemical effects mediating signal transduction, involv-
ing G-protein-coupled stimulation of cAMP (cyclic adenosine monophosphate)
or Ca2+ cascades. Activation of CREB results in increased expression of BDNF,
which acts to promote neurogenesis and cellular plasticity, and which may account
for the therapeutic effects of antidepressants. These neuroplasticity and cellular
resilience pathways provide novel targets for antidepressant drug development
(Figure 3.5).
3.3.3 Hypothalamic-pituitary-adrenal-immune axis

Alterations in the hypothalamic-pituitary-adrenal (HPA) axis have long been rec-
ognized to be associated with MDD. The biological effects of stress are mediated
via secretion of corticotropin-releasing factor/hormone (CRF/CRH), leading
to increased secretion of adrenocorticotropic hormone (ACTH) and release
of glucocorticoids. Glucocorticoids alter noradrenergic receptor sensitivity via
regulation of the beta-adrenoreceptor-coupled adenylate cyclase system in the
brain. Chronic stress results in hypersensitivity of the HPA axis, and MDD is
associated with increased concentrations of CRF in cerebrospinal fluid, increased
CRF immunoreactivity and gene expression of CRF in the hypothalamic paraven-
tricular nucleus, and downregulation of CRF-R receptors in the frontal cortex.
Prolonged glucocorticoid secretion has neurotoxic effects, particularly on neuro-
genesis in the hippocampus (Figure 3.5).
The dexamethasone suppression test in combination with the CRH-stimulation
test (dex/CRH) is the most sensitive neuroendocrine measure of impaired cor-
tisol response and HPA sensitivity. Although it has good sensitivity for detect-
ing MDD, the dex/CRH still lacks sufficient specificity (to distinguish MDD from
other conditions such as schizophrenia and panic disorder) to be used as a diag-
nostic test. Other clinical implications of increased CRF and glucocorticoid pro-
duction in MDD include the possibility that dampening the CRF response may
have therapeutic effects, and several novel CRF and glucocorticoid antagonists
are in early-phase clinical trials as antidepressants.
There is also increasing evidence that disturbances in immune function and
neuroinflammatory mechanisms play a role in the pathogenesis of MDD. Acute
and chronic stress can activate the immune-inflammatory system, with produc-
tion of inflammatory proteins including C-reactive protein and proinflammatory
cytokines such as IL-6 and TNF-α. Bidirectional pathways to the brain can enable
these peripheral proinflammatory mediators to influence neural activity via activa-
tion of brain-resident microglia to produce depressive symptoms and behaviours.
Consequently, anti-inflammatory agents are also being investigated as novel anti-
depressant medications.
chapter 3
18 • pathogenesis
Box 3. Polysomnographic abnormalities of sleep in major depressive

disorder
• Early onset of rapid eye movement (REM) sleep (i.e. shortened REM latency)
• Increased time in REM sleep
• Increased REM density
• Decreased slow-wave sleep (SWS)
• Shift of SWS away from the early part of the night
• Disturbances in slow-wave activity (SWA)
3.3.4 Sleep and circadian rhythms

Sleep complaints (insomnia, hypersomnia) have long been considered cardinal
features of clinical depression, so it is not surprising that biological studies have
focused on dysregulation of sleep in MDD. Polysomnography has been used to
detect many abnormalities of sleep in MDD, and indeed offers some of the most
robust biological markers in depression (Box 3.). There remains controversy
over whether depression causes sleep changes, or vice versa. There is increasing
evidence that sleep changes are trait markers, predate onset of depression, and
predict relapse in remitted patients, thereby suggesting a pathogenetic role for
sleep in MDD.
Theories of sleep involve both homeostatic and circadian factors. The two-
process model suggests an interactive balance between the homeostatic need
for sleep, which increases with longer time awake, and a circadian propensity
for sleep, which shows a circadian pattern for sleepiness and attention. The
human circadian system is controlled by a biological pacemaker located in the
suprachiasmatic nucleus of the hypothalamus. This biological clock is regulated
by external zeitgebers (synchronizers), including the light/dark cycle, external
bright light, and social cues. Many circadian rhythms, such as cortisol, melatonin,
and thyroid-stimulating hormone, are disrupted in depression, with evidence
for both circadian phase shifts and decreased amplitude of rhythms. These
disturbances may be caused by primary dysfunction of the circadian clock or
by secondary disruption of zeitgebers such as stress-induced changes in sleep,
photic (light) exposure, or social behaviour (Figure 3.6). Circadian theories are
also intimately associated with seasonal affective disorder—particularly, phase-
delayed circadian rhythms that are corrected by appropriately timed bright light
exposure (see Chapter 9).
3.4 Neuropsychology
3.4. Cognition and memory
Patients with depression demonstrate a number of cognitive and memory defi-
cits, especially in selective attention and explicit (working) memory. In addition,
chapter 3
pathogenesis • 19
Behaviour Environment Biology Disorder
Photic Sleep
zeitgebers functioning
Rhythmic Depressive
social symptoms
behavior
Non-photic Circadian
zeitgebers functioning
Predisposition/
genetics
Figure 3.6 Model of sleep and circadian rhythm dysfunction in depression.
there are deficits in long-term storage and retrieval of declarative memory,

and in executive cognitive functioning such as selecting strategies and monitor-
ing performance. Finally, depression is also associated with disturbances in ‘hot’
cognition, or emotion-dependent cognitive processing. Many of the cognitive
problems have been associated with reduced cerebral blood flow and metabol-
ism to dorsolateral prefrontal cortex and dorsal anterior cingulate cortex. These
findings are of clinical importance for mechanisms of cognitive–behavioural ther-
apy for depression (see Chapters 5 and 7).
The hippocampus is critically involved in memory formation, as part of the cir-
cuit involved in information processing and creation of emotional and declarative
memories. Hippocampal volume is decreased in patients with depression, espe-
cially with recurrent or chronic episodes or a past history of trauma. Impaired
neurogenesis has been invoked to explain this finding, as increased glucocorticoid
secretion from prolonged stress is particularly neurotoxic to hippocampal neu-
rons (Figure 3.5). The neurogenesis theory also accounts for therapeutic effects
of antidepressants, since these drugs activate the cAMP cascade to release BDNF
and CREB, which serve to increase neurogenesis in hippocampus.
Functional neuroimaging studies have highlighted disturbances in higher order
organization and interconnectivity of brain regions involving specific neural cir-
cuits (Figure 3.7). These circuits link lower order subcortical functions and regions
(autonomic and regulatory) to those involving reward systems (limbic and paral-
imbic systems) and higher cortical function (cognition). In depression, network
dysfunction involving these limbic-cortical circuits—with underactivity in cortical
regions (dorsolateral prefrontal cortex, dorsal anterior cingulate cortex) and
overactivity in the limbic (amydala, hippocampus, nucleus accumbens), paralimbic
(ventral anterior cingulate cortex, ventromedial prefrontal cortex), and integra-
tive cortical regions—are hypothesized to result in the mood and behavioural
symptoms and associated hypothalamic dysregulation.
chapter 3
20 • pathogenesis
DL PFC
Dorsal ACC
Cortical Rostral PFC SCC

OM PFC (Cg25)
Ventral ACC Amygdala

Hippocampus
Limbic VM PFC
N. Accumbens
Hypothalamus
Figure 3.7 Limbic- cortical dysregulation model. Regions in light shading indi-
cate overactivity and regions in dark shading indicate underactivity. Abbreviations:
ACC, anterior cingulate cortex; DL, dorsolaeral; N, nucleus; OM, orbitomedial;
PFC, prefrontal cortex; SCC (Cg25), subcallosal (subgenual) cingulate cortex; VM,
ventromedial.
The emotion-dependent ‘hot’ cognitive deficits in depression include negatively

biased responses in attention and working memory, hypersensitivity to negative
feedback, and excessive self-focus and rumination. In contrast to the circuitry of
‘cold’ cognitive dysfunction, the neural circuits for hot cognitive deficits primarily
involve connections between ventromedial prefrontal cortex and emotional pro-
cessing areas such as amydala.
In the limbic-cortical dysregulation model, alterations at various levels may
produce therapeutic effects. For example, cognitive–behavioural therapy may
modify cortical circuits, while antidepressant drugs may selectively affect circa-
dian or other limbic circuits; the net effect of both interventions may produce the
same adaptive changes in the entire system. One particularly interesting region
is the white matter subcallosal cingulate (subgenual cingulate, Brodmann area
Cg25), which modulates negative mood and shows hyperactivity in depressed
states, while response to varied antidepressant treatment is associated with
reduced activity in this region. This is one area targeted for deep brain stimulation
in treatment-refractory depression (see Chapter 9).
3.4.2 Environment and life events

Depression often follows a major psychosocial stressor, especially with the first
or second depressive episode. Adverse childhood experiences such as maltreat-
ment, loss of a parent, and inadequate social support are also common amongst
depressed patients. Increasing evidence has determined that stress and trauma
chapter 3
pathogenesis • 21
can affect biological systems of interest in depression. For example, animal stud-
ies have shown that early maternal deprivation leads to hypersensitivity of the
HPA axis in adulthood, with decreased hippocampal cell proliferation similar to
the reduced hippocampal volumes found in neuroimaging studies of patients with
depression and childhood trauma. This may have implications for treatment, as
studies have shown that patients with MDD and a history of early childhood
maltreatment have poorer outcomes in general, and better responses to psycho-
therapy than to antidepressant monotherapy.
Twin studies have shown an interaction between genetic risk and life events for
developing depression. However, not all stressful life events precipitate depres-
sion, and certain depressive episodes are not associated with stressors. A gene-
by-environment (G×E) interaction hypothesis, in which genetic vulnerability
influences the likelihood that exposure to stress will result in psychopathology,
may explain this discrepancy (Figure 3.8). Stressful life events have been shown
Normal
Level of Functioning
Impaired
Low High
Environmental stress
Genetically resilient (G main effect) – no effect of stress

Genetically neutral/‘wild-type’ (E main effect) – stress decreases function
Genetically vulnerable (G × E interaction) – stress decreases function
Genetically impaired (G main effect) – no effect of stress
Figure 3.8 Model of gene–environment (G×E) interactions. This figure illustrates

the potential interaction effects of environmental stress and genetic vulnerability.
Functioning is normal under conditions of low environmental stress, but impaired
under conditions of high environmental stress (curved line). Although high environ-
mental stress alone will degrade functioning (solid line), G×E interactions involve
a genetically determined increase in vulnerability to such environmental effects. In
contrast, genetically determined resilience (grey dashed line) or impairment (black
dashed line) are associated with normal or impaired functioning, respectively, inde-
pendent of levels of environmental stress.
Reproduced with permission from: Nugent NR, Tyrka AR, Carpenter LL, et al. Gene–environment
interactions: early life stress and risk for depressive and anxiety disorders. Psychopharmacology 20;
214:75–96
chapter 3
22 • pathogenesis
to have no effect on risk of developing a depression in women with the lowest
genetic vulnerability, but life events had increasing effects on depression risk in
those with increasing genetic loading for depression. These findings suggest that
environmental events, even those that happened in the past, can alter neurobio-
logical function for a long time.
The biological effects of early childhood adversity and life stressors may also
be mediated via epigenetic mechanisms, which involve functional modifications of
the genome that are influenced by environmental factors. MicroRNAs, small units
of non-coding RNA that help regulate gene function by influencing the translation
of target mRNAs, are also emerging targets for antidepressant drug discovery.
Further Reading
Abdallah CG, Sanacora G, Duman RS, et al. (205) Ketamine and rapid-acting
antidepressants: a window into a new neurobiology for mood disorder therapeutics.
Annu Rev Med 66: 505–23.
Cai S, Huang S, Hao W (205) New hypothesis and treatment targets of depression: an
integrated view of key findings. Neurosci Bull 31: 6–74.
Goldstein BL, Klein DN (204) A review of selected candidate endophenotypes for
depression. Clin Psychol Rev 34: 47–27.
Gudayol-Ferré E, Peró-Cebollero M, González-Garrido AA, et al. (205) Changes in
brain connectivity related to the treatment of depression measured through fMRI: a
systematic review. Front Hum Neurosci 9: 582.
Harvey AG (20) Sleep and circadian functioning: critical mechanisms in the mood
disorders? Annu Rev Clin Psychol 7: 297–39.
Hasler G, Drevets WC, Manji HK, et al. (2004) Discovering endophenotypes for
depression. Neuropsychopharmacology 29: 765–8.
Hasler G, Northoff G (20) Discovering imaging endophenotypes for major depression.
Mol Psychiatry 16: 604–9.
Kupfer DJ, Frank E, Phillips ML (202) Major depressive disorder: new clinical,
neurobiological and treatment perspectives. Lancet 379: 045–55.
Nugent NR, Tyrka AR, Carpenter LL, et al. (20) Gene–environment interactions: early
life stress and risk for depressive and anxiety disorders. Psychopharmacology
214: 75–96.
Rosenblat C, McIntyre RS, Alves GS, et al. (205) Beyond monoamines–novel targets
for treatment-resistant depression: A comprehensive review. Curr Neuropharmacol
13: 636–55.
Taylor C, Fricker AD, Devi LA, et al. (2005) Mechanisms of action of
antidepressants: from neurotransmitter systems to signaling pathways. Cell Sig
17: 549–57.
Wohleb ES, Franklin T, Iwata M, et al. (206) Integrating neuroimmune systems in the
neurobiology of depression. Nat Rev Neurosci 17: 497–5.
chapter 3
Chapter 4
Clinical features and diagnosis

Key points
• Depression is associated with a number of physical, emotional, and cognitive
symptoms.
• Sub-typing of major depressive disorder has implications for treatment choice
and selection.
• The differential diagnosis of depression includes bereavement, bipolar disorder,
and other medical or substance-induced conditions.
4.1 Clinical features

4.. Overview
Depression is associated with many different types of symptoms which can result
in a variable presentation in any given person. The features of depression can
be physical (sleep, energy, appetite, libido), emotional (low mood, anxiety, cry-
ing), or cognitive (guilt; pessimism; suicidal thoughts; problems with concentra-
tion, memory, and decision-making). Table 4. presents a common mnemonic for
depressive symptoms.
4..2 Symptoms
Low mood: While depressed people describe feelings of low mood, the emo-
tional misery experienced during a depression is qualitatively different from nor-
mal periods of sadness or grief that everyone experiences. Some have crying
spells, or feel like crying, while others describe a complete lack of emotional
response.
Interest/Pleasure: Loss of interest and pleasure (anhedonia) in activities or
social interactions which previously were pleasurable is another cardinal feature
of depression. Anhedonia also may show as indifference or boredom, and can be
present even when the person does not endorse low mood. Loss of sexual inter-
est, desire, or functioning is also common, which can lead to difficulty in intimate
relationships and marital conflict.
Sleep: Most depressed patients experience sleeping difficulties. The classic
presentation is waking from sleep early in the morning and being unable to fall
asleep again (terminal insomnia), but restless sleep and frequent waking during
the night (middle insomnia) are also common. Difficulty falling asleep at the begin-
ning of the night (early insomnia) is usually seen when anxiety also is present.
chapter 4
24 • clinical features and diagnosis
Table 4. SIGECAPS mnemonic for the clinical features of depression

Depressive symptom Presentation
(SIG: E-CAPS)
Sleep • insomnia or hypersomnia (atypical)
Interest/Pleasure • reduced pleasure (anhedonia), lack of motivation, loss
of interest
Guilt • guilt and self-blame, irrational/delusional thoughts
Energy • low energy, tired, fatigued
Concentration • inattentive, indecisive, distractible
Appetite • decreased or increased (atypical), weight loss or gain
(atypical)
Psychomotor activity • agitation or retardation
Suicide • hopelessness, suicidal thoughts, plans, attempts
In contrast, hypersomnia or oversleeping also can be a symptom of ‘atypical’

depression.
Energy: Low energy and/or fatigue are frequent complaints in depression,
as is difficulty in getting started or initiating tasks. The fatigue experienced can
be physical or mental, and may be associated with poor sleep and appetite. In
severe cases, routine activities such as daily hygiene, grooming, or eating may
be impaired. An extreme form of fatigue is ‘leaden paralysis’, in which patients
describe a feeling like their limbs are made of lead, or that they are walking
through water.
Guilt: Feelings of worthlessness and guilt can often consume an individual’s
thoughts during a depressive episode. Depressed patients may misinterpret triv-
ial daily events and take responsibility for negative events out of their control;
these can sometimes be of delusional proportion. Excessive worry and anxiety
can accompany and exacerbate guilt.
Concentration: Difficulty with concentration and decision-making is often
experienced in depression. Memory complaints are usually due to problems with
attention and distractibility. In elderly patients, the cognitive complaints may be
misdiagnosed as early dementia. Problems with concentration, memory, and
indecisiveness can greatly impair work functioning, especially in ‘white collar’
workers.
Appetite/Weight: Loss of appetite, taste, and enjoyment in eating can lead
to significant weight loss, and some patients may need to ‘force’ themselves to eat.
However, other patients may crave carbohydrates and sweets when depressed,
or self-treat by ‘comfort’ eating. Overeating, accompanied by decreased activity
and exercise, can lead to weight gain and metabolic syndrome. Changes in weight
may also impact on self-image and self-esteem.
chapter 4
clinical features and diagnosis • 25
Psychomotor activity: Psychomotor changes, which are subjective changes
in motor function without objective abnormalities on testing, are commonly seen
in depression. Psychomotor retardation consists of slowing (slowed body move-
ments, lack of facial expression, long latency of speech response) which, at its
extreme, can manifest as mute or catatonic presentations. Anxiety can also present
as psychomotor agitation (talking quickly, pacing, restlessness, inability to sit still).
Racing thoughts may be a symptom of mania, but is also a descriptor for anxiety.
Suicide: Some type of suicidal ideation, ranging from fleeting thoughts of wishing
everything would end to elaborate plans for suicide, is present in nearly two-thirds
of people with depression. Even when suicidal thoughts are serious, depressed
patients often lack the energy and motivation to attempt suicide. However, suicide
remains a significant issue as 0–5% of hospitalized depressed individuals eventu-
ally die by suicide. A period of high risk for suicide is during initial treatment, when
energy and motivation may improve before the cognitive symptoms (e.g. hope-
lessness), making it possible for suicidal patients to act on their thoughts and plans.
Other symptoms: Although not formally indicated as criteria for the diagno-
sis, a number of other symptoms and signs, including anxiety, irritability, cognitive
dysfunction, and pain, are associated with depression. These are discussed fur-
ther in Chapter 5.
4.2 Classification and diagnosis of depression

4.2. Classification of depression
The major classification systems used in clinical practice, DSM- 5 (Diagnostic
and Statistical Manual of Mental Disorders, 5th edn) and ICD-0 (International
Classification of Diseases, version 0), categorize diagnoses based primarily on
symptoms, course, and prognosis. However, it should be noted that alternative
classification systems, such as the Research Domain Criteria (RDoC) developed
by the National Institute of Mental Health in the United States, are attempting to
classify psychiatric conditions based on existing and emerging knowledge about
neural systems in the brain.
The DSM- 5 outlines three major sub- classifications for depression: major
depressive disorder (MDD), persistent depressive disorder, and other depressive
disorders. Figure 4. outlines a simple algorithm to distinguish these depressive
disorders from bipolar disorder.
4.2.2 Major depressive disorder

MDD is characterized by the presence of one or more major depressive episodes
(Box 4.). The diagnostic criteria require a threshold number of symptoms that
must be present much of the time, most days, for at least 2 weeks, although the
duration is usually much longer by the time that help is sought. The symptoms
also must significantly impair functioning or cause significant distress. Finally, other
causes of depressive symptoms must be excluded.
chapter 4
Yes 5 out of 9 Yes Prior manic/ No Persistent Yes Persistent

Sad mood or
symptoms hypomanic symptoms depressive
low interest?
now? episode? >2 years? disorder
No
No Yes
5 out of 9 Yes Prior manic/ Yes Major

Bipolar
symptoms in hypomanic depressive
disorder
past? episode? disorder
No
No
Dysthymia Major
Persistent Yes (Persistent depressive
symptoms
depressive disorder with
>2 years?
disorder) residual
symptoms
No Other
specified
depressive
disorders
Figure 4. Differential diagnosis of depression.
MDD is identified as either single episode or recurrent, with the latter consist-
ing of two or more major depressive episodes with a remission interval of at
least 2 months. MDD can also be ‘sub-typed’ according to several specifiers and
by severity; these sub-types can be used to differentiate presentations of depres-
sion that have implications for recognition (distinctive symptoms or pattern),
prognosis, or treatment selection.
4.2.3 Persistent depressive disorder

Persistent depressive disorder, with symptoms present for at least 2 years,
encompasses chronic MDD with full syndromic criteria, MDD in partial remission,
and dysthymia. Dysthymia, or dysthymic disorder, is a chronic, low-grade mood
disorder during which the full criteria for a major depressive episode (MDE) are
not met (Box 4.2). Dysthymic symptoms can develop slowly, often unrecog-
nized by the individual, and persist for a minimum of two years (median 5 years).
Individuals with dysthymia often develop episodes of major depression (termed
‘double depressions’), which may prompt them to seek treatment.
However, persistent depressive disorder now includes both chronic MDEs,
with full symptom criteria for 2 years, and MDEs with residual symptoms that
persist longer than 2 years. Specifiers for persistent depressive disorder include
‘with pure dysthymic syndrome’ (when criteria for an MDE have not been met
within the last 2 years) and ‘with persistent major depressive episode’ (when full
criteria for MDE have been met throughout the last 2 years).
4.2.4 Other depressive disorders

Several other disorders are now included under ‘Depressive Disorders’ in DSM-5
(Box 4.3). Depressive disorders that occur secondary to substance use and other
medical conditions are described in sections 4.4.2 and 4.4.3.
chapter 4
Box 4. Summary of DSM-5 criteria used to diagnose a major depressive

episode
• Five or more of the following nine symptoms present nearly every day for at
least 2 weeks, with at least one symptom including depressed mood or loss
of interest or pleasure, and associated with significant distress or impairment
in psychosocial functioning:
•depressed mood (feeling down, blue, tearful)
•fatigue or poor energy levels
•prominent and/or recurrent thoughts of death or suicide
•problems with concentration, memory, or decision-making
•insomnia or hypersomnia
• significant loss of interest in usual activities, or loss of pleasure/enjoyment
(anhedonia)
•marked feelings of guilt or self-blame (which may be delusional)
•loss of appetite or weight, or increased appetite or weight. In children,
this may present as failure to achieve a typical weight for their age.
•observable psychomotor agitation or retardation.
• There has never been a manic or hypomanic episode.
• The episode is not better explained by other diagnoses, including substance
use (e.g. illicit drugs or medications), other medical conditions (e.g. hypothy-
roidism), or other psychiatric conditions (e.g. schizoaffective disorder, schizo-
phrenia, or other psychotic disorders).
Source data from American Psychiatric Association, Diagnostic and Statistical Manual of Mental
Disorders, 5th Edition DSM-5, 203, American Psychiatric Association
4.3 Sub-types of depression

4.3. Specifiers of major depressive disorder
Several specifiers (sub-types) of MDD have been established based on clinical
features and patterns of depressive episodes. These DSM-5 depressive speci-
fiers sub-classify depression with the intent to improve treatment selection and/
or predict prognosis. Table 4.2 outlines the depressive specifiers along with their
key features.
4.3.2 Severity
Both the DSM-5 and the ICD-0 categorize three separate levels of sever-
ity for MDD: mild, moderate, and severe (Table 4.3). The DSM-5 distinguishes
the severity based on the number and severity of symptoms and the extent of
chapter 4
Box 4.2 Summary of DSM-5 criteria used to diagnose persistent depressive

disorder
• Depressed mood for most days for at least 2 years (in children and adoles-
cents, this can present as irritable mood with a duration of at least  year),
accompanied by two or more of the following 6 symptoms, and associated
with significant distress or impairment in psychosocial functioning:
•feelings of hopelessness
• low self-esteem
•problems with concentration, memory or decision-making
•fatigue or low energy
•insomnia or hypersomnia
•loss of appetite or increased appetite.
• During the 2 years of symptoms ( year for children and adolescents), there has
never been a 2-month period in which symptoms have been absent. Full symp-
tom criteria for a major depressive episode may be present during the 2 years.
• There has never been a manic or hypomanic episode.
• The episode is not better explained by other diagnoses, including substance
use (e.g. illicit drugs or medications), other medical conditions (e.g. hypothy-
roidism), or other psychiatric conditions (e.g. cyclothymic disorder, schizoaf-
fective disorder, schizophrenia, or other psychotic disorders).
Box 4.3 Other disorders classified as depressive disorders in DSM-5

Disruptive mood dysregulation disorder: This is a disorder of childhood
(age 6–8 years) characterized by persistent irritable or angry mood and severe
temper outbursts or acts of physical aggression. These behaviours are out of
proportion to a situation, not consistent with the developmental level, and not
part of a hypomanic or manic episode.
Premenstrual dysphoric disorder: In most menstrual cycles during the
previous year, symptoms regularly occurred during the last week of the luteal
phase and remitted within a few days of the onset of menses.
Other specified depressive disorders: These include presentations such as
minor depression (sub-syndromal episodes with insufficient symptoms), recur-
rent brief depression, and short-episode (i.e. 4–3 days) depressive episode.
chapter 4
Table 4.2 DSM-5 specifiers (sub-types) of MDD

Sub-type DSM-5 specifier Key features
Melancholic With melancholic Non-reactive mood, anhedonia,
depression features weight loss, guilt, psychomotor
retardation or agitation, morning
worsening of mood, early morning
awakening
Atypical With atypical features Reactive mood, oversleeping,
depression overeating, leaden paralysis,
interpersonal rejection sensitivity
Psychotic With psychotic features Hallucinations or delusions,
(delusional) either mood-congruent or
depression mood-incongruent
Catatonic With catatonic features Catalepsy (waxy flexibility), catatonic
depression excitement, negativism or mutism,
mannerisms or stereotypies, echolalia
or echopraxia. This sub-type is
uncommon in clinical practice.
Anxious With anxious distress Symptoms of anxiety including feeling
depression tense or unusually restless, difficulty
concentrating because of worry,
fearing that something terrible may
happen, and worry about losing
control
Mixed episodes With mixed features Sub-syndromal hypomanic symptoms
including elevated mood, inflated self-
esteem or grandiosity, racing thoughts
or flight of ideas, talking more than
usual or pressured speech, increased
energy or activity, decreased need
for sleep, impulsive and reckless
behaviours
Seasonal With seasonal pattern Regular onset and remission of
affective depressive episodes during a particular
disorder (SAD) season (usually autumn/winter onset)
Peripartum With peripartum onset Onset of depressive episode
depression during pregnancy or within 4 weeks
postpartum
chapter 4
Table 4.3 Depression severity criteria

Depression DSM-5 criteria ICD-0 criteria
severity
Mild . Minimal number of criterion . Two typical symptoms
symptoms with mild distress and 2. Two other core symptoms
manageable intensity
2. Minor impairment in social/
occupational functioning
Moderate . Number of symptoms, distress, . Two typical symptoms
and intensity between mild 2. Three or more other core
and severe symptoms
2. Moderate impairment in social/
occupational functioning
Severe . Most criterion symptoms are . Three typical symptoms
present with serious distress and 2. Four or more other core
unmanageable intensity symptoms
2. Marked impairment in social/ Also sub-typed as with or
occupational functioning without psychotic symptoms
Source data from: American Psychiatric Association, Diagnostic and Statistical Manual of Mental
Disorders, 5th Edition DSM-5, 203, American Psychiatric Association; International Classification of
Diseases (ICD), version 0, 992, World Health Organization.
associated impairment in social and/or occupational functioning. The ICD-0,

however, differentiates the severity of depression based on the number and type
of symptoms present in the depressed individual. While these criteria may be of
heuristic value, validated depression rating scales are more clinically useful for
assessing severity (see Chapter 6 and Appendix).
Severity of depression may influence treatment choices. For example, psycho-
therapy is as effective as pharmacotherapy for mild-to-moderate depression, but
severe depression shows better response to combination treatment. Emerging
evidence also suggests that some antidepressants may be more effective than
others for severe depression (see Chapter 8).
4.4 Differential diagnosis

4.4. Bereavement
Bereavement or grief over loss of relationships can share similar symptoms
(e.g. intense sadness, insomnia, poor appetite) with a major depressive epi-
sode. However, bereavement is no longer an explicit exclusion criterion for
an MDE because it often cannot be distinguished from other types of stresses,
chapter 4
such as loss of a job. Instead, the severity and duration of symptoms and their
impact on psychosocial functioning can help distinguish between grief and MDD
(Table 4.4).
4.4.2 Depressive disorder due to another medical condition

Depressive symptoms can result from the direct physiological effects of a specific
pre-existing medical condition. Conversely, the physical symptoms of a primary
medical illness may obscure the diagnosis of a comorbid MDD (see Chapter 0).
The Hospital Anxiety and Depression scale (HADS) is a useful screening tool
for medically ill patients in that it uses questions that focus on cognitive symp-
toms rather than somatic ones. MDD is prevalent in numerous chronic illnesses
(Table 4.5), but may be particularly common in diabetes, cardiovascular disease
(e.g. post-myocardial infarction), thyroid disease, and neurological disorders (e.g.
Parkinson’s disease, multiple sclerosis, dementia).
4.4.3 Substance/medication-induced depressive disorder

Side effects of drugs (whether prescribed or illicit) can also lead to depressive
symptoms, hence substance-induced mood disorders must be considered in
the differential diagnosis of MDD (Box 4.4). Evidence from the history, physical
examination, or laboratory findings is used to establish whether abuse, depend-
ence, intoxication, or withdrawal states are physiologically inducing a depressive
episode. While substance-induced depressive symptoms usually resolve with dis-
continuation of the substance, some intense forms of withdrawal can last over
a month.
4.4.4 Bipolar disorder

A history of mania or hypomania signifies a bipolar disorder, but since () bipolar
disorder often starts with a depressive episode, and (2) bipolar patients spend
more time in depressive episodes than in mania/hypomania, it is important to
Table 4.4 Features that help distinguish bereavement from a major

depressive episode
Feature Bereavement Major depressive episode
Mood experience Feelings of loss or Persistent sadness or
emptiness anhedonia
Feelings of worthlessness Absent Present
Suicidal ideas Absent Common
Delusions of guilt, etc. Absent Possible
Psychomotor changes Mild agitation Marked slowing
Functional impairment Mild Marked to severe
chapter 4
Table 4.5 General medical conditions associated

with depressive symptoms
Neurological disorders Endocrine disorders
Alzheimer’s disease Adrenal
Cerebrovascular disease Cushing’s
Cerebral neoplasms Addison’s
Cerebral trauma Hyperaldosteronism
CNS infections Menses related
Dementia Parathyroid disorders
Epilepsy Thyroid disorders
Extrapyramidal diseases Vitamin deficiencies
Huntington’s disease B2/folate
Hydrocephalus Vitamin C
Migraine Niacin
Multiple sclerosis Thiamine
Narcolepsy Other disorders
Parkinson’s disease Acquired immune deficiency
Progressive supranuclear palsy syndrome (AIDS)
Sleep apnoea Cancer
Wilson’s disease Cardiopulmonary disease
Systemic disorders Klinefelter’s syndrome

Viral and bacterial infections Myocardial infarction
Inflammatory disorders Porphyrias

Rheumatoid arthritis Postoperative states
Sjögren’s syndrome Renal disease and uraemia
Systemic lupus erythematosus Systemic neoplasms
Temporal arteritis
carefully rule out bipolarity when diagnosing MDD. In fact, 5–0% of individuals
that experience a major depressive episode will have a manic or hypomanic epi-
sode in their lifetime. Depressive symptoms that suggest bipolarity include racing
thoughts, psychotic symptoms, atypical features (hypersomnia, overeating), early
chapter 4
Another random document with
no related content on Scribd:
The Project Gutenberg eBook of The ranch of the
tombstones
This ebook is for the use of anyone anywhere in the United States
and most other parts of the world at no cost and with almost no
restrictions whatsoever. You may copy it, give it away or re-use it
under the terms of the Project Gutenberg License included with this
ebook or online at www.gutenberg.org. If you are not located in the
United States, you will have to check the laws of the country where
you are located before using this eBook.
Title: The ranch of the tombstones
Author: W. C. Tuttle
Release date: May 5, 2024 [eBook #73545]
Language: English
Original publication: New York: The Ridgway Company, 1922
Credits: Roger Frank and Sue Clark
*** START OF THE PROJECT GUTENBERG EBOOK THE RANCH

OF THE TOMBSTONES ***
The Ranch of the Tombstones
A Complete Novelette by W. C. Tuttle
Author of “The Range Boomer,” “Flames of the Storm,” etc.
Two men swung their horses through the tumble-down gateway of

the Half-Moon Ranch and rode slowly toward the old, rambling
ranch-house.
The man in the lead was a tall, thin, unshaven cowboy, with a
long, sad countenance and a pair of bright, grin-wrinkled eyes. He
rode standing straight in his saddle, with the brim of his sombrero
pulled down over his eyes.
The other man was shorter, heavier, with a heavy-lined face and
half-shut eyes. A few strands of roan-colored hair straggled from
under the brim of his hat, which rested on the back of his head.
They drew rein and looked the place over. The tall one nodded
toward the side of the house, and they both rode around to the rear,
from whence came the sound of a voice raised in anger.
“Cook!” exclaimed the voice scornfully. “You? Huh! Do yuh think
the Half-Moon outfit wear steel bills and digests their food through a
gizzard? Why, dang yore hide, yuh can’t even burn stuff decently.
Set yoreself up to cook fer an outfit, do yuh? Where’d you learn to
cook? Cook, ——! Yo’re fired! No, I don’t want to hear yuh explain
how yuh got drunk on one li’l drink and forgot which way home was.
No sir! Pack yore war-bag and drift. I’ve got enough troubles without
annexin’ a lot of bad stummicks around here. Yo’re fired; sabe? If
you can’t understand English, I’ll write it out in Swedish and mail it to
yuh.”
The tall cowboy’s face wrinkled into a grin, and he started to say
something to his companion, but just at that moment a woman
opened the kitchen-door and looked out at them.
She was a tiny wisp of a woman, dressed in faded calico. About
fifty years of age, with a mild, sweet face and soft, blue eyes. She
stared at the two cowboys for a moment, and a flush crept into her
tanned face.
“Ma’am,” said the tall cowboy taking off his hat, “I plumb betcha
that cook knows where to head in at about now.”
“Did—did you hear—me?” she faltered.
“Yes’m. I’m ‘Hashknife’ Hartley and my pardner’s name is ‘Sleepy’
Stevens. Nod to the lady, Sleepy.”
“I am Mrs. Snow,” said the lady. “‘Frosty’ Snow is my husband. He
owns this Half-Moon Ranch.”
“T’ meetcha,” bowed Hashknife, and then seriously, “Ma’am, if that
cook ain’t took the hint yet, I’d admire to repeat yore words to him.”
“The—there ain’t no cook here now,” confessed Mrs. Snow.
“Ain’t? Why——”
“He won’t quit, don’tcha see? His name’s ‘Swede Sam,’ and if ——
ever made a more ignorant person than Swede Sam he sure kept
him under cover for loco-seed.”
“Didja ever try firin’ him?” asked Hashknife.
“Sure. But he won’t quit. Every day I practise on a new style of
firin’ him. And what you just heard was what I’m framing up to tell
him when he shows up again. We’ve done everythin’ except kill him
outright, but he just grins and says:
“‘Das goot yoke. Ay am de cook, you bet.’”
Hashknife laughed joyfully. He liked Mrs. Snow because she could
see the humor of life.
“Where is he now?” asked Sleepy.
Mrs. Snow shook her head slowly.
“I dunno. A few weeks ago he cooked up a big mess of prunes
and forgot where he put ’em. Yesterday he drank the result, and lit
out for Caldwell; singin’ somethin’ that didn’t sound like a Swedish
church-hymn. I reckon he’s asleep in Casey McGill’s saloon now. He
thinks Casey’s a Swede.”
“Much stock runnin’ in this Lodge-Pole country, ma’am?” asked the
practical Sleepy.
“Ye-e-es—I reckon you’d say there was.”
“We’re lookin’ for jobs, ma’am,” explained Hashknife. “Me and
Sleepy are what you’d call top-hands.”
“Never seen a puncher that wasn’t,” declared Mrs. Snow. “Frosty
says there’s been a epidemic in the cow-country, which has made
top-hands out of every danged buckaroo what has two legs to wear
chaps.”
“They do get graduated fast, I reckon,” agreed Hashknife grinning.
“Me and Sleepy earned ours. Do we get the job?”
Mrs. Snow smiled and shook her head. She liked the looks of
these two bronzed, practical-looking men, but the Half-Moon was full
handed.
“We’re runnin’ full of help, boys. Frosty said he’d likely have to cut
down pretty soon.”
“Well, that’s too danged bad,” observed Hashknife. “I’d sure like to
work for you, ma’am. Know any ranch that might be honin’ for two
more to feed?”
Mrs. Snow smiled and shook her head, but sobered as she
squinted at them.
“Might try the Tombstone Ranch.”
“Sounds right cheerful, ma’am,” observed Hashknife. “Do they
raise ’em already carved?”
“Kinda,” admitted Mrs. Snow seriously. “Place belongs to old Amos
Skelton, the meanest old son-of-a-gun that ever pulled on a boot.
Everybody hates him.”
“Must amount to somethin’ then,” observed Sleepy.
“What does his iron look like—his brand?” asked Hashknife,
reaching for the cigaret makings.
“It’s the old 33 outfit. Folks named it the Tombstone about a year
ago. Bill Wheeler owned the old 33 and he let Caldwell put their
graveyard on his ranch. It was a kinda nice spot, where the grass
stays green most of the time. Then old Amos comes along and buys
Bill out. Amos is a danged old blow-hard and most everybody starts
in hatin’ him at the drop of a hat.
“Long comes Halloween Eve and some brainless cowpunchers
goes down to the graveyard, swipes the tombstones, and when old
Amos wakes up the next mornin’ his front yard is set full of them epi-
tafts.
“It was a good joke on Amos, don’t you think?”
“Did he laugh?” queried Hashknife.
“Not so’s you could notice it,” smiled Mrs. Snow. “He took a plow
and harrer up to the graveyard, and when he got through cultivatin’ it
would take a higher power than exists in the Lodge-Pole country to
tell where all them tombstones belonged. Yessir, he sure did remove
all the brands. Them tombstones are all in his front yard yet, and I
reckon they’ll stay.”
Hashknife and Sleepy laughed immoderately. Mrs. Snow looked
severe for a moment, but joined in the laugh.
“Any punchers workin’ for that outfit?” asked Hashknife, still
laughing.
“One—‘Quinin’ Quinn.”
“Why for the medicine cognomen?” asked Hashknife.
“Bitter. Quinn ain’t smiled since he was born. Fact. Ain’t got no
grin-wrinkles on his face—not one. Nobody plays poker with him,
’cause of his face. Him and old Amos makes a good pair—to let
alone.”
“Well, we’re sure much obliged to you, Mrs. Snow,” said
Hashknife. “We’ll mosey along to Caldwell, I reckon. If you can’t
make your cook understand anythin’, send for me. I sure sabe one
word he’ll jump for.”
“Tell it to me, will you?”
“Skoal.”
“Shucks!” Mrs. Snow laughed shortly. “I sabe that one. It’s like
sayin’, ‘Here’s my regards.’”
“Yeah, that’s true,” admitted Hashknife solemnly. “But yuh might
yelp it just before you hit him with the ax.”
They turned their horses and rode back around the house,
heading toward Caldwell.
Ahead of them the dusty road circled through the hills, as though
following the lines of least resistance.
There was little flat land in the Lodge-Pole range, but it was ideal
for cattle; the breaks giving protection for feed in Summer and for
stock in Winter. Cottonwood grew in abundance along the streams,
and every cañon seemed heavily stocked with willow. The hills were
scored with stock-trails, leading from water to the higher ground.
“Don’t like this country,” declared Sleepy after they had ridden
away from the Half-Moon, “too many places to shoot from cover.”
“Sleepy, you ought to have been an undertaker,” said Hashknife.
“Death sure does have a attraction for you, cowboy. To me this looks
like a land of milk and honey.”
“Milk and honey, like ——! More like strong liquor and hornets.”
Hashknife laughed. He and Sleepy argued continually, swore
affectionately at each other and shared the blanket of a cowboy’s
joys and woes.
“Look at the doughnut,” grinned Hashknife. “Consider the rim of
brown dough instead of lookin’ through the hole all the time. Nothin’
ever looks right to you, Sleepy.”
“I said ‘strong liquor’,” declared Sleepy, leaning forward in his
saddle, “and here comes the proof.”
A horse and rider had topped a rise just beyond them, and there
was no doubt but what the rider was sitting drunkenly in his saddle.
The horse was going slowly, and in anything but a straight line, as if
trying to balance its rider.
“Drunker ’n seven hundred dollars,” declared Sleepy. “Ho-old fast!”
he grunted, as the rider almost toppled from the saddle.
The horse stopped as they rode up, standing at right angles to the
road, snuffing at the dust. The rider swayed sidewise and Hashknife
grabbed him by the arm.
“Drunk ——!” snorted Hashknife. “This man’s been shot!”
“My Gawd, yes!” gasped Sleepy, dismounting and going around to
the other side.
“More ’n once, too,” declared Hashknife, “or he’s smeared himself
with the blood.”
They took the man off his horse and laid him beside the road. His
flannel shirt was soaked with blood, and an examination showed that
the man had been shot twice. One bullet had struck him high up in
the left shoulder, while the other had torn its way through his body on
the right side, about midway between shoulder and waist.
He was unconscious from loss of blood and his breath came
jerkily.
“There ain’t a danged thing we can do for him,” said Hashknife,
getting to his feet. “Looks to me like he’d been hit with a thirty-thirty.”
Sleepy nodded as he looked up from an examination of the man’s
face.
“Betcha forty dollars that this here is Quinin Quinn. Didja ever see
such a sour face in your life?”
“’F you got two thirty-thirties through your carcass, I reckon you’d
kinda sour, too,” retorted Hashknife. “’F we knowed where the
Tombstone Ranch was, we’d take him there.”
“Must be between here and Caldwell. This feller likely headed f’r
home and missed the gate. If we don’t find the ranch, I reckon we
can find the town.”
“And that,” said Sleepy, as they draped the man over his saddle,
“is the first danged thing I ever suggested that you didn’t argue
about, Hashknife.”
“First time you ever spoke sense, Sleepy.”
“Glad you give me credit for this once.”
“I’ll give you credit, when you got it comin’. Get your lariat, Sleepy.
We’ve got to tie this jigger kinda tight.”
Sleepy got his rope and proceeded to tie his end of the man to the
saddle.
“Lots’a times I never get no credit,” grunted Sleepy. “Lots’a times
you takes all the credit.”
“Givin’ you credit now, ain’t I, Sleepy?”
“Yeah—this time—I could tell you a lot of times——”
“Shall we set down and argue and let this man die, or would you
rather shut your face and give him a chance?”
“Who’s arguin’?” demanded Sleepy, swinging into his saddle.
“’F I ever open my mouth——”
“You expose your ignorance,” finished Hashknife. “Ride on the
other side and see that he don’t slip loose.”
“Yeah, I’ll do that, too,” agreed Sleepy, suiting his action to the
word. “But,” he added, looking across the body of the wounded man,
“don’t think you’ve got all the brains, Hashknife—nor a big part of
’em. I never did see a tall man what had any too much sabe. Caesar
was a short man, and Napoleon was small and——”
“And look what happened to Napoleon,” grinned Hashknife. “They
pastured him on an island all alone.”
“How about Caesar, eh?”
“I dunno a —— thing about him,” admitted Hashknife. “What
happened to him, Sleepy?”
“I dunno f’r sure, but—betcha forty dollars that’s the Tombstone
Ranch.”
They rode around the point of a hill and below them was a
ranchhouse, sprawled in a clump of cottonwoods. A long feed-shed,
its roof twisted out of a straight line, stretched from a series of pole
corrals along the bank of a willow-grown stream.
A thin streamer of smoke was drifting from the crooked stove-pipe.
Between the gate and the ranch-house the ground was dotted with
white slabs, seemingly laid out in orderly rows.
“That’s her,” agreed Hashknife. “Graveyard and all.”
They rode down to the gate and up past the graveyard to the front
door. There was no sign of an inhabitant, until Hashknife dismounted
and started for the door, when the door was suddenly flung open and
Hashknife faced the muzzle of a double-barreled shotgun. The man
behind the gun was as gray as a rabbit, slightly stooped and with a
face as hard as chiseled granite.
“Hook your feet to the dirt and keep your hands above your waist!”
he growled.
Then he saw Sleepy.
He peered closer and the muzzle of the shotgun came down.
“Your name Stevens?” he asked.
“Hey!” gasped Sleepy. “You’re ‘Bliz’ Skelton! Well, you danged
pelican! Whatcha know about that?”
Sleepy fairly fell off his horse and bow-legged his way up to the
door, where he and Skelton shook hands.
“This is Hashknife Hartley, my pardner, Bliz.”
“Ex-cuse m’ scatter-gun,” said Skelton, as he shook hands with
Hashknife.
“Danged old dodo!” Sleepy grinned widely. “Ain’t seen you since
you owned the O-Bar-O in Eagle River. You ain’t changed much,
’cept to get homelier ’n ——. Mrs. Snow said that Amos Skelton
owned this ranch. Never heard nobody call yuh anythin’ but
Blizzard.”
“Christened Amos,” grunted Skelton, squinting out at the horses.
“Plumb forgot the wounded man!” grunted Hashknife, leading the
way out.
“——!” gaped Skelton. “That’s Quinin! He’s my hired man. What
happened to him, anyway?”
Sleepy and Hashknife unfastened the ropes, while they told
Skelton of how they had found Quinin. The old man’s face grew
tense and he spat viciously, but said nothing. They carried Quinin
into the house and placed him on a bed. Hashknife took hold of a
limp wrist and squinted down at the man. Then he took a tiny mirror
from his vest pocket and held it to the man’s lips. The surface
remained unclouded.
Hashknife slowly replaced the mirror and looked at Skelton.
“He was your hired man—not is, Skelton.”
“Dead?”
Hashknife nodded and reached for the “makings.”
“Got any idea who threw the lead?” he asked.
Skelton shook his head.
“Trouble hunter, Bliz?” asked Sleepy.
“No!” Emphatically. “Quinin minded his own business.”
Hashknife lighted his cigaret and looked around the room. It
contained a box-stove, a table, littered with cigaret papers, two
bunks and a few chairs.
“Me and Quinin lived in here,” said Skelton. “Built our bunks in
here so there’d only be one room to clean.”
“What’s the trouble around here?” asked Hashknife suddenly.
Skelton stared at him.
“What trouble?”
“Folks don’t like you, Skelton. Feller don’t get disliked for nothin’.
Either you’re wrong, or folks see things wrong. Me and Sleepy are
danged good listeners.”
“That’s a fact, Bliz,” nodded Sleepy.
“I’m —— if I know,” admitted Skelton. “I’ve had this ranch about a
year and a half and I ain’t made a cent—nor a friend.”
“Mebbe they’re sore about the graveyard,” said Sleepy.
“I don’t blame ’em,” agreed Skelton. “It was a dirty trick, but I didn’t
have a thing to do with it.”
“You plowed out the grave-mounds,” reminded Hashknife.
“I did, like ——!” snapped Skelton. “I tell you I’m gittin’ tired of
denyin’ that charge.”
“Oh!” grunted Hashknife softly.
“I left them tombstones where somebody planted ’em; but I sure
didn’t smooth out them mounds, y’betcha. I’m wonderin’ that
somebody ain’t killed me over it, ’cause it’s sure a killin’ matter to
obliterate ancestors thataway.”
“’S a wonder yuh never sold out,” grunted Sleepy.
“Been asked to.” Skelton grinned for the first time. “Yes sir, it has
been hinted at considerable.”
“You’re bull-headed, Bliz,” grinned Sleepy. “I’d sure as —— sell out
if I was you.”
“Yeah? Mebbe you would, Sleepy—I dunno. They laid that
tombstone job on to me, and everybody hates me fer it; and m’ cattle
disappears reg’lar-like, and once in a while somebody takes a whang
at me with a rifle. But outside of that——”
Skelton spat and shook his head.
“What price do you hold on the ranch?” asked Hashknife.
“One hundred thousand dollars.”
“Oh ——!” gasped Hashknife weakly. “You’re old enough to know
better than that, Skelton.”
Skelton nodded seriously and scratched the palms of his hands on
his hips.
“Age don’t cut no ice, Hartley. This danged ranch ain’t worth more
’n eight, nine thousand, with them tombstones throwed in to boot; but
I’m —— if anybody’s goin’ to run Bliz Skelton off the place! I ain’t the
runnin’ kind, y’betcha. And as long as I’ve got a shell left for that old
sawed-off shotgun, I ain’t goin’ t’ run; sabe?”
“Tha’s all right,” mumbled Hashknife. “You know your own
capacity. What’ll we do with the dead man?”
“Take him to Caldwell, I reckon. I’ll hitch up to the wagon. I
suppose Jake Blue and Doc. Clevis’ll have a —— of a lot of
questions to ask now.”
“Who’re they?” asked Sleepy.
“Sheriff and coroner.”
Skelton stopped in the doorway and looked back.
“I’m —— glad yuh came along when you did. ’F I had to take him
in alone I’d sure be stackin’ m’self agin’ a lot of misery.”
“I betcha,” nodded Hashknife. “As it is, we’ll split the misery three
ways.”
“Takes somethin’ powerful to stir me in this —— heat; but right now I

grows excited.”
“Pinch” Johnson leaned back against the doorway of Barney
Stout’s blacksmith-shop and spat explosively. Barney lifted a
perspiring face and ceased rasping on the hoof of a piebald bronco.
His rasp fell to the floor with a clatter, and he came to the doorway,
rubbing his horny hands on his leather apron.
“Ol’ Amos bringin’ comp’ny to town,” grunted Pinch.
“One’s that Half-Moon Swede,” observed Barney, “and he’s
drunker ’n —— yet. Started out to walk to the ranch, and he was
takin’ up both sides and the middle of the road.”
“And them ain’t all!” grunted Pinch, getting to his feet.
“They’s a pair of boots stickin’ out the end of that wagon, Barney!”
Skelton drove up in front of Shipman’s general store and tied his
team to a porch-post. Several men crossed from the War-Bonnet
saloon, and one of them was Jake Blue, the sheriff—a skinny, blear-
eyed personage, of much self-importance and undoubted ability with
a gun.
“Looks t’me like somebody done got hurt,” observed Pinch wisely.
He crossed the street with Barney hurrying along behind him.
The sheriff and the other men looked over the sides of the wagon-
box curiously.
“What’samatter?” asked Blue. “Drunk?”
“Dead,” said Hashknife.
“Zasso?” Mr. Blue had a habit of speaking a whole sentence as if it
were only a single word.
He moved to the end-gate of the wagon and looked at the body
from that angle.
“Howdedie?”
“Quiet-like,” said Hashknife, manufacturing a cigaret.
“Huh!”
Mr. Blue seemed to discover Hashknife for the first time. He
masticated his tobacco rapidly and glanced at Skelton.
“Howaboutcha?”
Skelton told in a few words, while more folks came and looked at
the dead man.
“Where’d you come from?” asked the sheriff, looking at Hashknife.
“Recently?”
“Yeah.”
“Tombstone ranch.”
“I mean—before that.”
Hashknife snapped his cigaret away and leaned back in his
saddle.
“I was borned in Pecos, Texas, about thirty-two years ago——”
“What in —— do I care about that?” snapped Blue.
Hashknife looked surprized at the interruption.
“Pardner, you asked where I came from, didn’t you? I’m tryin’ to
tell you.”
“Zasso? Well, we’ll let that slide fer now while we talks about other
things. Will somebody find Doc Clevis?”
A man from the War-Bonnet signified his willingness to find the
doctor, while the crowd waited and grew to greater proportions.
Doc Clevis was easy to find, and a few minutes later he arrived on
the scene, bustling with importance. He was over six feet tall,
dressed in a loose-fitting, rusty-black suit and short boots. A thin
fringe of hair circled his otherwise bald head and surmounted a face
which was a mixture of unutterable sadness and no little evil.
He climbed into the wagon and sat humped on the edge of the
wagon-box, while he examined the body. Finally he nodded sadly
and looked at the circle of onlookers.
“He’s dead,” he announced solemnly.
“My ——!” marveled Hashknife. “You’re a wonder, Doc.”
“Been dead quite a while,” said the doctor.
“Wonders’ll never cease,” grinned Hashknife.
Doc Clevis squinted at him, as if wondering if this tall cowboy was
in earnest or not.
“Where does the Swede figure into this?” asked Pinch.
“We found him settin’ beside the road,” explained Skelton. “He’s
too drunk to know anythin’.”
“Lemme look at that rifle,” ordered the sheriff.
Sleepy handed down the rifle, and the crowd moved in to look at it.
The sheriff levered out three cartridges and slipped a white cigaret-
paper into the breech.
“Been shot lately,” he announced, peering down the barrel.
“It was beside the road,” said Skelton.
“Yeah?”
The sheriff looked quizzically at Skelton. “You found the Swede
beside the road, too? ’Pears to me that you found a lot of things
beside the road. Was the rifle near the Swede?”
“’Bout six feet from him.”
“How far from the Swede did yuh find Quinin Quinn?”
“’Bout two miles.”
“That don’t mean nothin’,” said Barney Stout. “Quinin was still
pluggin’ along when they found him. Anyway, that Swede never shot
him.”
“Zasso?”
Mr. Blue fastened his watery eyes upon Barney and lifted his
sparse eyebrows.
“Mebbe you know who shot him,” he said.
“Well,” faltered Barney, “I dunno who shot him, but that —— Half-
Moon cook was so drunk——”
“Yo’re excused!” snapped Blue, and then to Skelton:
“This here is goin’ t’ need investigatin’, Skelton. I dunno anythin’
about these two strangers who horns in on this deal—do you?”
“This’n,” nodded Skelton, indicating Sleepy. “I’ve knowed Sleepy
Stevens f’r a long time; and when he takes a pardner, I kinda backs
this here pardner. Know what I mean, Blue?”
“Gotcha. What do you make of it, Doc?”
“He was shot twice, and he’s dead,” replied Doc. “I ain’t advancin’
any theory who done it, sheriff.”
“It’s a —— good thing we called yuh, Doc,” said Hashknife
seriously. “I used to live in a place where we didn’t have no doctor,
and it sure was ——. Why, I’ve knowed times when we kept dead
men propped up around town for weeks—waitin’ to be sure they
were dead. Lookin’ back at them days, I’m wonderin’ what killed ’em.
Mebbe they was shot—I dunno.”
“Are you plumb ignorant, or jist actin’ smart?” asked the sheriff.
“That,” said Hashknife seriously, “that is the secret of my success.
Nobody ever found out, and I couldn’t tell ’em, ’cause I didn’t know
m’self.”
“Thasso?”
The sheriff’s jaw muscles bulged, like twin walnuts, and he hooked
his thumbs into the waist-band of his overalls, as he squinted at
Hashknife’s serious face.
“You came to a —— good place for to be found out.”
“Well, that’s right nice of you, sheriff. What do you reckon I ought
to do for the information—kiss you?”
“Haw! Haw! Haw!” roared Pinch Johnson. “I’d admire to see you
do it, stranger.”
Mr. Blue’s face did not belie his name, except that it went purple
from the added flood of red. He opened his mouth, as though a
ready retort burned his tongue, then he shut his jaws tightly and
turned to the doctor—
“When’ll you hold a inquest, Doc?”
“T’morrow, I reckon,” said the doctor, rubbing his bald head with a
rotary motion, as if polishing it. “Take that long to git evidence, won’t
it?”
Blue nodded and turned to Hashknife—
“You two fellers ain’t aimin’ to pull out soon, are you?”
Hashknife shook his head.
“No-o-o. We’re plumb stuck on your town.”
Blue grunted his unbelief. He might be ignorant, but not a fool.
“You ain’t got no puncher now, have you, Skelton?”
Skelton shook his head.
“Ain’t a lot of extra hands around this country,” observed Blue.
“Well, Doc, I reckon we better have Quinin moved into your place.
Mind haulin’ him down there, Skelton?”
Skelton did not mind. He turned his team around and headed for
the doctor’s office, with several men following. Hashknife and Sleepy
rode across to a hitch-rack, tied their horses, and went into the War-
Bonnet.
The War-Bonnet was a large place for a town the size of Caldwell,
but it looked prosperous. There was not much activity during the day,
so the place was nearly deserted when Hashknife and Sleepy came
in.
A couple of girls were on the small stage-like platform at the end of
the room, practising a few dance steps, while with one hand a pallid
young man thumped out a melody on the piano.
A bartender humped his white-clad elbows on the bar, while he
deeply perused a paper-backed novel. A “swamper” was scrubbing
back of the bar. His activities seemed to irritate the bartender, who
knew that sooner or later he would have to move and break the
thread of his story.
Hashknife and Sleepy walked up to the bar and looked around the
place. The bartender sighed, folded over a leaf of his book to mark
his place, and came down to them.
“’Smatter over there?” he indicated the street with a jerk of his
sleek-combed head.
“Feller got leaded up,” said Hashknife. “Feller named Quinn.”
“Quinin Quinn, eh? Dead? The son-of-a-gun! Whatcha drinkin’?
Seen Swede Sam over there, too. He ain’t mixed up in it, is he?
Whatcha drinkin’? Know Quinn? Never smiled. No sir, that hombre
didn’t know how. Ain’t no reason for killin’ him off. Feller’s got a right
to look sour, ain’t he? I’d sure have to have a good reason before I’d
kill any man. Son-of-a-gun’s dead, eh? Well, well! Whatcha drinkin’?”
“See-gars,” said Hashknife grinning.
The bartender produced a well-worn cigar-box and disclosed a few
dried-out perfectos.
“Ain’t many cigar smokers around here,” he volunteered. “Don’t
pay to keep a big stock. Them’s real good Key Wests, y’betcha. I
smoked one oncet. Got drunk and careless. ’F you lick them outside
leaves, like you do a cigaret-paper, they’ll stick. Them Key Wests
allus kinda unravels thataway. I stuck ’em oncet, but they——”
Two very bad cigars went into a cuspidor, and the bartender
looked sad.
“I didn’t lick ’em,” he explained. “I used glue.”
“Tha’s all right,” grunted Hashknife. “A cigar ain’t never good after
the first drag or two.”
The bartender turned and threw the two-bits into the till.
“Have a drink on the house?” he asked.
Hashknife shook his head.
“Feller that’d use glue on cigars is liable to put cyanid in his hooch.
Who owns this ornate parlor?”
“‘Spot’ Easton. Didja ever hear of Spot?”
Hashknife leaned against the bar and admitted that he did not
know the gentleman. Just at this moment a man came in the door, a
frowsy looking man, with drink-bleared eyes and uncertain step. He
slouched up to the bar and leered at the bartender; a leer which was
intended to be an ingratiating smile, but which missed by a wide
margin.
“Nossir!” The bartender shook his head violently. “Spot said to lay
off givin’ you liquor, ‘Lonesome’.”
“Spot did?” The old man seemed surprized to hear it.
He wiped the back of his hand across his lips and stared at the
mirror on the back-bar. There was no question but what he needed a
bracer; his whole nervous system cried out for assistance.
“You get the drink, grampaw,” said Hashknife, tossing a two-bit
piece on the bar.
“Spot don’t want him—” began the bartender.
“Hooch!” snapped Hashknife. “What in —— do I care what Spot
wants?”
“He’ll get sore about it,” argued the bartender.
“Do I have to wait on him m’self?” asked Hashknife.
The bartender slid out the bottle and a glass. The old man seemed
undecided whether to take it or not, but Hashknife settled the
question by pouring the drink for him. The old man drank nervously
and upset the glass as he put it back. He steadied himself on the bar
uatil the liquor began to percolate and then sighed with relief.
A man came from the rear of the place and halted near the end of
the bar. He was rather flashily dressed for the range country. His
black hair was slightly tinged with gray. His features were narrow and
he wore a small mustache, which was waxed to needle-like points.
He scowled at the bartender, who got very busy wiping glasses.
The old man considered Hashknife and Sleepy for a moment, and
began to search his pockets. He drew out a crumpled envelop and

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Appendix: Sample rating scales 3

Epidemiology and burden

Table 2. Prevalence of DSM-​IV MDD in general populations

Location 2 month Lifetime

* Data on Canada is from the Canadian Community Health Survey.

2.2 Course and prognosis

2.3 Burden of illness

Box 2. Prognostic indicators of a prolonged recovery in patients

2.3.2 Socioeconomic costs

Low back pain

2.3.3 Costs of untreated depression

2.3.4 Costs of treatment

Higher income Upper-middle income Lower-middle income

Biological Psychological Social

Physical illnesses, Life experiences,

environmental influences on disease risk. Estimates from twin studies of genetic

3.2.2 Linkage and association studies

Neuroanatomical abnormalities in major depression

NMDAR BDNF bcl-2 ?

Figure 3.2 Example of how neurochemical abnormalities may relate to candidate

Figure 3.3 Example of how neurochemical abnormalities may relate to candidate

serotonin transporter (SERT), leading to increased availability of neurotransmit-

Figure 3.4 Characterization of antidepressant effects using an interdisciplinary

delayed desensitization of presynaptic 5-​HTA autoreceptors and downregulation

3.3.2 Beyond monoamines

3.3.3 Hypothalamic-​pituitary-​adrenal-​immune axis

Box 3. Polysomnographic abnormalities of sleep in major depressive

3.3.4 Sleep and circadian rhythms

Figure 3.6 Model of sleep and circadian rhythm dysfunction in depression.

there are deficits in long-​term storage and retrieval of declarative memory,

Cortical Rostral PFC SCC

Ventral ACC Amygdala

The emotion-​dependent ‘hot’ cognitive deficits in depression include negatively

3.4.2 Environment and life events

Genetically resilient (G main effect) – no effect of stress

Figure 3.8 Model of gene–​environment (G×E) interactions. This figure illustrates

Clinical features and diagnosis

4.1 Clinical features

Table 4. SIGECAPS mnemonic for the clinical features of depression

In contrast, hypersomnia or oversleeping also can be a symptom of ‘atypical’

4.2 Classification and diagnosis of depression

4.2.2 Major depressive disorder

Yes 5 out of 9 Yes Prior manic/ No Persistent Yes Persistent

5 out of 9 Yes Prior manic/ Yes Major

Figure 4. Differential diagnosis of depression.

4.2.3 Persistent depressive disorder

4.2.4 Other depressive disorders

Box 4. Summary of DSM-​5 criteria used to diagnose a major depressive

4.3 Sub-​types of depression

Box 4.2 Summary of DSM-​5 criteria used to diagnose persistent depressive

Box 4.3 Other disorders classified as depressive disorders in DSM-​5

Table 2. Prevalence of DSM-IV MDD in general populations

delayed desensitization of presynaptic 5-HTA autoreceptors and downregulation

3.3.3 Hypothalamic-pituitary-adrenal-immune axis

there are deficits in long-term storage and retrieval of declarative memory,

The emotion-dependent ‘hot’ cognitive deficits in depression include negatively

Figure 3.8 Model of gene–environment (G×E) interactions. This figure illustrates

Box 4. Summary of DSM-5 criteria used to diagnose a major depressive

4.3 Sub-types of depression

Box 4.2 Summary of DSM-5 criteria used to diagnose persistent depressive

Box 4.3 Other disorders classified as depressive disorders in DSM-5

Table 4.2 DSM-5 specifiers (sub-types) of MDD

associated impairment in social and/or occupational functioning. The ICD-0,

4.4.3 Substance/medication-induced depressive disorder