Successful management of major

depressive disorder
Chapter 1: Diagnosis, epidemiology, and comorbidity

Diagnostic criteria

In diagnosing a major depressive episode (MDE), it is important to distinguish between normal

sadness (‘feeling the blues’) and clinical depression. An MDE involves increased intensity of
symptoms that often precede a full blown depressive episode is important in both primary care
and psychiatry. In one investigation of prodromal symptoms, depressed mood, loss of
interest/pleasure, impaired concentration, hopelessness, worrying/brooding, decrease self-
esteem and irritability were identified with the greatest frequency. Furthermore, there was a
relationship between the number of prodromal symptoms and subsequent risk for recurrence.
The mean prodromal duration ranged from 6 weeks to 23 months.

Criteria for an MDE according to the DSM-5, require the presence of at least five of nine
symptoms, including depressed mood (sad, empty or hopeless feelings) and/or loss of interest
or pleasure, during the same 2-week period, and change from previous level functioning (Box
1). These criteria reflect only minor changes from DSM-IV, notably, the addition of ‘hopeless’
as a descriptor of depressed mood and the removal of ‘bereavement’ as an exclusion criterion.
In the case of bereavement, the clinician is encouraged to exercise judgement within the context
of the patient’s psychiatric history and cultural expressions of grief. Additional specifiers that
may be attached to the MDE diagnosis, and could potentially influence treatment selection are
‘with anxious distress’, ‘with mixed features’ and ‘with peripartum onset’. The previous
diagnoses of ‘dysthymic disorder’ and ‘chronic major depressive disorder’ in DSM-IV are now
subsumed under the diagnosis of ‘persistent depressive disorder’ in DSM-5.
 Box 1. The DSM 5 criteria for major depressive episode
A. The symptoms cause clinically significant distress or impairment in social, occupational or other
important areas of functioning.
 5 (or more) of the following criteria have been present during the same 2-week period and represent
a change from previous functioning; at least 1 symptom is either depressed mood or loss of interest
or pleasure. Note: do not include symptoms clearly attributable to a medical condition.
 Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g.,
feels sad, empty, hopeless) or observation made by others (e.g., appears tearful). Note: in children
and adolescents, can be irritable mood.
 Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly
every day (as indicated by either subjective account or observation made by others)
 Significant weight loss when not dieting or weight gain (e.g., change of more than 5% of body
weight in a month), or decrease or increase in appetite nearly every day. Note: in children, consider
failure to make expected weight gain.
 Insomnia or hypersomnia nearly every day.
 Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective
feelings of restlessness or being slow down).
 Fatigue or loss energy nearly every day.
 Feelings of worthlessness or excessive or inappropriate guilt (that may be delusional) nearly every
day (not merely self-reproach or guilt about being sick).
 Diminished ability to thing or concentrate, or indecisiveness, nearly every day (either by subjective
account or as observed by others).
 Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific
plan, or a suicide attempt or a specific plan committing suicide.
B. The episode is not attributable to the physiological effect of substance or another medical condition.
Additional specifiers:
-With anxious features
-With mixed features
-With melancholic features
-With atypical features
-With mood-congruent psychotic features
-With mood-incongruent psychotic features
-With catatonia
-With peripartum onset
-With seasonal pattern
 Note: criteria A-C represent a major depressive episode.
 Note: responses to significant loss (e.g., bereavement, financial ruin, losses from natural disaster, a
serious medical illness or disability) may include the feelings of intense sadness, rumination about
the loss, insomnia, poor appetite and weight loss noted in Criterion A, which may resemble a
depressive episode. Although such symptoms may be understandable or considered appropriate to
the loss, the presence of major depressive episode addition to the normal response to a significant
loss should also be carefully considered. This decision inevitably requires the exercise of clinical
judgement based on the individual’s history and cultural norms for the expression of distress in the
context of loss.
The heterogeneity of symptom expression is well illustrated by Ostergaard and colleagues who
identified almost 1500 potential symptom combinations that can satisfy criteria for an MDE
diagnosis. These symptoms do not occur with equal frequency, with fewer patients reporting
reduced appetite, pessimistic thoughts and suicidal intent, given the high prevalence of mood
disorders in individuals who die by suicide. Episode may also be categorized according to
severity. In large epidemiological survey, severe cases were the most prevalent (48%), while
14% were classified as mild and 39% as moderate. Severity also has considerable implications
for functional impairment and disease burden.

Epidemiology

MDD is among the most prevalent disorders with a lifetime prevalence of 16% and a 12 month
prevalence of 6-7% among adults in the USA. Rates are similar across high- and low-to-middle
income nations: in average lifetime and 12 month prevalence rates for MDEs were 14.6 and
5.5%, respectively, for high-income countries compares with 11.1 and 5.9% respectively, in
low-to-middle income countries. These figures are also in line with reports from various
European countries, including Germany, the Netherlands, Norway, Italy, and Hungary, where
lifetime prevalence rates using DSM-IV criteria for MDD ranged from 15.1 to 17.8%, and 12
month prevalence was between 5.8 and 10.7%. further epidemiological studies using DSM-5
criteria are waited, although it is unlikely that prevalence rate will differ substantially, given
the relative similarity between DSM-IV and DSM-5 criteria.

Socioeconomic burden

According to the ‘Grand Challenges in Global Health’, unipolar depression (MDD) is the third
leading contributor to global disease burden, and accounts for 65.5 million disability adjusted
life years (DALYs), the highest across all mental, neurological and substance disorder. Despite
undoubted advances in treatment options for MDD and other psychiatric disorders, in
Australians study the reduction in years lived disease (YLDs) was only offset by 20% with
optimal therapy, resulting in a significant health benefit.
 Table 1. severity of role impairment (Sheehan Disability Scale) associated with 12 month major depressive disorder in the NCS -R
sample

MDD cases in SDS category (%; 95% CI)

SDS domains
None Mild Moderate Severe Very Severe

Severity of role impairment

Home 9.2 (6.4-12.0) 21.8 (17.2-26.3) 34.8 (30.0-39.6) 27.4 (22.9-32.0) 6.8 (4.4-9.2)

Work 20.4 (16.8-24.1) 25.9 (21.6-30.3) 25.6 (22.1-29.1) 18.5 (15.0-21.9) 9.6 (7.5-11.7)

Relationship 14.8 (11.2-18.5) 21.9 (17.6-26.2) 29.0 (25.6-32.4) 26.9 (23.4-30.3) 7.4 (5.0-9.8)

Social 12.1 (8.8-15.4) 16.7 (12.3-20.2) 27.7 (23.9-31.5) 31.4 (27.5-35.3) 12.0 (9.7-14.4)

Overall↑ 3.1 (1.8-4.5) 9.5 (6.8-12.2) 28.1 (23.5-32.7) 40.2 (36.2-44.1) 19.1 (16.0-22.3)

Mean no. of days out of role due

to depression in the past 365 0 2.8 (0-5.7) 11.4 (0-23.1) 33.1 (22.7-43.6) 96.5 (67.0-125.9)
days↓
↑
Highest severity category across all four SDS role domains.
↓
Mean days out of role are presented separately in subgroups of respondants defined by their highest severity category across all four
SDS role domains (F4.617 +17.1; p < 001).
CI: Confidence interval; CIDI: Composite International Diagnostic Interview; DSM-IV: Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition; MDD: Major Depressive Disorders; NCS-R: National Comorbidity Survey Replication; SDS: Sheehan
Disability Scale.
Reproduced with permission from [22].

based retrospective, observational study of patients receiving treatment for MDD between 2000
Much of this health burden can be attributed to treatment resistant depression (TRD). In a US-

and 2007, TRD was associated with 40% higher medical care cost. Annual cost ranged from
US$5729 in non-TRD patients to $13,167 in TRD patients. Similarly, in a large claims
database, average 2-years costs were double in employees with TRD (based on a third
antidepressant prescription) compared with MDD controls. TRD patients were also more likely
to have higher rates of additional mental health disorders including chronic pain and
fibromyalgia. An interventions is cost-effective when it costs a maximum of £20,000-30,000
(US$ 34,000-51,000) per QALY. For collaborative care in primary care (usually the most
expensive organization for the treatment of MDD), the highest cost per QALY reported were
under $50,000 meaning that the vast majority of interventions are cost-effective.

In addition to healthcare costs, health economic evaluation studies indicate that mood disorders
and their comorbidities are the most costly conditions to employers. According to one study,
the majority of cost associated with MDD actually stems from a reduction in job productivity
(presenteeism) and absenteeism. There is also evidence that depression severity predicts
employment status, presenteeism and absenteeism. Severity of the present episode is one of the
most important factors when assessing its social impact; the number of days out of role due to
depression in the past 365 days increases from 3 (mild severity) to 96 (very severe), while it is
11 days for moderate severity and 33 days for severe depression (Table 1).

Psychiatric comorbidities

In the national comorbidity survey-replication (NCS-R), three out of four respondents with
lifetime MDD also met the criteria for at least one other Axis I diagnosis (DSM-IV); with
anxiety disorders (60%), substance use disorders (25%) and impulse control disorders (30%)
being most prevalent (Table 2). Similarly, in the national epidemiologic survey on alcohol and
related conditions (NESARC), the most frequently detected psychiatric disorders associated
with depressive episodes were anxiety disorders (41%), alcohol use disorders (40%), and
personality disorders (31%). These authors describe how the presence of MDD increase the
risk developing another syndrome, taking into account many confounders, such as secondary
depressive episodes and overlapping socio-demographic risk factors. Even with such a specific
estimation of the risk, all screened psychiatric disorders are more prevalent in patients with
MDD (Table 3).
There is a bidirectional relationship between depressive disorders and physical health in that
prior episodes of depression serve as a risk factor for onset of numerous medical illnesses and
vice versa, with medically ill patients displaying an increased risk for depressive episodes
(Table 4). The relationship between heart disease and depression provides a good example,
where prospective studies indicate that pre-existing depression increase the risk of
cardiovascular disease and mortality, and antecedents of cardiovascular disease increase the
risk of subsequent depression. Individuals with obesity, diabetes, chronic pain, epilepsy and
other CNS disorders are at high risk of developing depression.

Effect of MDD on mortality

The link between MDD and mortality is confounded by the medical comorbidities associated
with this population, as well as high rates of suicide. In an investigation of all suicide cases in
the Canadian province of New Brunswick over a 14 month period, 65% of suicide completers
had a mood disorder diagnosis and in 42% od cases, mood and substance-related disorders
were concurrent. Higher than expected morality rates from non-suicidal causes were observed
in Danish register-based cohort study pf 5.5 million people, comparing individuals who were
admitted to hospital with identified MDD to a reference population who had never been
admitted to hospital, irrespective of sex, age and type of death (natural or unnatural reasons).
Deaths attribute to suicide demonstrated a distinct gender difference, whereby the mortality
rate ratio (MMR) for females (37.2) was almost twice as high compared with males (25.9),
although twice as many males died by suicide in absolute numbers. Statistics for other causes
of death include: cardiovascular disease (MMR =1.5); malignant neoplasm (MMR = 1.17); old
age disorders including stroke disease (MMR = 1.8), respiratory disease (MMR = 2.0); and
endocrine/metabolic conditions (MMR = 1.6). the observed MRRs for each of these causes of
death exceed standardized mortality rates.
Chapter 2: Genes and the environment

Demographic and psychosocial factors

MDD occurs more frequently in women, has a peak age of onset in early adulthood and
gradually declines in incidence with age. Beyond sex an age, other demographic risk factors
include low level of education or low levels or mastery, high unemployment of financial
pressure and living alone (especially after separation, bereavement or divorce).

The number of prior MDEs steadily increases the risk for episode recurrence from 15% after
the first onset to 50% after the second episode, and approaches 100% by the 10th MDE (Figure
1). Abuse of alcohol, cannabis or tobacco also increases the risk of depressive episodes. Indeed,
the presence of virtually any co-morbid Axis I disorder increases the risk of later MDD (Table
3), and personality traits, such as neuroticism, confer additional risk. All of these factors, likely
due to their interconnectedness, individually have poor predictive value.
Using a decision tree approach to assess risk of recurrence based on initial levels of symptoms
and other demographic variables, substance use (particularly smoking and alcohol use),
employment status, financial pressure and educational level provided the highest prediction
power. Life events, religious service attendance, age group, weight and self-rated health were
also predictors in the decision tree. Casual links between environmental factors and depression
onset have been rigorously explored, with childhood maltreatment and chronic stress being the
strongest mediators of poor treatment outcome. Proximal stressor also have a negative effect
on treatment outcome with emerging evidence that adverse life events may result in enduring
alternations in brain regions controlling emotional and cognitive processing.

Gene-environment interaction

A consensus in family studies of adult with MDD is the risk to offspring is three-times greater
than in normal controls. The risk of depression is higher among the relatives of probands with
early-onset recurrent MDD, and the presence of depressive episodes in parents during their
offspring’s early childhood development phase further increase the risk of developing MDD.

The proportion of total variance in a trait due to genetic variation (the heritability) for MDD
has been estimated from twin studies at 37%. This suggests that while genetic factors play a
significant role, MDD cannot be considered a genetic disorder (two0third of the factors
involved are not explained by genetic variability). Given the broad spectrum of symptom
heterogeneity, it is not surprising that studies have failed to identify a universal risk factors or
common pathway to MDD. Interactions among many sources of vulnerability (gene-
environment interactions) are the most likely explanation for MDD. For example, losing a
loved one may represent a stressful event (including a drastic change of life) or the opportunity
for a fresh start (relief from caregiver burden). Moreover, sever stressful life events seem to be
more deleterious for subjects who have a family history of mood disorders, often referred to as
the ‘stress-diathesis’ theory of MDD.

Support for the gene by environment interaction (GxE) model in triggering an MDE coms from
several large cohort studies, including one where the classic candidate in MDD (the gene
coding for the serotonin transporter 5-HTT) was indeed involved in the occurrence of a new
episode of depression, but was dependent on the interaction between the functional
polymorphism in the promoter region of the serotonin transporter gene and number of stressful
life events experienced in the previous 3 months. Specifically, individuals with one or two
copies of the short allele of the 5-HTT promoter polymorph were at greater risk for onset of
depression (Figure 2)

Role of epigenetic factors

Among the several methods by which experience can produce long-lasting changes in protein
levels, epigenetic modifications seem to be particularly relevant to the pathophysiology of
depression and antidepressant action. Epigenetic changes offer a mechanism by which
environmental experience can modify gene function in the absence of DNA sequence changes,
and suggest an interesting explanation for: (1) the high discordance rates in monozygotic and
the presence of individual differences among inbred rodents; (2) the fact that early and specific
environmental factors (such as childhood maltreatment) constitute a significant risk factor for
adult MDD and, (3) the chronic relapsing nature of the illness, all of which speak to the
existence of an acquires vulnerability.

Personality and emotionality styles may also be attributes to individual differences in

neurobiological substrates, in addition to being a risk factor for depression when facing
environmental challenges; this suggest that vulnerability genes play a mediator role. Epigenetic
mechanism concern all induced modifications of gene expression (therefore different from
variation of gene sequencing), explain how some genes are being transcribed (producing
mRNA and then proteins) while others are not. Access to the gene for transcription can be
decreased (i.e., epigenetic regulation) through the addition of a methyl radical in certain parts
of the gene (untitled ‘CpG island’) or a modification of proteins (histones) around which the
DNA winds (Figure 3).

Methylation (of cytosine) on the glucocorticoid receptor (GR) gene seems to be important in
influence of maternal behavior on adult emotional processing. Adult offspring of rats born to
mothers with low rates maternal licking and grooming show increased anxiety and reduced
expression of GR within the hippocampus compared with offspring mothers at the promoter
region for brain-derived neurotrophic factor (BDNF) in the hippocampus is required for
chronically administered imipramine to reverse certain deleterious effect of social defeat,
indicating a role in antidepressant action. Evidence is also emerging that disruption of the small
non-coding RNA molecules (microRNA) may be associated with the pathophysiology of
depression and could be a target for novel treatments.
Chapter 3: Changes in neurobiology

Neural circuitry

Links between clinical psychiatry, neuroscience, and neuroimaging, have contributed to current
understanding of biological disturbances in MDD. Several prefrontal and limbic structures, and
their interconnected circuits, are implicated in affective regulation, including the ventromedial
prefrontal cortex (VMPC), lateral prefrontal cortex (LPFC), dorsolateral prefrontal cortex
(DLPFC), anterior cingulate cortex (ACC), ventral striatum (including the nucleus accumbens),
insula, amygdala, and the hippocampus. These regions regulate learning contextual memory
processes, executive function, emotion and reward, and have been implicated in depression and
antidepressant action. Early automatic stages of emotion regulation recruit more lateral
prefrontal neural regions that may be mediated by the rostral/dorsal anterior cingulate gyrus
(ACG) functioning. Dysfunctional automatic regulation may impair successful voluntary
regulation of emotions, and provide targets for future therapeutic approaches to the treatment
of MDD.

Regional blood flow studies suggest hyperactivity in the VMPC (which mediates pain,
aggression, sexual functioning, and eating behaviors) and in the LPFC (which assesses risk and
modulates maladaptive and perseverative affective states), combined with hypoactivity in the
DLFPC (which maintains executive function, effortful sustained attention, and working
memory processes), are associated with MDD. Using fMRI paradigms, connectivity studies
also suggest a decrement in the ‘communication’ between amygdala and ACC regions,
explaining a decrease capacity of the cortex to regulate subcortical areas mediating negative
emotions – usually referred to as a deficit in ‘top-down’ control.

Activity within amygdala and subgenual cingulate cortex is strongly correlated with dysphoric
emotions. The nucleus accumbens, a striatal subregion, is important for reward and for hedonic
deficits in depression. These forebrain networks are significantly modulated by monoamine
projections from midbrain and brainstem nuclei: dopamine (DA) from the ventral tegmental
area; serotonin (5-HT) from the dorsal raphe in periaqueductal grey area, and noradrenalin
(NE) from the locus coeruleus. In addition to controlling alertness and awareness, these
neurotransmitters modulate salience of emotional stimuli. However, other neurotransmitter and
molecular system, including neuropeptides, neurotrophic factors, cytokines, sigma-1 receptor
modulators, vasopressin receptor antagonist and melatonin target, play a role in generating
depressive symptoms (Figure 4).

Neurotransmitter & molecular abnormalities

The ‘monoamine hypothesis’ of depression (i.e., depression is caused by decreased monoamine

function in certain brain region) emerged from the discovery that the first generation of
antidepressant agents either inhibited neuronal reuptake (mainly by blocking the 5-HT and/or
NE transporters), or blocked their degradation (the monoamine oxidase inhibitors.)
hypoactivity of monoamines, especially 5-HT, NE and DA, has indeed been reported in the
midbrain. The problem is that antidepressant agents increase monoamine transmission after
minute or hours, whereas clinical response to most antidepressants is observed only after
several weeks. Therefore, monoamines could be a common pathway that represent one way,
but not sole pathway to improving depression. This hypothesis would explain how very
different approaches, such as sleep deprivation, light therapy, electroconvulsive therapy (ECT)
and other neurostimulation therapies, can all produce antidepressant effect. At least for some
types of depression, a key element could be the level of DA in the prefrontal cortex, in
accordance with its core role in reward and hedonic processes. Indeed, increased DA
transporter levels and decrease DA levels were detected in patients with MDD. Higher levels
of D2 receptor binding were also observed in depressed patients in the right and left putamen,
which correlated with motor retardation.

Another mechanism that may explain the activity of antidepressant treatments is

neuroplasticity. A marked cellular effect of antidepressant pharmacotherapy is the induction of
adult hippocampal neurogenesis-the process by which neural progenitor cells in hippocampal
subgranular zone (SGZ) divide mitotically to form new neurons that differentiate and integrate
into the dentate gyrus. The mechanisms by which new neurons might restore mood are
unknown, but activity-dependent increases in neurogenesis allow hippocampal networks to
adapt and learn new experience.

Neuroendocrine & inflammatory dysregulation

Many biological pathways are influenced by external stress. Failure to return to pre-stress levels
of activity appears to occur in several systems in depressant patients. Physical or physiological
stress increase serum glucocorticoid concentrations. Small increases in serum glucocorticoid
concentrations have been observed in depression, and some depression-like symptom can be
produced in rodents by chronic administration of glucocorticoids. Patients with Cushing’s
syndrome, who have extremely high concentrations of circulating cortisol, also show
depressive features and atrophic changes in the hippocampus. Nevertheless, this is not
consistent for all type of depressive disorders, as atypical depression, a subtype characterized
by hyperphagia and hypersomnia, seems to be associated with hypocortisolaemia. Cytokines,
which are humoral mediators of innate and adaptive immunity, are also important modulators
of mood, explaining why, for example, 30% of individuals treated with recombinant interferons
(proinflammatory cytokines) develop depression.

In summary, DSM-5 proposes subtle, but important, modifications in the core concepts of
depression. Indeed, the presence of ‘explicative’ conditions, such as bereavement, cannot now
be considered as abolishing the reality disorder. This decision indirectly reinforces the idea that
MDD, although sometimes viewed as a ‘natural consequence’ of external stress, is disorder per
se, that provokes one of the highest societal burdens in the world. Therefore, trying to delimit
risk factors and understand abnormal mechanism involved in MDD has led to interesting
hypotheses, including genetic vulnerability (and more recently epigenetics), abnormal neuronal
circuitry (and maybe more specifically a deficit in top-down regulation by the prefrontal cortex
of the amygdala-hippocampus complex), neuroplasticity deficiency (and even more
specifically a decrease of neurogenesis in certain parts of the brain), or a dysregulation of
inflammatory processes. It is important to add that these are not mutually exclusive correlates
of the clinical syndrome and maybe reflect different levels of analysis.

Even if we still do not have clear answer, these distinct fields of research are probably highly
overlapping. Furthermore, they are sufficiently relevant that in an attempt to characterize
molecular/cellular influence on brain activity and ultimately symptom and behavior expression,
a cross-cutting dimensional approach to psychiatric diagnosis referred to as RDoC has been
proposed by the National Institute of Mental Health (Figure 5). Investigators are encourage to
explore domains:

 Negative valence and acute threat (fear);

 Positive valence and reward learning;
 Cognitive systems and working memory;
 Social processing and attachment/perception
 Arousal and regulatory-biological rhythms.
Determining how these domains overlap or in some cases remain distinct may help to delineate
subtypes of depressed patients, for whom ‘dysfunction-specific’ therapies may be developed.
Chapter 4: general principles of treatment of MDD

Since the course of MDD is more likely to involve recurrent major depressive episodes rather
than a simple episode, acute and maintenance aspects of treatment should be considered from
the outset (Table 5). Once patients have achieved remission, the ultimate goal of maintenance
treatment is to prevent recurrence. This require attention to residual symptoms comorbid
conditions and focus on function (e.g., return to work or other meaningful activities) and overall
quality of life. Improving outcomes in the treatment of depression depends on optimal use
current treatments and an awareness of new and emerging alternatives. Recommendations for
current treatments are based on current guidelines including those of the Canadian Network for
Mood and Anxiety Treatments (CANMAT). Attention to measurement-based care and
treatment adherence is also an important aspect of good patient management.

Criteria to grade evidence

Efficacy studies are graded according to the quality of evidence, based on the CANMAT
guidelines for management of MDD. Level 1 evidence requires at least two randomized
controlled trials with adequate sample size and/or meta-analysis with narrow confidence
intervals. Level 2 evidence requires at least one randomized controlled or trial and/or meta-
analysis with wide confidence intervals, while level 3 evidence is based on non-randomized
controlled prospective studies or large case series. A first-line treatment requires at least level
2 evidence plus expert agreement; a second-line treatment requires at least level 3 evidence
plus expert agreement; and a third line treatments is based on expert consensus. In some cases,
medication with level 1 evidence of efficacy but unclear long-term safety or tolerability may
be ‘downgrade’ to a second-line recommendation.

Measurement based care

Applying measurement-based care is a more reliable method of diagnosing and treating MDD
than relying on clinician perceptions alone. Several self-report and physician-administered are
available to evaluate the severity of symptoms and the effect of treatment (Table 6). The Patient
Health Questionnaire (PHQ-9) has gained increasing acceptance as an aid to diagnosis and a
tool to evaluate treatment outcomes (Figure 6). The Hamilton Rating Scale for Depression
(HRSD) and the Montgomery Asberg Depression Rating Scale (MADRS) are the most
accepted outcome measures in research trials. In the case of the HSRD, an abbreviated 7-item
version has proved to be a simple and easily administered tool in routine clinical practice
(Figure 7).

The goal for acute treatment is remission. Given the high prevalence of depression in the
workforce, clinician should also explore the impact of depressive symptom on work and
activities by asking specific questions that relate to function (Figure 8). The Sheehan Disability
Scale (SDS) (Figure 9) and the Lam Employment Absence and Productivity Scale (LEAPS)
(Figure 10) are useful measures to assess functionality.

Adherence

Adherence to antidepressant treatment is pivotal component of any therapy. Unfortunately, a

large minority of patients do not adhere to treatment instructions, forgetting to take their
medications at consistent dose, sometimes missing doses for days or weeks, or discontinuing
completely. Non-compliance is associated with a recurrence of MDD and symptom severity.
Adherence to antidepressant therapy declines with time; at 1 month, 82% of patients reported
taking the correct doses, and this decreased to 60% after the first 3 months. In one review,
approximately 40% of patients discontinued medication within the first 30 days and over 70%
had discontinued by 90 days. Men are more likely to drop out of treatment then women and
treatment adherence deteriorates markedly after 4 months. These authors also observed
temporary improvement in adherence leading up to and just after medical visits, highlighting
the importance of regular follow-up asking about adherence at each visit. Adherence is equally
important in assessing psychotherapy outcomes (e.g., homework between cognitive therapy
sessions). Irrespective of therapy selection, treatments are not effective if not taken correctly.

`
Table 5. Phases of antidepressant treatment
Treatment phase duration goals activities
Acute and continuation 0-6 months  Remission symptoms  Establish therapeutic
 Restore function alliance
 Educate
 Select and use
treatment(s)
 Monitor progress
Maintenance 6-24 months  Return to full function and quality of life  Educated
 Prevention of recurrence  Rehabilitate
 Treat comorbidities
 Monitor for recurrence
Reproduced with permission from (252)

Table 6. Patient rated screening instruments for major depressive disorder.

Instrument Website Ref.
Beck Depression Inventory www.harcourtassessment.com (50)
Zung Self-Rating Depression Scale Healthnet.umassmed.edu
PRIME-MD (self-report format) www.montana.edu Archives – PHQ.doc (50)
Patient Health Questionnaire-9 www.phqscreeners.com (226)
Shedler’s Quick PsychoDiagnostics Panel www.nfer-nelson.co.uk (227)
Hospital Anxiety and Depression Scale (228)
Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) www.mentalhelp.net/poc/view_doc. (229)
Php?type=doc&id=973&cn=5
Goldberg Depression Questionnaire (52)
Inventory to Diagnose Depression (230)
Montgomery-Asberg Depression Rating Scale -Self Report (MADRS-S) (231)
Carroll Rating Scale for Depression (CRS-D) (232)
Hamilton Depression Inventory (HDI) (233)
Chapter 5: Evidence-based psychotherapies

Cognitive behavior therapy

Cognitive behavioral therapy (CBT) and interpersonal therapy (IPT) have the best evidence
base and are the most widely delivered psychotherapies for depression. They share an emphasis
on brevity (typically around 16 weekly sessions), reproducibility (manual based) and activity
from both the patient (homework) and the therapist (Table 7).

CBT has robust evidence to support its use as an acute and maintenance therapy. While it was
developed to be administered alone, CBT may also ‘chronic depression’. The basic premise is
that a depressed person thinks negatively about his or her world needs to learn different
strategies to appraise and deal with day-to day life issues. A course of therapy is typically
divided into early, middle and late phase (Table 8),

Interpersonal therapy

IPT focuses on relationship difficulties in the context of life events and transitions. In its
original format. IPT addressed problems with role transitions, role disputes, interpersonal
deficits or unresolved grief. As with CBT, there are defined tasks during initial, middle and
latter phases therapy (Table 8). There are also positive results for IPT in special populations,
including older depressed adults and women with perinatal depression. IPT has also been
evaluated in depressed patients with comorbid disorders, in study of IPT in depressed women
with co-morbid alcohol dependence, measures of drinking behavior, depressive symptoms, and
interpersonal functioning all improved significantly over the treatment period and were
sustained at follow-up. Since this treatment is frequently delivered in combination with
pharmacotherapy, the added benefit of the combination has been difficult to establish.

Third-wave cognitive behavior therapies

A third wave of psychotherapies with an emphasis on behavioral activation has emerged end
is in the early stages of critical evaluation. Cognitive behavioral analysis systems
psychotherapy (CBASP) is synthesis of CBT and IPT. It was developed to treat chronic
depression, and proved to be effective in combination with antidepressant medication in a large
US trial. Surprisingly, there have been no published replication studies, although a secondary
analysis from the original study supported a superior role for CBASP alone or in combination
with nefazodone, compared with the antidepressant alone, in depressed patients who had a
history of childhood trauma.

The premise for acceptance and commitment therapy (ACT) is that depression results from
‘experimental avoidance’ and the therapy aims to increase acceptance of distressing thoughts,
beliefs and ultimately promote behavioral change and enhance quality of life.

Mindfulness-based cognitive therapy (MBCT) was specifically developed as a relapse-

prevention strategy for depressed patients in remission. It combines meditation techniques with
psychoeducation and other aspects of cognitive therapy, with a focus on transforming
dysfunctional thoughts into internal events separated from the self. In an RCT, relapse rates in
remitted depressed patients receiving MBCT were similar to those on maintenance
antidepressants and in both cases, lower than the placebo group.

Behavioral activation (BA) has emerged as a standalone therapy encompassing

psychoeducation, activity monitoring, promoting value driven activities and trouble shooting.
The enduring effects of BA were comparable treatment with medications in an RCT.

Cognitive remediation therapy

Cognitive remediation therapy has also emerged as an important strategy for depressed
patients, particularly for those who plan to return to the workforce. Typically, remediation
therapy aims to enhance processing speed, attention, memory and executive function through
computerized drills, strategy monitoring and application of skills to real-life situations.

Combined use of psychotherapy & medication

While the combination of psychotherapy and medication intuitively makes sense, not all studies
have confirmed an advantage to the combined approach. Practical concerns, including cost and
availability of trained therapists, may outweigh the additional benefits. In a meta-analysis of
18 studies with over 1800 patients, there was a modest advantage to the combine approach
compared with psychotherapy alone. When psychotherapy and pharmacotherapy are
combined, it is usually on sequential basis with the psychotherapy being added to partial or
non-responders. On the other hand, when concurrent combines treatments were compared with
pharmacotherapy alone, there was an advantage in terms of symptom reduction and,
particularly in studies lasting longer than 12 weeks, a reduction in drop-our rates.
Subsequently, in a meta-analysis of combined pharmacotherapy and psychotherapy outcomes
in treatment of chronic depression, there were no difference in long-term symptom outcomes
between combined treatments and pure pharmacological interventions, although small but
statistically significant advantages for combined therapies were noted in quality if life
measures.
Table 7. Goals of short therm evidence based therapies for depression

psychotherapy premise activities

Cognitive behavioral therapy Distorted belief about the self, the world and future  Recognize negative cognition
maintain depressive affect  Respond to negative thoughts and
behavior
 Problem solve and test assumption

Interpersonal therapy Current interpersonal issues maintain depressive affect  Identify issue (role transition, role
dispute, grief, interpersonal deficits)
 Focus on social context

Behavioral activation Depression is a consequence of compromised  Increase activity and access to rewarding
environmental sources of positive reinforcement experiences
 Focus on negative relationship patters

Cognitive behavioral analysis In chronic depression, the situational and interpersonal  Use cognitive, behavioral and
system of psychotherapy avoidance pattern maintains depressive affect interpersonal strategies
 Address inertia, avoidance, social
withdrawal

Modified with permission from (251)