Depression

Author: Jerry L Halverson, MD

Signs and symptoms

Most patients with major depressive disorder present with a normal appearance. In
patients with more severe symptoms, a decline in grooming and hygiene may be
observed, as well as a change in weight. Patients may also show the following:

Psychomotor retardation
Flattening or loss of reactivity in the patient's affect (ie, emotional expression)
Psychomotor agitation or restlessness

Major depressive disorder

Among the criteria for a major depressive disorder, at least 5 of the following
symptoms have to have been present during the same 2-week period (and at least 1
of the symptoms must be diminished interest/pleasure or depressed mood) [1] :
Depressed mood: For children and adolescents, this can also be an irritable
mood
Diminished interest or loss of pleasure in almost all activities (anhedonia)
Significant weight change or appetite disturbance: For children, this can be
failure to achieve expected weight gain
Sleep disturbance (insomnia or hypersomnia)
Psychomotor agitation or retardation
Fatigue or loss of energy
Feelings of worthlessness
Diminished ability to think or concentrate; indecisiveness
Recurrent thoughts of death, recurrent suicidal ideation without a specific
plan, or a suicide attempt or specific plan for committing suicide
Diagnosis

Screening instruments

Self-report screening instruments for depression include the following:

Patient Health Questionnaire-9 (PHQ-9): A 9-item depression scale; each item is

scored from 0-3, providing a 0-27 severity score.
Beck Depression Inventory (BDI) or the Beck Depression Inventory-II (BDI-II): 21-
question symptom-rating scales providing a 0-63 severity score.
BDI for primary care: A 7-question scale adapted from the BDI.
Zung Self-Rating Depression Scale: A 20-item survey.
Center for Epidemiologic Studies-Depression Scale (CES-D): A 20-item instrument
that allows patients to evaluate their feelings, behavior, and outlook from the previous
week.
Laboratory studies

No diagnostic laboratory tests are available to diagnose major depressive disorder,

but focused laboratory studies may be useful to exclude potential medical illnesses
that may present as major depressive disorder.

Management

In all patient populations, the combination of medication and psychotherapy

generally provides the quickest and most sustained response. [2, 3]

Pharmacotherapy

Drugs used for treatment of depression include the following:

Selective serotonin reuptake inhibitors (SSRIs)

Serotonin/norepinephrine reuptake inhibitors (SNRIs)
Atypical antidepressants
Tricyclic antidepressants (TCAs)
Monoamine oxidase inhibitors (MAOIs)
St. John's wort ( Hypericum perforatum)

Psychotherapy
Evidence-based psychotherapeutic treatments for adults with major depressive
disorder include the following: [4]
Interpersonal psychotherapy (IPT)
Cognitive-behavioral therapy (CBT)
Problem-solving therapy (PST)
Behavioral activation (BA)/contingency management
Evidence-based psychotherapeutic treatments for children and adolescents with
major depressive disorder include the following: [5]
Interpersonal psychotherapy (IPT)
Cognitive-behavioral therapy (CBT)
Behavior therapy (BT)

In mild cases, psychosocial interventions are often recommended as first-

line treatments. The American Psychiatric Association (APA) guideline
supports this approach but notes that combining psychotherapy with
antidepressant medication may be more appropriate for patients with
moderate to severe major depressive disorder. [6]
Electroconvulsive therapy
Electroconvulsive therapy (ECT) is a highly effective treatment for depression. The
indications for ECT include the following:
Need for a rapid antidepressant response
Failure of drug therapies
 History of good response to ECT
Patient preference
High risk of suicide
High risk of medical morbidity and mortality

Stimulation techniques

Transcranial magnetic stimulation (TMS) is approved by the FDA for treatment-

resistant major depression.

Vagus nerve stimulation (VNS) has been approved by the FDA for use in adult
patients who have failed to respond to at least 4 adequate medication and/or ECT
treatment regimens. The stimulation device requires surgical implantation.

Background

As many as two thirds of people with depression do not realize that they
have a treatable illness and therefore do not seek professional help.

In the primary care setting, where many of these patients first seek treatment, the
presenting complaints often can be somatic, such as fatigue, headache, abdominal
distress, or sleep problems. (See Presentation.)

The American Psychiatric Associations Diagnostic Statistical Manual of Mental

Disorders, Fifth Edition (DSM-5) [1] classifies the depressive disorders as disruptive
mood dysregulation disorder, major depressive disorder (including major depressive
episode), persistent depressive disorder (dysthymia), premenstrual dysphoric
disorder, and depressive disorder due to another medical condition. In addition,
depressive disorders may be further categorized by specifiers that include
peripartum onset, seasonal pattern, melancholic features, mood-congruent or mood-
incongruent psychotic features, anxious distress, and catatonia. The common
feature of the depressive disorders is the presence of sad, empty, or irritable mood,
accompanied by somatic and cognitive changes that significantly affect the
individuals capacity to function. What differs among them are issues of duration,
timing, or presumed etiology.
Pathophysiology

The underlying pathophysiology of major depressive disorder has not been

clearly defined. Current evidence points to a complex interaction between
neurotransmitter availability and receptor regulation and sensitivity
underlying the affective symptoms.

Clinical and preclinical trials suggest a disturbance in central nervous

system serotonin (5-HT) activity as an important factor. Other
neurotransmitters implicated include norepinephrine (NE), dopamine (DA),
glutamate, and brain-derived neurotrophic factor (BDNF).

The role of CNS 5-HT activity in the pathophysiology of major depressive

disorder is suggested by the therapeutic efficacy of selective serotonin
reuptake inhibitors (SSRIs). In addition, studies have shown that an acute,
transient relapse of depressive symptoms can be produced in research
subjects in remission using tryptophan depletion, which causes a
temporary reduction in CNS 5-HT levels. However, the effect of SSRIs on
5HT reuptake is immediate, but the antidepressant effect requires exposure
of several weeks' duration.

Vascular lesions may contribute to depression by disrupting the neural

networks involved in emotion regulationin particular, frontostriatal
pathways that link the dorsolateral prefrontal cortex, orbitofrontal cortex,
anterior cingulate, and dorsal cingulate. [8] Other components of limbic
circuitry, in particular the hippocampus and amygdala, have been
implicated in depression.

In one study, positron emission tomographic (PET) images showed

abnormally diminished activity in an area of the prefrontal cortex in patients
with unipolar depression and bipolar depression. This region is related to
emotional response and has widespread connections with other areas of
the brain, including the areas that appear to be responsible for the
regulation of DA, noradrenaline (locus ceruleus), and 5-HT (raphe nuclei).
Etiology

The specific cause of major depressive disorder is not known. As with most
psychiatric disorders, major depressive disorder appears to be a
multifactorial and heterogeneous group of disorders involving both genetic
and environmental factors.

Genetics

Genetic factors play an important role in the development of major depression.

Evidence from twin studies suggests that major depression has a concordance of
40-50%. First-degree relatives of depressed individuals are about 3 times as likely to
develop depression as the general population; however, depression can occur in
people without family histories of depression, as well.

Stressors

Although major depressive disorder can arise without any precipitating stressors,
stress and interpersonal losses certainly increase risk. For example, loss of a parent
before the age of 10 years increases the risk of later depression. Cognitive-
behavioral models of depression posit that negative cognitions and underlying all-or-
nothing schemata contribute to and perpetuate depressed mood. [26]

Chronic pain, medical illness, and psychosocial stress can also play a role in major
depressive disorder. Older adults may find medical illness psychologically
distressing, and these illnesses may lead to increased disability, decreased
independence, and disruption of social networks. [30] Chronic aversive symptoms such
as pain associated with chronic medical illness may disrupt sleep and other
biorhythms leading to depression.

Other psychosocial risk factors for depression in late life include the following [31] :

Impaired social supports

Caregiver burden
Loneliness
Bereavement
Negative life events

Prognosis
Major depressive disorder has significant potential morbidity and mortality,
contributing as it does to suicide, incidence and adverse outcomes of
medical illness, disruption in interpersonal relationships, substance abuse,
and lost work time. With appropriate treatment, 70-80% of individuals with
major depressive disorder can achieve a significant reduction in symptoms,
although as many as 50% of patients may not respond to the initial
treatment trial.

Twenty percent of individuals with major depressive disorder untreated at 1

year will continue to meet criteria for the diagnosis, whereas an additional
40% will have a partial remission. Pretreatment irritability and psychotic
symptoms may be associated with poorer outcomes. Partial remission
and/or a history of prior chronic major depressive episodes are risk factors
for recurrent episodes and treatment resistance.

A study of first-episode psychotic depression by Tohen et al found that most

patients achieved syndromal remission (86%) and recovery (84%);
however, only 35% recovered functionally. Earlier syndromal recovery was
associated with subacute onset, lower initial depression scores, and lack of
mood-incongruent psychotic features. Within 2 years, almost half the
patients experienced new episodes. In 41% of patients, the diagnosis was
changed, usually to bipolar or schizoaffective disorders. [56]

Clinical Presentation

History

Patients with major depressive disorder may not initially present with a
complaint of low mood, anhedonia, or other typical symptoms. In the
primary care setting, where many of these patients first seek treatment, the
presenting complaints often can be somatic (e.g., fatigue, headache,
abdominal distress, or change in weight). Patients may complain more of
irritability or difficulty concentrating than of sadness or low mood.
Children with major depressive disorder may also present with initially
misleading symptoms such as irritability, decline in school performance, or
social withdrawal. Elderly persons may present with confusion or a general
decline in functioning; they also experience more somatic complaints,
cognitive symptoms, and fewer complaints of sad or dysphoric mood.

Familial, social, and environmental factors

Depression can be familial. Thus, a thorough family history is quite important.

Familial, social, and environmental factors appear to play significant roles in the
course of depressive illness in children and youths, even in preschool children.

Dysphoric mood

A dysphoric mood state may be expressed by patients as sadness, heaviness,

numbness, or sometimes irritability and mood swings. They often report a loss of
interest or pleasure in their usual activities, difficulty concentrating, or loss of energy
and motivation. Their thinking is often negative, frequently with feelings of
worthlessness, hopelessness, or helplessness.

Psychosis

Patients with major depressive disorder commonly show ruminative

thinking. Nevertheless, it is important to evaluate each patient for evidence
of psychotic symptoms, because this affects initial management.

Psychosis, when it occurs in the context of unipolar depression, is usually

congruent in its content with the patient's mood state; for example, the
patient may experience delusions of worthlessness or some progressive
physical decline.

Symptoms of psychosis should prompt a careful history evaluation to rule

out any of the following:

Bipolar affective disorder

Schizophrenia
Schizoaffective disorder
Substance abuse
 Organic brain syndrome
Physical Examination

No physical findings are specific to major depressive disorder; instead, the

diagnosis is based on the history and the mental status examination.
Nevertheless, a complete mental health evaluation should always include a
medical evaluation to rule out organic conditions that might imitate a
depressive disorder. Most of these fall into the following major general
categories:

Infection
Medication
Endocrine disorder
Tumor
Neurologic disorder

Appearance and affect

Most patients with major depressive disorder present with a normal appearance. In
patients with more severe symptoms, a decline in grooming and hygiene can be
observed, as well as a change in weight. Patients may show psychomotor
retardation, which manifests as a slowing or loss of spontaneous movement and
reactivity, as well as demonstrate a flattening or loss of reactivity in the patient's
affect (i.e., emotional expression). Psychomotor agitation or restlessness can also be
observed in some patients with major depressive disorder.

Speech

Speech may be normal, slow, monotonic, or lacking in spontaneity and content.

Pressured speech should suggest anxiety or mania, whereas disorganized speech
should prompt an evaluation for psychosis. Racing thoughts could also be an
indication of anxiety, mania, or hypomania.

Major Depressive Disorder

The specific DSM-5 criteria for major depressive disorder are outlined
below.
At least 5 of the following symptoms have to have been present during the
same 2-week period (and at least 1 of the symptoms must be diminished
interest/pleasure or depressed mood) [1] :

Depressed mood: For children and adolescents, this can also be an

irritable mood
Diminished interest or loss of pleasure in almost all activities
(anhedonia)
Significant weight change or appetite disturbance: For children, this
can be failure to achieve expected weight gain
Sleep disturbance (insomnia or hypersomnia)
Psychomotor agitation or retardation
Fatigue or loss of energy
Feelings of worthlessness
Diminished ability to think or concentrate; indecisiveness
Recurrent thoughts of death, recurrent suicidal ideation without a
specific plan, or a suicide attempt or specific plan for committing
suicide

The symptoms cause significant distress or impairment in social, occupational or

other important areas of functioning.

The symptoms are not attributable to the physiological effects of a substance (e.g., a
drug of abuse, a medication) or another medical condition.

The disturbance is not better explained by a persistent schizoaffective disorder,

schizophrenia, delusional disorder, or other specified or unspecified schizophrenia
spectrum and other psychotic disorders

There has never been a manic episode or a hypomanic episode

Depressive disorders can be rated as mild, moderate, or severe. The

disorder can also occur with psychotic symptoms, which can be mood
congruent or incongruent. Depressive disorders can be determined to be in
full or partial remission.
Depression with Anxious Distress

Anxious distress is defined as the presence of at least 2 of the following

symptoms[1] :

Feeling keyed up or tense

Feeling unusually restless
Difficulty concentrating because of worry
Fear that something awful may happen
Feeling of potential loss of control

Severity is further specified as:

Mild: Two symptoms

Moderate: Three symptoms
Moderate-severe: Four or five symptoms
Severe: Four or five symptoms with motor agitation

High levels of anxiety are associated with higher suicide risk, longer
duration of illness and greater likelihood of nonresponse to treatment.

Depression With Melancholic Features

In depression with melancholic features, either a loss of pleasure in almost

all activities or a lack of reactivity to usually pleasurable stimuli is present.
Additionally, at least 3 of the following are required:

A depressed mood that is distinctly different from the kind that is felt
when a loved one is deceased
Depression that is worse in the morning
Waking up 2 hours earlier than usual
Observable psychomotor retardation or agitation
Significant weight loss or anorexia
Excessive or inappropriate guilt
According to DSM-5, this subtype is applied only when there is a near-
complete absence of the capacity for pleasure, not merely a diminution. A
depressed mood that is described as merely more severe, longer lasting or
present without a reason is not considered a distinct quality. Melancholic
features are more frequent in inpatients and are less likely to occur in
milder major depressive episodes. They are also more likely to be
comorbid with psychotic features.

Depression With Catatonia

The DSM-5 criteria for diagnosis of depressive episodes with catatonia

requires the presence of 3 or more of 12 psychomotor features during most
of the episode: [1]

Stupor
Catalepsy
Waxy flexibility
Mutism
Negativism
Posturing
Mannerism
Stereotypy
Agitation, not influenced by external stimuli
Grimacing
Echolalia
Echopraxia

Atypical Depression

An episode of depression may be identified as having atypical features.

Characteristics of this subtype are mood reactivity and exclusion of
melancholic and catatonic subtypes in addition to 2 or more of the following
for a period of at least 2 weeks:

Increased appetite or significant weight gain

Increased sleep
Feelings of heaviness in arms or sensitivities of the legs that extend
far beyond the mood disturbance episodes and result in significant
impairment in social or occupational functioning
 A pattern of longstanding interpersonal rejection sensitivity that
extends far beyond the mood disturbance episodes and results in
significant impairment in social or occupational functioning

Seasonal Affective Disorder

About 70% of depressed people feel worse during the winter and better
during the summer. To meet the DSM-5 diagnostic criteria [1] for major
depressive disorder with seasonal pattern, depression should be present
only at a specific time of year (e.g., in the fall or winter) and full remission
occurs at a characteristic time of year (e.g., spring). An individual should
demonstrate at least 2 episodes of depressive disturbance in the previous
2 years, and seasonal episodes should substantially outnumber
nonseasonal episodes. Patients with seasonal affective disorder are more
likely to report atypical symptoms, such as hypersomnia, increased
appetite, and a craving for carbohydrates.

Major Depressive Disorder with Psychotic Features

The presentation of severe major depressive disorder may include

psychotic features. Psychotic features include delusions and hallucination
and may be mood congruent or mood incongruent. Mood-congruent
psychoses are often consistent with classic depressive themes, such as
personal inadequacy, guilt, disease, or deserved punishment. Mood-
incongruent psychoses are not consistent with these typical themes but
may also occur in depression.

Major depressive disorder with psychotic features is considered a

psychiatric emergency. Patients may require psychiatric hospitalization.

Other Specificed Depressive Disorders

The DSM-5 includes a category of disorders with features of depression

that do not meet criteria for a specific depressive disorder. Examples
include the following: [1]

Recurrent brief depression

Short duration depressive episode
Depressive episode with insufficient symptoms
Consult the DSM-5 for further details regarding the diagnostic criteria for
other specified depressive disorders

Metabolic Depression

Several studies report an association between metabolic syndrome and

depression. Vogelzangs et al suggest that later in life, waist circumference
and not metabolic syndrome can predict onset of depression. Specifically,
the larger the waistline, the higher the incidence of depression. [89] However,
longitudinal studies have also shown that depression predicts subsequent
obesity and centripetal obesity, likely because of poor diet, lack of exercise,
and psychobiologic changes such as increased cortisol levels.

On the other hand, individuals with depression who have metabolic

syndrome may simply be more likely to have persistent or recurrent
depression. Thus, depression with metabolic abnormalities could be
labeled metabolic depression, a possible chronic subtype of depression.

Cultural Influences on Expression of Depression

Cultural influences on the presentation of depression can be significant.

The practitioner should be aware of differences in the expression of
psychological distress in patients from other countries or cultures.

Culturally distinctive experiences (e.g., fear of being hexed or bewitched;

experience of visitations from the dead) should be distinguished from actual
hallucinations or delusions that may be part of a major depressive episode
with psychotic features.

Suicidal Ideation

Patients with depression should be assessed for suicidal ideation,

especially if agitation is present. When a patient has contemplated or
attempted suicide, the burden is on the health care provider to directly
explore the situation with the patient in as much detail as possible to
determine the current presence of suicidal ideation as well as accessible
means and plans. Discussing these is the most important step clinicians
can take in an attempt to prevent suicide in an at-risk patient.

Workup

Approach Considerations

Depression screening tests can be valuable, with the most widely one used
being the Patient Health Questionnaire-9 (PHQ-9). It is important to
understand, however, that the results obtained from the use of any
depression screening or rating scales do not diagnose depression and may
be imperfect in any population, especially in elderly patients.

Screening Tests

The U.S. Preventive Services Task Force (USPSTF) recommends

screening for depression in the general adult population, including older
adults and pregnant and postpartum women. [93] It is important to
understand that the results obtained from the use of any depression rating
scales are imperfect in any population, especially the geriatric population.

The simplest screening test is a single question: Are you depressed? A

pooled analysis found that single-question screening had a specificity of
97% but an overall sensitivity of 32% and, thus, would identify only 3 of
every 10 patients with depression in primary care. [94]

The following 2-question test addresses depressed mood and anhedonia:

During the past month, have you been bothered by feeling down,
depressed, or hopeless?
During the past month, have you been bothered by little interest or
pleasure in doing things?

In a cross-sectional study, these 2 screening questions showed a sensitivity

of 97% and a specificity of 67%. [95]
Diagnostic Considerations

The differential diagnosis for depression includes a wide variety of medical disorders,
such as the following:

Central nervous system diseases (eg, Parkinson disease, dementia, multiple

sclerosis, neoplastic lesions)
Endocrine disorders (eg, hyperthyroidism, hypothyroidism)
Drug-related conditions (eg, cocaine abuse, side effects of some CNS depressants)
Infectious disease (eg, mononucleosis)
Sleep-related disorders

Related psychiatric disorders

Major depressive disorder must be differentiated from dysthymia. Patients with

dysthymia present with low mood for at least 2 years as a primary symptom; they
have insufficient symptoms to meet criteria for major depressive disorder. However,
dysthymia may predate a depressive episode.

Misdiagnosis of bipolar disorder as recurrent unipolar depression may occur if the

clinician does not identify the presence of hypomania between depressive episodes.
This leads to inadequate treatment and, theoretically, could lead to a precipitation of
a hypomanic, manic, or mixed episode.

Patients with anxiety disorders are at higher risk for developing comorbid
depression. In such patients, it is important to identify the anxiety disorder, because
affected individuals often require specific treatment approaches. Commonly
encountered anxiety disorders include the following:

Generalized anxiety disorder

Obsessive-compulsive disorder
Panic disorder
Phobic disorders
Posttraumatic stress disorder