Major Depression

Ms. W

Ms. W is a 47-year-old, married woman with two adolescent children. She presented with symptoms of depressed mood, loss of interest and pleasure, poor concentration, hypersomnia, feelings of worthlessness, and inappropriate guilt. Ms. W denied symptoms of hypomania/mania in the past or currently. Screening with the Mood Disorders Questionnaire (MDQ) for bipolar disorder was negative. Her symptoms met diagnostic criteria for major depression. She has experienced three prior episodes since her late 20s with a full recovery between episodes. The current
episode began 6 weeks ago. She initially refused medication because she did not like the side effects she experienced while on previous trials of antidepressants (ADs).

It is estimated that up to 14 million US adults will suffer from a major depression in any given year.¹ The American Psychiatric Association estimates the lifetime risk for experiencing a major depressive episode is 10% to 25% for women and 5% to 12% for men. This disorder is three times more likely to occur if an individual has a first-degree relative with depression. The risk is two to three times higher in females than males but this gap may be narrowing more recently with a higher number of young males experiencing depression. Depressive disorders are prevalent, debilitating, pose a higher risk for suicide, are associated with an increased risk of medical (e.g., cardiac) and other psychiatric (e.g., anxiety-related disorders) comorbidities, and are prone to recurrence. Further, a substantial proportion of individuals are insufficiently responsive to standard therapeutic approaches. Clinically meaningful levels of depression can occur in a variety of disorders, including:

Major depressive disorder (single or recurrent, with or without melancholia, with or without psychosis, seasonal pattern)
Bipolar disorder (depressed or mixed episodes)
Dysthymic disorder (less severe, more chronic depressive symptoms)
Cyclothymic disorder (fluctuation between dysthymic and hypomanic episodes)
Other psychiatric disorders (e.g., schizoaffective disorder, depressed type)
Secondary to a general medical condition (e.g., dementia with depression)
Substance-induced mood disorder (e.g., stimulant withdrawal)

DIFFERENTIAL DIAGNOSIS

An important differential diagnosis involves distinguishing unipolar major depression from bipolar disorder, depressed episode. This may be difficult as the depressed phase of both disorders is similar and one
or more depressions often precede the development of the characteristic hypomanic or manic episodes that define bipolar disorder. Nevertheless, it is critically important to clarify the diagnosis early in the course because treatment approaches are very different. The use of screening assessments such as the MDQ and the procurement of collateral sources of information can be helpful in this context (see Chapter 8). Another important differential issue is the presence of psychotic symptoms, which usually requires combining standard antidepressants (ADs) plus an antipsychotic. Finally, some patients experience recurrent depression that coincideswith particular seasons. Seasonal affective disorder (SAD) often presents with atypical symptoms (e.g., hypersomnia, carbohydrate craving, and weight gain) and bright light therapy (BLT) may be effective (usually as an adjunct) for standard antidepressant treatments, particularly with the fall-onset pattern.

Regardless of the diagnosis, significant depressions usually involve disruption in mood, vegetative functions, and cognition (see Table 2-1). To meet diagnostic criteria, a major depressive episode should present with mood changes and associated vegetative and cognitive symptoms that persist for at least 2 weeks. Depression may be difficult to recognize given the myriad of presentations that occur across the life cycle. Table 2-2 lists some of the more common issues that characterize depression in various age-groups.

Treatment-Resistant Depression

Treatment-resistant depression (TRD) is variably defined but a minimum criteria usually involves the persistence of significant depression despite two adequate treatment trials (e.g., two antidepressant trials, a cognitive behavioral therapy [CBT] trial and one
antidepressant trial). In this context, critical issues to consider are accuracy of diagnosis, adequacy of treatment (e.g., dose, number of sessions, duration), and patient adherence. On the basis of the results of the NIMH-sponsored Sequenced Treatment Alternatives to Relieve Depression (STAR^*D) study, after two failed adequate trials the chances of achieving remission fall into the 10% to 20% range. Therefore, there is a significant need to develop more effective strategies in this population.

TABLE 2-1 Symptoms of Depression

Mood
▪	Depressed mood
▪	Diminished interest or pleasure (anhedonia)
Vegetative functions
▪	Weight or appetite change
▪	Sleep disturbance
▪	Psychomotor agitation or retardation
▪	Fatigue or loss of energy
Cognition
▪	Worthlessness/guilt/psychosis
▪	Diminished concentration or indecisiveness
▪	Hopelessness
▪	Suicidal ideation/intent/behavior
(Adapted from Janicak PG, Davis JM, Preskorn SH, et al. Principles and practice of psychopharmacotherapy, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2006.)

An important complication with unrecognized, inadequately treated, or persistent TRD is the increased risk of suicide which is the ninth leading cause of death in the United States for all ages and the third leading cause in adolescents and young adults. Depression contributes to 70% of suicides with a 15% mortality rate associated with untreated, recurrent major depression. Therefore, the need to assess for suicidal risk and to monitor carefully whenever a treatment intervention is initiated, altered, or stopped is paramount to prevent an otherwise
unnecessary tragedy. While controversial, the U.S. Food and Drug Administration (FDA)-mandated black box warning for ADs to potentially increase suicidal ideation or behavior in pediatric, adolescent, and young adult populations does underscore the need to monitor these patients very carefully when these agents are prescribed.

TABLE 2-2 Common Issues that Characterize Depression in Different Age-Groups

Prepubertal children
▪	Somatic complaints
▪	Agitation
▪	Anxiety
▪	Phobias
Adolescents
▪	Substance abuse
▪	Antisocial behavior
▪	Restlessness
▪	Truancy and other school difficulties
▪	Promiscuity
▪	Rejection hypersensitivity
▪	Poor hygiene
Adults
▪	Somatic complaints (particularly cardiovascular, gastrointestinal, genitourinary)
▪	Low back pain or other orthopedic symptoms
Elderly
▪	Cognitive deficits
▪	Pseudodementia
▪	Somatic complaints
(Adapted from Janicak PG, Davis JM, Preskorn SH, et al. Principles and practice of psychopharmacotherapy, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2006.)

NEUROBIOLOGY OF DEPRESSION

Our understanding of the neurobiology of depression is closely linked to the effects of various treatments (i.e., medications, psychotherapy, device-based treatments) on the central nervous system (CNS). Approaches to elucidating the mechanism subserving mood disorders involve multiple areas, including:

Genetic risk is supported by family, twin, and adoption studies. Further, interactions with the environment and genetics appear critical to the development of depressive episodes. From another perspective, pharmacogenetics may soon help to predict chances of responding, dose requirements, and predilection to adverse effects (AEs).
Neuroanatomic localization of dysregulated neural circuits is supported by imaging and postmortem studies.
Neurotransmitter systems implicated in depression include the serotonin, nonadrenergic, and dopaminergic systems. Other systems also considered include the cholinergic, glutamatergic, γ-aminobutyric acid (GABA)ergic, histaminergic, and opioid systems.
Neuroendocrine system may also play a role. For example, elevated cortisol levels due to dysregulation in the hypothalamic-pituitary axis (HPA) is an area of study regarding biomarkers for depression as well as novel treatment approaches (e.g., corticotropin-releasing hormone [CRH₁] antagonists).
Other hypotheses involve disruption in electrolytes (e.g., K⁺); biological rhythms (e.g., SAD; and the immune system (e.g., proinflammatory cytokines).

TREATMENT OF MAJOR DEPRESSION

Various treatment approaches or their combination have demonstrated benefit for depression. They include:

Pharmacotherapy
- ADs
- Anxiolytics
- Mood stabilizers
- Antipsychotics (APs)
Device-based therapy
- Electroconvulsive therapy (ECT)
- Vagus nerve stimulation (VNS)
- Possibly:
  - Bright light therapy
  - Transcranial magnetic stimulation (TMS)
  - Deep brain stimulation (DBS)
Psychotherapy
- CBT
- Interpersonal psychotherapy (IPT)
- Marital/family counseling
- Group therapy

We will discuss each as a single approach and then explore the data to support their sequencing or combined use.

Pharmacotherapy for Major Depression

ADs can be divided into first- or second-generation agents (see Table 2-3) and further categorized by their putative mechanism of action (see Table 2-4).

On the basis of a balance between efficacy and safety/tolerability, the selective serotonin reuptake inhibitors (SSRIs) have become the first-line treatment approach for most patients. Factors that may dictate a specific SSRI or an alternate agent include a prior personal or family history of benefit to a certain antidepressant, susceptibility to certain AEs (e.g., sexual dysfunction), presence of comorbid psychiatric/medical disorders, potential for adverse drug interactions, and patient preference. Two critical issues to assure adequacy of an AD trial are the use of maximally tolerated doses (e.g., 40 mg of citalopram) for an adequate duration (e.g., 6 to 12 weeks). Increasingly, the goal is to achieve remission (i.e., minimal symptoms, good functioning) rather than response, usually defined as at least a 50% reduction in symptom severity. If adequacy and adherence are assured but benefit falls short of this target, then the next strategy involves switching to an alternate agent (within or out of class) particularly when response is absent to minimal. When there is a partial but insufficient response, an alternative approach is to augment the effect of the first treatment. This may involve combining medications or adding psychotherapy (e.g., CBT, IPT). In the context of the switching strategy, the results of the STAR^*D study for unipolar major depression indicate that an alternate SSRI (i.e., sertraline), an agent working through the catecholamine system (i.e., bupropion sustained release [SR]), a dual-acting agent (i.e., both serotonin and norepinephrine [NE] reuptake blockade [i.e., venlafaxine XR]), or CBT all produce similar levels of remission. Alternatively, augmenting with bupropion SR, buspirone (i.e., 5-hydroxytryptamine [HT]1A agonist), or CBT were also equally effective.² Another strategy, recently supported by clinical trials and increasingly employed in practice, is the addition of lower doses of a second-generation antipsychotic (SGA) (e.g., aripiprazole, quetiapine, risperidone) to augment the primary AD even in the absence of psychotic symptoms. In this context, aripiprazole is the first agent to receive FDA approval as an add-on treatment for major depressive disorder.

TABLE 2-3 Medications for Treatment of Depression

*Class/Generic Name*	*Trade Name*	*Usual Daily Dosage (mg/d)*
FIRST-GENERATION AGENTS
TCA
Amitriptyline	Elavil	75-300
Clomipramine	Anafranil	100-250
Desipramine	Norpramine	75-300
Doxepin	Sinequan	75-300
Impramine	Tofranil	75-300
Nortriptyline	Pamelor	75-300
Protriptyline	Vivactil	20-60
Trimipramine	Surmontil	75-300
MAOI
Isocarboxazid	Marplan	40-60
Phenelzine	Nardil	30-90
Selegiline^a	Emsam	20 mg/20 cm² patch
Tranylcypromine	Parnate	30-60
SECOND-GENERATION AGENTS
SSRI
Citalopram	Celexa	20-40
Escitalopram	Lexapro	10-20
Fluoxetine	Prozac	10-60
Fluvoxamine^b	Luvox	100-300
Paroxetine	Paxil	10-50
Sertraline	Zoloft	50-200
NRI
Atomoxetine^b		60-120
DSNRI
Duloxetine	Cymbalta	30-60
Venlafaxine	Effexor	75-375
N-Desvenlafaxine	Pristiq	50-100
Aminoketone
Bupropion	Wellbutrin	150-450
Tetracyclic
Amoxapine	Ascendin	200-600
Maprotiline	Ludiomil	75-225
Mirtazapine	Remeron	15-45
Triazolopyridine
Nefazodone^c	Serzone	100-600
Trazodone	Desyrel	150-600
^aTransdermal system approved for depression. ^bNot approved by the U.S. Food and Drug Administration for depression. ^cSerzone no longer available; generic form of nefazodone still available.
SSRI, selective serotonin reuptake inhibitor; SNRI, selective norepinephrine reuptake inhibitor; DSNRI, dual serotonin norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; MAOI, monoamine oxidase inhibitor.
(Adapted from Janicak PG, Davis JM, Preskorn SH, et al. Principles and practice of psychopharmacotherapy, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2006.)

TABLE 2-4 Major Classes of Antidepressants Defined by Putative Mechanism of Action

5-HT and NE reuptake inhibition
▪	Tricyclic antidepressants (TCAs)
▪	Venlafaxine
▪	Duloxetine
5-HT reuptake inhibition
▪	Serotonin selective reuptake inhibitors (SSRIs)
5-HT₂ receptor blockers and SE uptake inhibition
▪	Nefazodone
Alternate 5-HT and NE actions
▪	Mirtazapine
NE reuptake inhibition
▪	Atomoxetine
DA and NE reuptake inhibition
▪	Bupropion
Monoamine oxidase inhibitors (MAOIs)
▪	Phenelzine
▪	Tranylcypromine
▪	Selegiline TS
HT, hydroxytryptamine; NE, norepinephrine; DA, dopamine; TS, transdermal system.