Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

51. Major Depressive Disorder

Christian J. Teter, Judith C. Kando, and Barbara G. Wells


 Images Extensive treatment guidelines are available to assist in the treatment of major depressive disorder, including medication management. Clinicians treating individuals with major depressive disorder should be familiar with these guidelines.

 Images When evaluating a patient for the presence of depression, it is essential to rule out medical causes of depression and drug-induced depression.

 Images The goal of pharmacologic treatment of depression is the resolution of current symptoms (i.e., remission) and the prevention of further episodes of depression (i.e., relapse or recurrence).

 Images When counseling patients with depression who are receiving antidepressant medications, the patient should be informed that adverse effects might occur immediately, while resolution of symptoms may take 2 to 4 weeks or longer. Adherence to the treatment plan is essential to a successful outcome, and tools to help increase medication adherence should be discussed with each patient.

 Images Antidepressants are generally considered equally efficacious in groups of patients with major depressive disorder. Therefore, other factors, such as age, side effect profile, and past history of response, are used to guide the selection of antidepressants.

 Images When determining if a patient has been nonresponsive to a particular pharmacotherapeutic intervention, it must be determined whether the patient has received an adequate dose for an adequate duration and whether the patient has been medication adherent.

 Images Pharmacogenetic tests (e.g., the FDA-approved AmpliChip to evaluate CYP2D6 and CYP2C19 polymorphisms) are now commercially available. However, there are no standard or well-accepted recommendations for the use of pharmacogenetic testing as it relates to antidepressant treatment of major depressive disorder.

 Images When evaluating response to an antidepressant, in addition to target signs and symptoms, the clinician must consider quality-of-life issues, such as role, social, and occupational functioning. In addition, the tolerability of the agent should be assessed because the occurrence of side effects may lead to medication nonadherence, especially given the chronicity of the disease and need for long-term medication management.

A diagnosis of major depressive disorder (MDD) is given when an individual experiences one or more major depressive episodes without a history of manic, mixed, or hypomanic episodes. A major depressive episode is defined by the criteria listed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR).1 Depression is associated with significant functional disability, morbidity, and mortality. Newer generations of antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), are effective and better tolerated than older agents, such as the tricyclic antidepressants (TCAs) and the monoamine oxidase inhibitors (MAOIs). In addition, substantial efforts have been undertaken to improve the ability of clinicians to recognize and appropriately treat the signs and symptoms of depression. This chapter focuses exclusively on the diagnosis and treatment of MDD.

Images In the absence of well-accepted evidence-based medicine for the medication management of MDD, the reader is referred to the Practice Guideline for the Treatment of Patients with Major Depressive Disorder, which is available at This extensive document (now available in its third iteration) is a practical guide to the management of depression based on the best available data as well as clinical consensus.2


The true prevalence of depressive disorders in the United States is unknown. The National Comorbidity Survey Replication found that 16.2% of the population studied had a history of MDD in their lifetime, and more than 6.6% had an episode within the past 12 months.3 Women have a higher risk of depression than men from early adolescence until their mid-50s, with a lifetime rate that is 1.7 to 2.7 times greater.4 Although depression can occur at any age, adults 18 to 29 years of age experience the highest rates of major depression during any given year.3 The estimated lifetime prevalence of major depression in individuals aged 65 to 80 recently was reported to be 20.4% in women and 9.6% in men.5 Depressive disorders are common during adolescence, with comorbid substance abuse, suicide attempts, and deaths occurring frequently in these young patients.6,7 Depressive disorders and suicide tend to occur within families. For example, approximately 8% to 18% of patients with major depression have at least one first-degree relative (father, mother, brother, or sister) with a history of depression, compared with 5.6% of the first-degree relatives of those without depression.8 Furthermore, first-degree relatives of patients with depression are 1.5 to 3 times more likely to develop depression than normal controls.1,8,9 A recent meta-analysis found that the heritability of liability for major depression was 37%, whereas the remaining 63% of the variance in liability was due to individual-specific environment.10 Therefore, MDD is relatively common, occurs more frequently in women than in men, and prevalence is influenced by both genetic and environmental factors.


The etiology of depressive disorders is too complex to be totally explained by a single social, developmental, or biologic theory. Several factors appear to work together to cause or precipitate depressive disorders. The symptoms reported by patients with MDD consistently reflect changes in brain monoamine neurotransmitters (NTs), specifically norepinephrine (NE), serotonin (5-HT), and dopamine (DA).1113 See Figure 51-1 for a visual explanation of how these monoamine NTs are regulated at the level of the neuron and within the synapse.


FIGURE 51-1 Monoamine neurotransmitter (NT) regulation at the neuronal level. NTs carry messages between cells. Each NT generally binds to a specific receptor, and this coupling initiates a cascade of events. NTs are reabsorbed back into nerve cells by reuptake pumps (i.e., transporter molecules) at which point they may be recycled for later use or broken down by enzymes. For their primary mechanism of action, most antidepressants are thought to inhibit the transporter molecules and allow more NT to remain in the synapse. (Data from U.S. Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse, Office of Science Policy and Communications, Science Policy Branch; figure reproduced from the Mind Over Matter educational series.)


Several years before the introduction of antidepressants, the cause of depression was linked to decreased brain levels of the NTs NE, 5-HT, and DA, although the actual cause remains unknown. This biogenic amine hypothesis evolved as a result of several observations made in the early 1950s. It was noted that the antihypertensive drug reserpine depleted neuronal storage granules of NE, 5-HT, and DA and produced clinically significant depression in 15% or more of patients.14

Although the reuptake blockade of monoamines (e.g., NE, DA, and 5-HT) occurs immediately on administration of an antidepressant, the clinical antidepressant effects (i.e., measurable improvement) are generally delayed by weeks.11,15 This delay may be the result of a cascade of events from receptor occupancy to gene transcription.16 This delay in onset of action has caused researchers to focus on the adaptive changes induced by antidepressants.12Accordingly, theories that focus on adaptive (or chronic) changes in amine receptor systems have emerged. In the mid-1970s, it was recognized that chronic, but not acute, administration of antidepressants to animals caused desensitization of NE-stimulated cyclic adenosine monophosphate synthesis. In fact, for most antidepressants, downregulation of β-adrenergic receptors accompanies this desensitization.17 Studies of many antidepressants have demonstrated that either desensitization or downregulation of NE receptors corresponds to a clinically relevant time course for antidepressant effects.11 Other studies have revealed desensitization of presynaptic 5-HT1A autoreceptors following chronic administration of antidepressants.18 Thus, a theory based on changes in receptor sensitivity provides a cogent explanation of the delayed onset of therapeutic response of antidepressant drugs.11 The dysregulation hypothesis incorporates the diversity of antidepressant activity with the adaptive changes occurring in receptor sensitization over several weeks. In this theory, emphasis is placed on a failure of homeostatic regulation of NT systems rather than on absolute increases or decreases in their activities. According to this hypothesis, effective antidepressant agents restore efficient regulation to the dysregulated NT system.19

It is apparent that no single NT theory of depression is adequate. The 5-HT/NE link hypothesis maintains that both the serotonergic and noradrenergic systems are involved in an antidepressant response.17This hypothesis is also consistent with the rationale of the postsynaptic alteration theory of depression, which emphasizes the importance of β-adrenergic receptor downregulation for achieving an antidepressant effect.17 Furthermore, both serotonergic and noradrenergic medications downregulate β-adrenergic receptors, and there is a link between 5-HT and NE.17 This implies that medications that are effective in the treatment of depression act at both of these NT systems.

Traditional explanations of the biologic basis of depressive disorders have focused largely on NE and 5-HT; however, most of the evidence that coalesced into the biogenic amine hypothesis of depression does not clearly distinguish between NE and DA. There is an abundance of evidence suggesting that DA transmission is decreased in depression and that agents that increase dopaminergic transmission have been found to be effective antidepressants.20 Specifically, studies suggest that increased DA transmission in the mesolimbic pathway accounts for at least part of the mechanism of action of antidepressant medications.20 The mechanisms by which antidepressant drugs alter DA transmission remain unclear, but may be mediated indirectly by primary actions at NE or 5-HT terminals. The complexity of the interaction between 5-HT, NE, and possibly DA is gaining greater appreciation, but a more in-depth understanding of the precise mechanism is needed.

More recent insight into the possible mechanisms underlying depressive disorders comes from studies on brain-derived neurotrophic factor (BDNF). BDNF is a growth factor protein that regulates the differentiation and survival of neurons. A growing body of evidence suggests this process might be disrupted in depressive disorders. More specifically, chronic stress and an associated increase in glucocorticoids such as cortisol may cause a disruption of BDNF expression in the hippocampus. This process may be prevented, or possibly even reversed, by antidepressant medications.21 This is a relatively recent theory, which has not been firmly established. However, if proven valid, it demonstrates that antidepressants may help prevent deleterious effects of chronic stress and depressive symptoms.

Biologic Markers

Investigators continue to search for biologic or pharmacodynamic (PD) markers to assist in the diagnosis and treatment of depressed patients. Although no biologic marker has been discovered, several biologic abnormalities are present in many depressed patients. Approximately 45% to 60% of patients with major depression have a neuroendocrine abnormality, including hypersecretion of cortisol or a lack of cortisol suppression after dexamethasone administration (i.e., a positive dexamethasone suppression test). In fact, it has been suggested that the inability of the brain to suppress the hypothalamic–pituitary–adrenal (HPA) axis and the associated stress response could lead to the pathophysiology and symptoms of depression.22 According to this theory, there is a disruption somewhere in the normal negative feedback system that controls cortisol levels (see Fig. 59-3 for a visual display of this negative feedback system). There are many potential negative consequences of excess circulating cortisol, including disruption in BDNF expression as discussed above.

Unfortunately, the high rate of false-positive and false-negative results associated with neuroendocrine abnormalities in depressed patients limits the usefulness of testing for these markers, and has led to their relative lack of use in clinical practice. However, they still provide a clue as to the potential pathophysiology of depressive disorders, which may lead us to more effective treatment options.


Images When a patient presents with depressive symptoms, it is necessary to investigate the possibility of a contributing medical or drug-induced etiology. All depressed patients should have a complete physical examination, mental status examination, and basic laboratory workup, including a complete blood count with differential, thyroid function tests, and electrolyte determinations, to identify any potential medical problems. A listing of all possible medical conditions associated with depression is beyond the scope of this chapter. The DSM-IV-TR describes a diagnostic category for both “Mood Disorder due to a General Medical Condition” and “Substance-Induced Mood Disorder,”1which are common causative factors for depressive symptoms. For example, up to 40% of patients with certain neurologic disorders (e.g., stroke, Alzheimer’s disease) develop depressive symptoms at some point during the course of their illness.1 Furthermore, individuals experiencing withdrawal from substances of abuse (e.g., cocaine) commonly present with depressive symptoms.23

Table 51-1 lists medications commonly associated with causing or exacerbating depressive symptoms.2,24,25 A complete medication review should be performed because several medications (in addition to those listed in Table 51-1) may contribute to depressive symptoms. Once a medical condition or concomitant medication has been ruled out as the cause of the depressive symptoms, the patient should be evaluated for MDD. According to the DSM-IV-TR, a single major depressive episode is characterized by five or more of the symptoms described in Table 51-2. At least one of the symptoms is depressed mood (often an irritable mood in children or adolescents) or loss of interest or pleasure in nearly all activities.1 These symptoms must have been present nearly every day for at least 2 weeks and must represent a change from the patient’s previous level of functioning. The 5th edition of the Diagnostic and Statistical Manual omits the bereavement exclusion that appears as item D in Table 51-2. Some feel that this omission opens the door to misdiagnosis of normal grief as major depressive disorder. The diagnostic code for major depressive disorder is determined by whether this is a single or recurrent depressive episode, current severity, presence of psychotic features, and remission status. The diagnosis can be followed by specifiers that apply to the current episode. The possible specifiers include anxious distress, mixed features (i.e., presence of some manic/hypomanic features), melancholic features, atypical features, mood-congruent psychotic features, catatonia, peripartum onset, and seasonal pattern. The clinician must consider presenting symptoms, their duration, and the patient’s current level of social, occupational, or other important areas of functioning. Significant stressors or life events may trigger depression in some individuals but not others, and there may be an important precipitant at the beginning of the disorder.1 A patient diagnosed with MDD may have one or more recurrent episodes of major depression during his or her lifetime.

TABLE 51-1 Selected Medications Associated with Drug-Induced Depressive Symptoms


TABLE 51-2 DSM-IV-TR Criteria for Major Depressive Episode


Depression Rating Scales

Instruments to assess the severity of depressive symptoms can be used for both clinical and research purposes. For example, the Montgomery-Åsberg Depression Rating Scale (MADRS) is a clinician-administered scale that is commonly used in drug trials given its sensitivity to change.26 Other depression rating scales are self-administered. For example, the Beck Depression Inventory (BDI) takes only 5 to 10 minutes to complete by the respondent.27 For a more detailed explanation for both of these instruments, as well as other rating scales and evaluation approaches, please refer to eChapter 19.

Emotional Symptoms

A major depressive episode is characterized by a persistent, diminished ability to experience pleasure. A loss of interest and pleasure in usual activities, hobbies, or work is common. Patients appear sad or depressed, and they are often pessimistic and believe that nothing will help them feel better. The presence of feelings of worthlessness or inappropriate guilt may identify patients at risk for suicide.28 Anxiety symptoms are present in almost 90% of depressed outpatients. Patients often have guilt feelings that are unrealistic, and these may reach delusional proportions. Patients may feel that they deserve punishment and may view their present illness as a punishment. A patient suffering from major depression with psychotic features may hear voices (auditory hallucinations) saying that he or she is a bad person and that he or she should commit suicide. Depression with psychotic features may require hospitalization, especially if the patient becomes a danger to self or others.

Physical Symptoms

Physical symptoms often motivate patients, especially the elderly, to seek medical attention. Chronic fatigue is a common complaint, with a decreased ability to perform normal daily tasks. Fatigue often appears worse in the morning and does not improve with rest. Complaints of pain, especially headache, often accompany fatigue.

Sleep disturbances generally present as frequent early morning awakening with difficulty returning to sleep. This may coexist with difficulty falling asleep and frequent nighttime awakening. Less frequently, depressed patients complain of increased sleep (hypersomnia), although they experience daytime exhaustion or fatigue.

Appetite disturbances, including complaints of decreased appetite, often result in substantial weight loss, especially in the elderly.29 Some patients lose 2 lb (0.9 kg) or more per week without dieting. Other patients, especially in the ambulatory setting, may overeat and gain weight, although they actually may not enjoy eating. Some patients exhibit GI complaints, others cardiovascular complaints, especially palpitations. Patients frequently present with a loss of sexual interest or libido.30

Intellectual or Cognitive Symptoms

Intellectual or cognitive symptoms include a decreased ability to concentrate, slowed thinking, and a poor memory for recent events. Patients may appear confused and indecisive. Depression should be considered when cognitive symptoms are present in the elderly.29

Psychomotor Disturbances

Patients may appear noticeably slowed or retarded in physical movements, thought processes, and speech (psychomotor retardation). Conversely, depression may be accompanied by psychomotor agitation, manifesting as purposeless, restless motion (e.g., pacing, wringing of hands, or outbursts of shouting).


The Centers for Disease Control and Prevention lists suicide as the 11th leading cause of death among Americans and the 2nd leading cause of death among 25- to 34-year-olds. In 2006, there were 91 suicides per day in the United States.31 All patients diagnosed with MDD should be assessed for suicidal thoughts. Factors associated with an increased risk for suicide include psychiatric and substance use disorders, adolescence and younger age adults, physical illness, recent stressful life event, childhood trauma, hopelessness, and male gender.32 Those with a higher level of risk have high degrees of suicidal intent and describe more specific plans, in particular, plans that are violent and irreversible.32 It is important to remember that the risk of suicide in those recovering from major depression may increase as they develop the energy and capacity to act on a plan made earlier in a course of illness. Additionally, despite factors to help identify those at greatest risk, it remains very difficult to predict suicidality in any given individual. Therefore, when suicidal intent is suspected, it is important to ask, “Are you thinking about harming or killing yourself?” If the risk is significant, the patient must be referred immediately to an appropriate healthcare professional. Additionally, certain depression rating scales, such as the MADRS discussed above, include questions that target suicidality, which may help identify those patients at risk.

In September 2004, the FDA required manufacturers of antidepressants to add a boxed warning stating that antidepressants increase the risk of suicidal thinking and behavior in short-term studies in children and adolescents with depressive disorders. These risks have become a new source of concern among those treating their patients with antidepressants. In order to help deal with the confusion these risks have caused, experts have recommended the following33:

   1. It is especially important to closely monitor patients for suicidal ideation and behavior at the beginning of treatment and among younger patients.

   2. Discuss the possibility that adverse events may occur, including behavioral agitation or anger, and encourage patients to seek help should this occur.

   3. Deal with the subject of suicide directly.

It is important to note that there is little evidence to suggest that withholding antidepressant treatment decreases the risk of eventual suicide and may actually increase the risk. Furthermore, it may be that longer-term medication is needed for any protective effects against suicidality.33

In May 2007, the FDA released additional requests to the makers of antidepressants that the black box warning regarding suicidality be expanded to include warnings about the increased risk of suicidality (thinking and behavior) in young adults 18 to 24 years of age, during the initial stages of treatment.

In contrast to some of the concerns discussed above, recent evidence suggests that fluoxetine and venlafaxine may be associated with a “protective” effect from suicidality among adults and older patients; however, among youth, the medications lacked this apparent protective effect. It should be noted that Gibbons et al. did not find that fluoxetine and venlafaxine increased the risk of suicidality among youth.34The complex relationships between antidepressant use and suicidality will continue to be explored with the hopes of more unequivocal recommendations.


Desired Outcomes

The goals of treatment are to reduce the symptoms of acute depression, facilitate the patient’s return to a level of functioning like that before the onset of illness, and prevent further episodes of depression. Whether or not to hospitalize the patient is often the first decision that is made in consideration of the patient’s risk of suicide, physical state of health, social support system, and presence of a psychotic depression.

General Approach to Treatment

Images There are three phases of treatment for patients with MDD: (a) the acute phase lasting approximately 6 to 12 weeks in which the goal is remission (i.e., absence of symptoms); (b) the continuation phase lasting 4 to 9 months after remission is achieved, in which the goal is to eliminate residual symptoms or prevent relapse (i.e., return of symptoms within 6 months of remission); and (c) the maintenance phase lasting at least 12 to 36 months in which the goal is to prevent recurrence (i.e., a separate episode of depression).2,35 The risk of recurrence increases as the number of past episodes increases. The duration of antidepressant therapy depends on the risk of recurrence. Some investigators recommend lifelong maintenance therapy for persons at greatest risk for recurrence (persons younger than 40 years of age with two or more prior episodes and persons of any age with three or more prior episodes).2

Images Educating the patient and their support system (e.g., family and friends) regarding the delay in antidepressant effects and the importance of adherence should occur before and during the entire course of treatment. The treatment of MDD generally includes non-pharmacologic and pharmacologic strategies, which are discussed in further detail below.

Nonpharmacologic Therapy

In addition to pharmacologic interventions, psychotherapy should be employed whenever the patient is able and willing to participate. Psychotherapy alone is not recommended for the acute treatment of patients with severe and/or psychotic MDD. However, if the depressive episode is mild to moderate in severity, psychotherapy may be the first-line therapy.36 The effects of psychotherapy and antidepressant medications are considered to be additive. Combined treatment may be advantageous for patients with partial responses to either treatment alone and for those with a chronic course of illness. However, for uncomplicated, nonchronic MDD, combined treatment may provide no unique advantage.36 Although not extensively evaluated, cognitive therapy, behavioral therapy, and interpersonal psychotherapy appear equally effective.36 Maintenance psychotherapy as the sole treatment to prevent recurrence generally is not recommended. Often, medication alone may prevent a depressive recurrence during the maintenance phase.36

Electroconvulsive therapy (ECT) is a safe and effective treatment for certain severe mental illnesses, including MDD. Patients with depression are candidates for ECT when a rapid response is needed, risks of other treatments outweigh potential benefits, there is a history of poor response to antidepressants and a history of good response to ECT, and the patient expresses a preference for ECT.37 Guidelines developed by the American Psychiatric Association (APA) include indications and contraindications for the appropriate use of ECT, procedures for obtaining informed consent, and issues in administering ECT.37 A more recent nonpharmacologic approach is repetitive transcranial magnetic stimulation (rTMS), which has demonstrated efficacy in treating MDD and does not require anesthesia as does ECT.38

Pharmacologic Therapy

Antidepressants can be classified in several ways, including by chemical structure and the presumed mechanism of antidepressant activity. Although the link between the presumed mechanism of drug action and antidepressant response is tenuous, this classification has the advantage of being based on established pharmacology and clearly explains some of the common, but expected, adverse effects. The knowledgeable clinician can use these facts to tailor treatment to individual patient needs and thereby optimize treatment outcome. Currently available antidepressants, including dosing guidance, are provided in Table 51-3.2,15,35,3942

TABLE 51-3 Adult Dosing Guidance for Currently Available Antidepressant Medications



Images Studies have found that antidepressants are of equivalent efficacy in groups of patients when administered in comparable doses. Because one cannot predict which antidepressant will be the most effective in an individual patient, the initial choice is made empirically. Factors that often influence the choice of an antidepressant include the patient’s history of response, history of familial antidepressant response, patient’s concurrent medical illnesses and medications, presenting symptoms (e.g., fatigue as compared with psychomotor agitation), potential for drug–drug interactions, adverse events profile, patient preference, and drug cost. Although the pathophysiology of major depression remains elusive, the clinician can now select from multiple approved drug therapies with presumed different mechanisms of action2 as highlighted in Table 51-4.15,35,4144 Failure to respond to one antidepressant class or one antidepressant drug within a class does not predict a failed response to another drug class or another drug within the same class. Approximately 65% to 70% of patients with varying types of depression improve with drug therapy, compared with 30% to 40% who improve with placebo.

TABLE 51-4 Relative Potencies of Norepinephrine and Serotonin Reuptake Blockade and Selected Side Effect Profile of Antidepressants


Antidepressant Medication Classes

Selective Serotonin Reuptake Inhibitors

The efficacy of SSRIs is superior to placebo and comparable to other classes of antidepressants in treating patients with major depression.2,35 SSRIs are generally chosen as first-line antidepressants due to their safety in overdose and improved tolerability. Furthermore, the decision as to which SSRI to use within the class is typically based on the nuances of each medication, such as differences in drug interaction profile and pharmacokinetic (PK) parameters (e.g., half-life), or due to cost considerations. These concepts will be discussed in greater detail later in this chapter.

Serotonin–Norepinephrine Reuptake Inhibitors (SNRIs)

Tricyclic Antidepressants Although TCAs are effective in treating all depressive subtypes, their use has diminished greatly due to the availability of equally effective therapies that are much safer in overdose and better tolerated. All TCAs potentiate the activity of NE and 5-HT by blocking their reuptake. However, the potency and selectivity of TCAs for the inhibition of reuptake of NE and 5-HT vary greatly among these agents (Table 51-4). Because TCAs affect other receptor systems including the cholinergic, neurologic, and cardiovascular systems, adverse events are reported frequently during TCA therapy.15

Newer-Generation SNRIs Venlafaxine inhibits 5-HT reuptake at low doses, and NE reuptake at higher doses; thus, it is referred to as an SNRI. Desvenlafaxine, the primary active metabolite of venlafaxine, is also an SNRI and has been approved to treat depressive disorders. Duloxetine is an SNRI with both 5-HT and NE reuptake inhibition across all doses. Some studies suggest that the SNRIs may be associated with higher rates of response and remission than other antidepressants; however, most of these studies involved venlafaxine, and not all studies support this conclusion.43 A recent report from the Agency for Healthcare Research and Quality (AHRQ) found that discontinuation rates secondary to lack of efficacy are 34% lower (odds ratio = 0.66, 95% CI = 0.47 to 0.93) for venlafaxine compared with those for SSRIs.45

Mixed Serotonergic Medications (Mixed 5-HT)

Trazodone and nefazodone have dual actions on serotonergic neurons, acting as both 5-HT2 antagonists and 5-HT reuptake inhibitors. They may also enhance 5-HT1A-mediated neurotransmission.15Trazodone blocks α1-adrenergic and histaminergic receptors leading to increased side effects (e.g., dizziness and sedation) that limit its use as an antidepressant. Recently, a longer-acting extended-release preparation of trazodone was approved by the FDA. However, its place in the treatment of MDD is yet to be determined. Nefazodone’s use as an antidepressant has declined as well after reports of hepatic toxicity began to emerge. The FDA-approved nefazodone labeling includes a black box warning describing rare cases of liver failure.46 Trazodone and nefazodone are effective agents in treating major depression; however, both of them carry risks that limit their usefulness as antidepressants.

Recently, vilazodone became the first combination SSRI and 5-HT1A receptor partial agonist to be approved for the treatment of MDD based on two 8-week, placebo-controlled MDD trials.47 Vilazodone’s place in therapy has yet to be determined.

Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)

Bupropion has no appreciable effect on the reuptake of 5-HT, but it inhibits both the NE and DA reuptake pumps.18,44 These pharmacologic properties make bupropion unique among all currently available antidepressants.

Serotonin and α2-Adrenergic Receptor Antagonists

Mirtazapine enhances central noradrenergic and serotonergic activity through the antagonism of central presynaptic α2-adrenergic autoreceptors and heteroreceptors.48 Furthermore, it antagonizes 5-HT2 and 5-HT3 receptors as well as histamine receptors. The antagonism of 5-HT2 and 5-HT3 receptors has been linked to lower anxiety and GI side effects, respectively. Blockade of histamine receptors is associated with the sedative properties of mirtazapine.18

Monoamine Oxidase Inhibitors

MAOIs increase the concentrations of NE, 5-HT, and DA within the neuronal synapse through inhibition of the MAO enzyme. Similar to TCAs, chronic therapy causes changes in receptor sensitivity (i.e., downregulation of β-adrenergic, α-adrenergic, and serotonergic receptors).49 The MAOIs phenelzine and tranylcypromine are nonselective inhibitors of MAO-A and MAO-B. A selegiline transdermal patch was approved by the FDA for treatment of MDD that allows inhibition of MAO-A and MAO-B in the brain, yet has reduced effects on MAO-A in the gut39 (see tyramine interactions with MAOIs below).

Clinical Controversy…

Ketamine is a dissociative anesthetic that has received a great deal of attention in recent years for its apparent rapid efficacy at reducing depressive symptoms in patients with treatment-resistant depression.50Given that ketamine is not FDA-approved for depression, is available only IV, and is a known substance of abuse, use of this drug to treat depressive symptoms will require much more study. Currently, ketamine is an experimental pharmacotherapy for MDD.

Adverse Effects

Selective Serotonin Reuptake Inhibitors

The SSRIs have a low affinity for histaminic, α1-adrenergic, and muscarinic receptors, and therefore they produce fewer anticholinergic and cardiovascular adverse effects than the TCAs, and are not usually associated with significant weight gain.5153 The most common adverse effects, which generally are mild and short-lived, are GI symptoms (e.g., nausea, vomiting, and diarrhea), sexual dysfunction in both males and females, headache, and insomnia.52 A discontinuation or withdrawal syndrome may occur if SSRIs are abruptly discontinued. However, the longer the half-life of the drug and its active metabolite, the less likely a withdrawal syndrome will occur.53,54Although SSRIs are known to improve the anxiety symptoms associated with depression, a few patients experience an increase in anxiety symptoms or agitation early in treatment. Lastly, despite their excellent safety profile, there have been growing concerns with the SSRIs. For example, citalopram has been linked to a dose-dependent increase in QT interval that requires careful attention to maximum dosages.55

Serotonin–Norepinephrine Reuptake Inhibitors

The TCAs affect several NTs and produce a wide range of pharmacologic actions, including several unwanted, but expected, adverse effects. The most commonly occurring side effects are dose-related and are associated with blockade of cholinergic receptors (anticholinergic effects) and include dry mouth, constipation, blurred vision, urinary retention, dizziness, tachycardia, memory impairment, and, at higher doses, delirium.49 Although some tolerance does develop to these adverse effects, they have the potential to impact patient adherence, particularly in the elderly and those receiving long-term maintenance therapy. Orthostatic hypotension is a common, dose-related, and potentially problematic adverse effect that has been attributed to the affinity of the TCAs for adrenergic receptors.56 TCAs also cause cardiac conduction delays and may induce heart block in patients with a preexisting conduction disorder. TCA overdose can produce severe arrhythmias.56 Furthermore, the FDA released a warning in December 2009 that the desipramine prescribing information will be changed to reflect an increased risk of death in patients receiving desipramine who have a family history of sudden cardiac death, cardiac dysrhythmias, and cardiac conduction disturbances. More on this reaction can be found at the FDA’s MedWatch website. Therefore, caution should be exercised when prescribing these agents, especially in higher doses, to patients with clinically significant cardiac disease, and to patients with a family history of a cardiac event. Additional adverse effects that may lead to TCA nonadherence include weight gain and sexual dysfunction.57

The most commonly reported adverse effects with venlafaxine are similar to those of SSRIs and may be dose-related; they include nausea, sexual dysfunction, and activation.2 However, recent evidence strongly suggests that venlafaxine is associated with a higher incidence of nausea and vomiting compared with the SSRIs.45 Venlafaxine may also cause a dose-related increase in diastolic blood pressure, and baseline blood pressure is not a useful predictor of the occurrence of this phenomenon. Blood pressure should be monitored regularly during venlafaxine therapy, and dosage reduction or discontinuation may be necessary if sustained hypertension occurs.58 Duloxetine was relatively well tolerated in short-term clinical trials; however, experience in long-term studies and in a larger population of patients will more clearly define its risks and benefits. The most commonly reported adverse events were nausea, dry mouth, constipation, decreased appetite, insomnia, and increased sweating.43,59 According to the AHRQ report cited above, there were higher discontinuation rates secondary to side effects associated with both duloxetine and venlafaxine compared with the SSRI class of antidepressants.45

Mixed Serotonergic Medications

Trazodone and nefazodone have minimal anticholinergic effects and 5-HT agonist side effects, but they can cause orthostatic hypotension. Sedation, cognitive slowing, and dizziness are the most frequent dose-limiting side effects associated with trazodone.49 Common adverse effects associated with nefazodone include light-headedness, dizziness, orthostatic hypotension, somnolence, dry mouth, nausea, and asthenia (weakness). Due to the previously discussed potential for hepatic injury associated with nefazodone use, treatment should not be initiated in individuals with active liver disease or with elevated baseline serum transaminases.46 A rare but potentially serious adverse effect of trazodone is priapism, which is reported to occur in approximately 1 in 6,000 male patients. Some cases have required surgical intervention (1 in 23,000), and permanent impotence may result.60 There have been no reports of priapism associated with nefazodone use in men, but there is a published case report of nefazodone-induced clitoral priapism.60

Norepinephrine and Dopamine Reuptake Inhibitor

Adverse effects associated with bupropion include nausea, vomiting, tremor, insomnia, dry mouth, and skin reactions. The occurrence of seizures in patients taking bupropion appears to be strongly dose-related, and may be increased by predisposing factors such as history of prior seizure activity, severe alcohol withdrawal, head trauma, and CNS tumor. Additionally, bupropion use is contraindicated in patients with eating disorders such as bulimia and anorexia, as these patients are prone to electrolyte abnormalities and are therefore at higher risk for seizure activity. At daily doses of 450 mg (the FDA-approved maximum dose) or less, the incidence of seizures is 0.4%.61 Due to its pharmacologic profile (i.e., proadrenergic), bupropion may cause activation or agitation in some patients.18 Bupropion is associated with less sexual dysfunction compared with the SSRIs.45

Serotonin and α2-Adrenergic Receptor Antagonists

The most common adverse effects of mirtazapine are somnolence, weight gain, dry mouth, and constipation. Interestingly, side effects such as weight gain may be less with larger mirtazapine doses due to different mechanisms of action at different doses,53 such as increased noradrenergic transmission as the dose is increased. Weight gain associated with mirtazapine after 6 to 8 weeks is in the range of 0.8 to 3 kg.45

Monoamine Oxidase Inhibitors

The most common adverse effect of MAOIs is postural hypotension; this is more likely to occur with phenelzine than with tranylcypromine and may be minimized through divided dosage scheduling. Other common adverse effects include weight gain and sexual side effects (e.g., decreased libido, anorgasmia).2 Phenelzine has mild to moderate sedating effects, while tranylcypromine may exert a stimulating effect, and therefore insomnia can occur. In addition, fever, myoclonic jerking, and brisk deep tendon reflexes may occur.62 Hypertensive crisis, a potentially serious and life-threatening but rare adverse reaction, may occur when MAOIs are taken concurrently with certain foods, especially those high in tyramine, or some medications. Examples of potentially high tyramine foods and medications that should be avoided or used with caution are provided in Table 51-5.41,63,64 Ten milligrams of tyramine can cause a marked pressor effect, and 25 mg can result in a serious hypertensive crisis.65 These incidents may culminate in cerebrovascular accident and death. Symptoms of hypertensive crisis include occipital headache, stiff neck, nausea, vomiting, sweating, and sharply elevated blood pressure. Hypertensive crises can be treated with antihypertensive agents such as captopril.66 Education of patients taking MAOIs regarding dietary and medication restrictions is extremely important. Notably, according to the FDA-approved prescribing information for the transdermal selegiline patch, patients receiving the 6-mg/24-hour dose are not required to modify their diet. However, patients receiving the 9- or 12-mg/24-hour dose are still required to follow the dietary restrictions similar to the other MAOIs.

TABLE 51-5 Dietary and Medication Restrictions for Patients Taking Monoamine Oxidase Inhibitorsa


Serotonin Syndrome (SS)

Any antidepressant that increases serotonergic neurotransmission can be associated with SS. The typical triad of symptoms seen in SS includes mental status changes, autonomic instability, and neuromuscular abnormalities. However, SS has been identified in cases without all three of these symptoms being present. Therefore, alternative approaches to the well-accepted SS triad have been suggested. For example, it has been proposed that the presence of any of the following symptom clusters is highly diagnostic of SS: (a) tremor + hyperreflexia, (b) spontaneous clonus, (c) muscle rigidity + temperature >38°C (100.4°F) + ocular clonus or inducible clonus, (d) ocular clonus + agitation or diaphoresis, and (e) inducible clonus + agitation or diaphoresis.67

Pharmacokinetics and Pharmacodynamics

The PK of the antidepressants is summarized in Table 51-6.4143,6870 The diversity of SSRIs is evident not only in their chemical structures but also in their PK profiles.68,71 The unique PK attributes of each SSRI can be used to guide treatment. For example, the long half-life of fluoxetine and its active metabolite norfluoxetine may be beneficial in instances of partial nonadherence (e.g., missed doses). Conversely, caution must be taken to monitor for drug–drug interactions prior to combining another medication with fluoxetine. SSRIs are extensively distributed to the tissues, and all, with the possible exception of citalopram and sertraline, may have a nonlinear pattern of drug accumulation with long-term administration.51,71 Therefore, the relationship between the dose and observed effect (e.g., side effect) may change over time for the nonlinear SSRIs, and this needs to be considered during treatment.

TABLE 51-6 Pharmacokinetic Properties of Antidepressants


Bioavailability is low (30% to 70%) for most TCAs as a result of the first-pass hepatic effect, which shows great interindividual variation.72 The TCAs have a large volume of distribution and concentrate in brain and cardiac tissue in laboratory animals. They are bound extensively and strongly to plasma albumin, erythrocytes, α1-acid glycoprotein, and lipoprotein.72 The major metabolic pathways are demethylation, aromatic and aliphatic hydroxylation, and glucuronide conjugation. Enterohepatic cycling has been described.72,73 Metabolism of TCAs is linear within the usual dosage range. The elimination half-lives of the TCAs can vary greatly among individual patients.72

Venlafaxine is metabolized to an active metabolite, O-desmethylvenlafaxine, which contributes to the overall pharmacologic effect,74 and has received FDA approval as an antidepressant. Venlafaxine has the lowest plasma protein binding of any antidepressant (27% to 30%), which reduces the likelihood of drug interactions via this mechanism. As might be expected, different formulations of venlafaxine with different PK profiles have led to different adverse effect profiles. For example, venlafaxine extended-release formulation, with its sustained plasma concentrations, has been associated with higher rates of sexual dysfunction among men (37%) compared with the immediate-release formulation (6%).74

Bupropion is metabolized to multiple active metabolites (see Table 51-6). There are currently three formulations of bupropion (immediate release, sustained release, and extended release), which are considered bioequivalent.75The bupropion peak plasma concentrations are lower for the sustained-release formulation of bupropion, and it is believed this may contribute to a lower seizure risk with that formulation.76

Mirtazapine undergoes extensive biotransformation to several metabolites77 and is primarily eliminated in the urine (renal elimination). However, these metabolites are present at such low plasma concentrations as to minimally contribute to the overall pharmacologic profile of mirtazapine.

Altered Pharmacokinetics

In patients with cirrhosis, the half-lives of fluoxetine and norfluoxetine increased to 7.6 and 12 days, respectively.71 Patients with hepatic impairment had a twofold increase in plasma concentrations of paroxetine.78 Similarly, in patients with mild stable cirrhosis, the half-life of sertraline was 2.5 times greater than in patients without liver disease.79 Patients with renal impairment had a twofold to fourfold increase in paroxetine plasma concentrations compared with normal volunteers.78 Plasma concentrations of SSRIs in the elderly are reported to be greater than in younger patients.71

Factors that influence TCA plasma concentrations include disease states, genetics, age, cigarette smoking, and concurrent drug administration. Hepatic disease may result in increased TCA plasma concentrations.40 Renal failure does not alter nortriptyline metabolism, but the 10-hydroxy metabolite may accumulate, and protein binding may be diminished, with resulting enhanced sensitivity to the drug.72 Clinicians should be alert to the possibility of higher-than-expected plasma concentrations of some TCAs in the elderly.

The clearance of venlafaxine, mirtazapine, and their metabolites may be reduced among patients with hepatic or renal disease,69 and doses should be adjusted accordingly. Elderly patients may require a dose reduction with mirtazapine.69

Plasma Concentration and Clinical Response

Studies in acutely depressed patients have demonstrated a correlation between antidepressant effect and plasma concentrations for some TCAs. However, the patient’s clinical response, not plasma concentration, dictates dosage adjustments. Some patients with plasma concentrations outside the suggested therapeutic plasma concentration range respond, whereas others are nonresponsive regardless of their plasma concentration. See Table 51-3 for a listing of suggested therapeutic plasma concentration ranges. There are four TCAs (amitriptyline, nortriptyline, desipramine, and imipramine) with evidence to support an association between plasma concentrations and clinical response. However, the best established therapeutic range is for nortriptyline (50 to 150 ng/mL [190 to 570 nmol/L]),40 which appears to demonstrate a curvilinear plasma concentration–response relationship.

For the newer antidepressants, a correlation has not been established between plasma concentration and clinical response or adverse effects.

Plasma Concentration Monitoring

Because of interindividual variations in plasma concentrations achieved by a given dose, interpretation of plasma concentrations can be very difficult for the TCAs.40 Although plasma level monitoring is not performed routinely, some indications include inadequate response, relapse, serious or persistent adverse effects, use of higher-than-standard doses, suspected toxicity, elderly patients, pregnant patients, cardiac disease, suspected nonadherence, suspected PK drug interactions, and change in the manufacturer of the product. If plasma concentration monitoring is used to detect nonadherence, a cutoff as low as 30 ng/mL (~110 nmol/L) for the TCAs has been suggested to avoid confusion with low bioavailability or unusually rapid metabolism. Plasma concentrations should be obtained at steady state, usually after a minimum of 1 week at constant dosage. Sampling should be performed during the drug elimination phase, usually in the morning, 12 hours after the last dose. Samples collected in this manner are comparable for patients on once-, twice-, or thrice-daily regimens.72

Drug Interactions

Drug–drug interactions fall into two broad categories: PK or PD drug interactions. In contrast to the SSRIs, which have potential for both PK and PD interactions, other newer-generation antidepressants such as venlafaxine, duloxetine, mirtazapine, and bupropion have drug interactions that are primarily PD. This may be partly explained by the relative lack of cytochrome P450 inhibition among these newer agents compared with that among SSRIs (see Table 51-7).41,42,51,6870

TABLE 51-7 Second- and Third-Generation Antidepressants and Cytochrome (CYP) P450 Enzyme Inhibitory Potential



Because the TCAs are metabolized in the liver through the cytochrome P450 system, they may interact with other drugs that modify hepatic enzyme activity or hepatic blood flow. TCAs are also extensively protein bound, which can cause drug interactions through displacement from protein-binding sites. Many commonly used medications can interact when given concurrently with TCAs. Due to their frequent coadministration, a common drug interaction occurs between the TCAs and certain SSRIs, such as paroxetine and fluoxetine. These drugs are known to inhibit cytochrome P450 (e.g., CYP2D6) with the resultant increase in TCA plasma concentrations. Drug–drug interactions may occur when an SSRI is coadministered with another drug metabolized through the cytochrome P450 system. Two of the isoenzymes of the cytochrome P450 system, 2D6 and 3A4, are responsible for the metabolism of more than 80% of currently marketed drugs.70 The ability of an SSRI, or any antidepressant, to inhibit or induce the activity of these enzymes will be a significant contributory factor in determining its capability to cause a PK drug interaction when administered concomitantly. Table 51-7 shows the cytochrome P450 enzyme inhibitory potential of the second- and third-generation antidepressant agents. In patients receiving a stable dose of any medication known to interact with SSRIs, if an SSRI is to be initiated, the starting dose should be low and titrated carefully to evaluate the potential importance of the interaction. As nefazodone use has been severely limited due to its potential to induce liver toxicity, and trazodone is primarily used as a non–FDA-approved hypnotic at low doses, neither of these agents are likely to be involved in clinically significant drug interactions. However, it should be noted that nefazodone is a potent inhibitor of cytochrome P450 3A4.70


Certain PD drug interactions that may occur with SSRIs are concerning and require close monitoring. For example, the combination of an SSRI with another drug that augments serotonergic function (e.g., linezolid) can lead to SS, which is characterized by symptoms such as clonus, hyperthermia, and mental status changes,67 although these symptoms are not unanimously agreed upon; therefore, a washout period of 2 to 5 weeks (depending on the half-life of the SSRI) may be necessary before the initiation of another serotonergic medication. Lastly, the TCAs, SNRIs, and SSRIs can also potentially be involved in SS as described within Adverse Effects above and in Table 51-8.41,42,63,64

TABLE 51-8 Selected Drug Interactions of Newer-Generation Antidepressants


Clinical Controversy…

Recent research, in both mice and humans, suggests the possibility that NSAIDs may lessen the efficacy of SSRIs. A recent editorial in the American Journal of Psychiatry provided a thoughtful discussion on the topic.80 At this time evidence is insufficient to draw firm conclusions. However, given the volume of prescriptions for both NSAIDs and SSRIs, this is an area of pharmacotherapy that certainly deserves further research and thoughtful prescribing practices.

Lastly, refer to Monoamine Oxidase Inhibitors under Adverse Effects above and Table 51-5 to read more about the hypertensive crisis that may result following the coadministration of MAOIs and other medications that increase vasopressor response (e.g., amphetamines). Notably, MAOIs and TCAs may be coadministered safely in refractory patients with apparent increased efficacy compared with monotherapy; however, severe reactions (e.g., hypertensive crisis) and fatalities have occurred.2,72 Therefore, this combination should be used sparingly by experienced clinicians and monitored extremely carefully.

Adjunct to Pharmacotherapy

The APA Task Force on Complementary and Alternative Medicine (CAM) recently provided consensus-based recommendations on the use of CAM for the treatment of MDD.81 While these recommendations are not the focus of this chapter, clinicians treating patients with MDD should be cognizant of them.

Omega-3 Fatty Acids

It appears from the literature reviewed by the task force that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) omega-3 fatty acids can be used as augmentation in the treatment of MDD. Furthermore, EPA alone or the combination of EPA/DHA is likely more effective than DHA alone.

St. John’s Wort

There is a lack of consensus regarding St. John’s wort for the treatment of MDD. Furthermore, St. John’s wort induces hepatic metabolic enzymes and is associated with significant drug interactions. Therefore, the APA Task Force conservatively states that St. John’s wort may be reasonable for some individuals with mild to moderate MDD.

S-Adenosyl-L-Methionine (SAMe)

The use of SAMe received a favorable review by the APA Task Force. However, the final consensus was that more rigorous studies need to confirm the efficacy of SAMe for treating MDD.


The three compounds in this category are (a) folic acid, (b) folinic acid, and (c) 5-methyltetrahydrofolate (5-MTHF). These folate compounds are involved in the synthesis of key NTs, such as 5-HT. The task force states that augmentation with these compounds is reasonable, but more work is needed to clarify which subgroup of patients may achieve the greatest response. For example, in one study, only women responded to folic acid augmentation of fluoxetine treatment.


Physical activity has long been recommended for individuals with many ailments, and recent data suggest benefits in depressed patients. For example, positive preliminary findings led to the Treatment with Exercise Augmentation for Depression (TREAD) study, which is a study designed to confirm the promising initial findings. Recently published findings from this study showed that 16 kcal (67 kJ) per kilogram per week (KKW) exercise was associated with greater remission rates compared with 4 KKW, when both were used as augmentation to an SSRI.82 The task force concluded that integrating exercise into the MDD treatment plan is medically appropriate and confers many well-accepted health benefits.

Special Populations

Elderly Patients

Depression in the elderly is a major public health problem. Many elderly depressed patients are inadequately treated, or depression is missed or mistaken for another disorder, such as dementia. In the elderly, depressed mood, the typical signature symptom of depression, may be less prominent than other depressive symptoms such as loss of appetite, cognitive impairment, sleeplessness, anergia, and loss of interest in and enjoyment of the normal pursuits of life.83 Older adults may not recognize common symptoms associated with depression such as anhedonia (inability to experience pleasure), fatigue, and concentration difficulties. Somatic (physical) complaints are quite frequently the presenting symptoms in elderly depressed patients. Appropriate recognition and treatment of depression in the elderly is extremely important. In fact, individuals 65 years of age and older have a very high rate of suicidality.83Increased suicidal attempts in the depressed elderly may be due to access to firearms, diminished cognitive functioning, sleep disruptions, poor social interactions, and inattention among primary caregivers.84

Before initiating antidepressant treatment, a complete physical examination should be performed. In prescribing antidepressants, elderly patients may be either overtreated or undertreated. Overtreatment occurs when age-related PK and PD factors are overlooked. Undertreatment results from an overly conservative approach as a result of the patient’s advanced age or concurrent medical problems. SSRIs are usually selected as first-choice antidepressants in the elderly, and this may enable the clinician to avoid some of the problematic adverse effects commonly associated with TCAs (e.g., sedative, anticholinergic, and cardiovascular side effects). Furthermore, there is evidence to suggest that the long-term use of antidepressants such as SSRIs in the elderly, administered with either psychotherapy or clinical management, may prevent a depressive relapse.85 Bupropion and venlafaxine are often selected because of milder anticholinergic and less frequent cardiovascular side effects.86 Mirtazapine has been shown to be an effective antidepressant in the elderly (at least 65 years of age) and better tolerated than the SSRI paroxetine. Furthermore, secondary measures of anxiety and sleep were improved following mirtazapine administration.87

Pediatric Patients

Accumulating evidence indicates that childhood depression occurs quite commonly. Symptoms of depression in the young may vary from accepted diagnostic criteria and include several nonspecific symptoms such as boredom, anxiety, failing adjustment, and sleep disturbance.88

Data collected under controlled conditions that support the efficacy of antidepressants in children and adolescents are sparse, and no antidepressant, except fluoxetine, is FDA-approved for the treatment of depression in patients younger than 18 years of age, although other antidepressants (e.g., sertraline) have been studied in this population.89

The use of antidepressants in children and adolescents was complicated when, in March 2004, the FDA issued a black box warning in the product labeling for antidepressant medications warning clinicians and patients of the increased risk for suicidal ideation and behavior when antidepressants are used in this population. However, several retrospective longitudinal reviews of the use of antidepressants in children found no significant increase in the risk of suicide attempts or deaths.9092 Furthermore, adolescents suffering from depression who remain untreated may successfully commit suicide.93,94 Further study is needed to resolve this important clinical dilemma.

Several cases of sudden death have been reported in children and adolescents taking antidepressants, such as desipramine. A baseline electrocardiogram (ECG) is recommended before initiating treatment with a TCA in children and adolescents, and many clinicians recommend an additional ECG when steady-state plasma concentrations are achieved.95

The treatment of depression in children remains challenging, as depression can be difficult to diagnose and treat once identified. Antidepressants are used to treat depressed children and adolescents because no other definitive effective therapies are currently available. Also, demonstration of efficacy in this population, as well as in adults, is confounded by a high placebo response rate. However, the TCAs and several of the SSRIs remain viable treatment options when prescribed and monitored appropriately.

Pregnant and Lactating Patients

Approximately 14% of pregnant women develop a serious depression during pregnancy.96 The data presented in several recent publications should be considered when making treatment decisions for pregnant women suffering from major depression.9698 The first evaluation looked at the risk of discontinuing antidepressant therapy in pregnant women suffering from depression and found a significant risk of relapse. In this study, women who discontinued antidepressant therapy were five times more likely to have a relapse during their pregnancy than were women who continued treatment.98 Another study utilized population health data to determine whether exposure to SSRIs and depression in pregnant women differs from exposure to maternal depression alone. The authors found that prenatal exposure to SSRIs was associated with an increased risk of low birth weight and respiratory distress, and that this relationship remained after accounting for maternal illness severity.96 A study by Chambers et al. reported a sixfold greater likelihood of the occurrence of persistent pulmonary hypertension of newborn infants exposed to an SSRI after the 20th week of gestation.97 A recent editorial on the use of antidepressants in pregnancy lists four therapeutic principles to guide the clinician in treating women during pregnancy: (a) Pregnancy does not protect against the occurrence of depression, and the likelihood of relapse is very high in untreated women with recurrent illness. (b) Maternal depression adversely affects child development, and prenatal depression may adversely affect the offspring. (c) When attempting to balance benefit and risk, transient postnatal behavioral abnormalities in the offspring of treated mothers must not be assumed to portend long-term compromise. (d) SSRIs, the most commonly used and best-tolerated treatment for depression, carry a small but significant risk for a serious medical consequence.99

In September 2009, the APA and the American College of Obstetricians and Gynecologists released a report discussing the treatment of depression during pregnancy. One of the prominent conclusions of this report was that bothantidepressant treatment and untreated depression have been associated with potential problems during pregnancy. However, studies to date have not been able to adequately control for all the necessary variables involved in birth outcomes (e.g., maternal depressive disorder) and more work needs to be done.100

In summary, the risks and benefits of drug therapy during pregnancy must always be weighed, and concerns about the risks of untreated depression during pregnancy should be considered. These include the possibility of low birth weight secondary to poor maternal weight gain, suicidality, potential for hospitalization, potential for marital discord, inability to engage in appropriate obstetric care, and difficulty caring for other children.101 Several different approaches exist for dealing with pregnancy and antidepressant use. First, discontinuation of an antidepressant before conception is an option for women who are stable and appear likely to remain well while not taking antidepressant medication. Second, continuation of the antidepressant until conception may be reasonable. For those who have a history of depressive relapse after medication discontinuation, the antidepressant should be continued throughout pregnancy. Further evaluations of the newer antidepressant agents are needed to fully understand the risks associated with their use at various stages of the gestational period. Again, the risks of not treating depression in a pregnant woman should not be underestimated or minimized.

There is a great deal of uncertainty regarding long-term antidepressant exposure during breastfeeding due to the lack of data. However, both sertraline and paroxetine appear in relatively low concentrations in breast milk and in samples taken from infants.102

Relative Resistance and Treatment-Resistant Depression

The majority of “treatment-resistant” depressed patients are likely the result of inadequate therapy (relative resistance). This theory is supported by data from the National Institute of Mental Health (NIMH) Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which is generally considered to be one of the premier antidepressant trials among patients with depressive disorders.103 This study showed that one in three depressed patients who previously did not achieve remission using an antidepressant became symptom free with the help of an additional medication (e.g., bupropion SR) and one in four achieved remission after switching to a different antidepressant (e.g., venlafaxine XR).103 Furthermore, patients can be switched to another medication within the same class. For example, patients in the STAR*D study not responding to an initial SSRI were shown to be as likely to respond to another SSRI as they were to a medication from a different class.104

Although several different definitions for treatment-resistant depression have been proposed, the most widely accepted is depression, which has not achieved remission even after two optimal antidepressant trails.105 More than 40% of patients with MDD being treated with antidepressants meet these criteria.105 Three pharmacologic approaches that have been used with success for treatment-resistant depression include the following:

   1. The current antidepressant may be stopped and a trial with another agent initiated (i.e., switching). For example, the STAR*D trial compared switching to mirtazapine (up to 60 mg/day) versus nortriptyline (up to 200 mg/day) after two consecutive failed medication treatments.106 In the mirtazapine group, 12.3% of patients met the remission criterion of a score of 7 or less on the Hamilton Rating Scale for Depression (HAM-D), while 19.8% of nortriptyline patients met this criterion at the end of 14 weeks.

   2. The current antidepressant can be augmented by the addition of another agent such as lithium, or another antidepressant can be added (i.e., combination antidepressant treatment). For example, the STAR*D trial evaluated the addition of lithium or triiodothyronine (T3) to current antidepressant treatment. After approximately 10 weeks, T3 augmentation resulted in higher remission rates (24.7%) compared with lithium (15.9%). However, the differences between these two augmentation strategies were modest and not statistically significant.105

   3. The use of atypical antipsychotic agents to augment the antidepressant response. Aripiprazole was the first atypical antipsychotic to receive FDA approval for adjunctive use in adults with MDD. Additionally, olanzapine in combination with fluoxetine (Symbyax) was approved for treatment-resistant depression. Please refer to the FDA website for additional information on FDA approvals.

The APA practice guideline for the treatment of patients with MDD offers guidance for managing patients who fail to respond. These guidelines advise that if patients fail to respond to medication after 6 to 8 weeks, a reappraisal of the treatment regimen should be considered.2 Partial responders should consider changing the dose, augmenting the antidepressant, or adding psychotherapy or ECT. For those with no response, options include changing to a second antidepressant or the addition of psychotherapy or ECT. Comorbid medical or psychiatric conditions should be identified and treated because they may complicate treatment.

Images Before changing a patient’s treatment, the clinician is advised to evaluate the adequacy of the medication dosage and adherence with the prescribed regimen. Issues to be addressed in assessing the patient who has not responded to treatment include the following:

   1. Is the diagnosis correct?

   2. Does the patient have a psychotic depression?

   3. Has the patient received an adequate dose and adequate duration of treatment?

   4. Do adverse effects preclude adequate dosing?

   5. Has the patient adhered to the prescribed regimen?

   6. Was a stepwise approach to treatment used?

   7. Was treatment outcome adequately measured?

   8. Is there a coexisting or preexisting medical or psychiatric disorder?

   9. Are there other factors that interfere with treatment?

Clinical Application

A suggested algorithm for the management of uncomplicated MDD is shown in Figure 51-2. Recommended initial doses and dosage ranges are shown in Table 51-3. Antidepressant doses are generally titrated upwards depending on symptom response and adverse effects. Table 51-3 provides some medication-specific guidelines for dose titration. It is important to remember that 3 to 4 weeks is usually required before a mood-elevating response is seen. A 6-week trial at a maximum dosage is considered an adequate trial.2 It is crucial to counsel the patient about the expected lag time before the onset of clinical response. Patients uneducated in this regard often fail to adhere to their prescribed regimens.


FIGURE 51-2 Algorithm for treatment of uncomplicated MDD. (SSRI, selective serotonin reuptake inhibitor.)

Some antidepressant dosing regimens are particularly important from a safety standpoint. For example, bupropion must be carefully dosed in order to reduce seizure risk. Bupropion is usually initiated at 75 mg twice daily, and this dose may be increased to 100 mg three times daily after a few days. Most patients will respond at 300 mg/day; however, an increase to 450 mg/day, given as 150 mg three times daily, may be considered in patients with no or partial response after several weeks of treatment at 300 mg/day. Additionally, both a 12-hour and a 24-hour sustained-release formulation are available, allowing for less frequent dosing.

Caution is urged when dosing antidepressants in special populations. For example, in elderly patients, as a general rule, dosing is initiated at one half the initial dose administered to younger adults, and the dose is increased at a slower rate.

Personalized Pharmacotherapy

Images Pharmacogenetic applications in psychiatry have been explored for some time. Pharmacogenetic tests (e.g., the FDA-approved AmpliChip to evaluate CYP2D6 and CYP2C19 polymorphisms) are now available. However, there are no standard or well-accepted guidelines for the use of pharmacogenetic testing as it relates to antidepressant treatment.107 In contrast, PK parameters have long been one of the primary considerations when choosing among the antidepressants, particularly within a medication class.2 For example, PK parameters help the clinician choose a particular SSRI (e.g., longer fluoxetine half-life for partial nonadherence).


Images Several monitoring parameters, in addition to plasma concentrations, are useful in managing patients (Table 51-9).2,41,42 Patients must be monitored for adverse effects, such as sedation and anticholinergic effects, and for remission of previously documented target symptoms. The presence of side effects does not necessarily indicate adequate dosage. In addition, changes in social and occupational functioning should be assessed. Patients receiving venlafaxine should have their blood pressure monitored at regular intervals. Patients older than 40 years of age should receive a pretreatment ECG before starting TCA therapy, and followup ECGs should be performed periodically. Patients should be monitored for the emergence of suicidal ideation after initiation of any antidepressant. Weight gain and sexual dysfunction, common events associated with most antidepressants, are associated with nonadherence and should be monitored and discussed with the patient.

TABLE 51-9 Adverse Drug Reactions and Monitoring Parameters Associated with Select New-Generation Antidepressants



In addition to the clinical interview, psychometric rating instruments (such as those highlighted earlier in this chapter and in eChap. 19) allow for rapid and reliable measurement of the nature and severity of depressive and associated symptoms. It is helpful to administer the rating scales prior to treatment, 6 to 8 weeks after initiation of therapy, and periodically thereafter. Interviewing a family member or friend (with the patient’s permission) regarding symptoms and daily functioning also can assist in assessment of progress. Patients should be monitored at more frequent intervals early in treatment. Monitoring is then continued at regular intervals throughout the continuation and maintenance phases of treatment. Regular monitoring for reemergence of target symptoms should be continued for several months after antidepressant therapy is discontinued.

Finally, one useful set of criteria that can be used with a variety of psychometric scales was suggested by Mann.35 Following these criteria, the following definitions are used: (a) nonresponse is less than 25% decrease in baseline symptoms, (b) partial response is a 26% to 49% decrease in baseline symptoms, and (c) partial remission or response is greater than a 50% decrease in baseline symptoms. Consistent with other recommendations, remission is a return to baseline functioning with no symptoms present.2


Significant evidence exists to show that depression is common and chronic, and causes significant morbidity and mortality. Pharmacists, in conjunction with other healthcare providers, can play a crucial role in the screening, recognition, and treatment of this disorder. In fact, the U.S. Preventive Services Task Force recommends screening adults for depression in clinical practices that have systems in place to ensure accurate diagnosis, effective treatment, and followup.108 In addition, pharmacists and other healthcare clinicians play a crucial role in ensuring adherence to medication regimens through assessment of a patient’s willingness and ability to take a medication, including an assessment of financial viability, and through patient education regarding dosing, side effects and drug interactions, and guidance regarding followup appointments with prescribing clinicians.109





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