Pharmacotherapy Principles and Practice, Second Edition (Chisholm-Burns, Pharmacotherapy), 2nd Ed.

38 Major Depressive Disorder

Cherry W. Jackson, Marshall E. Cates, and Jacqueline M. Feldman


LEARNING OBJECTIVES

Upon completion of the chapter, the reader will be able to:

1. Explain the etiology and pathophysiology of major depressive disorder (MDD).

2. Identify symptoms and clinical features of MDD.

3. Differentiate antidepressants according to pharmacologic properties, adverse-effect profiles, pharmacokinetic profiles, drug interaction profiles, and dosing features.

4. Predict adverse-effect profiles of antidepressants based on pharmacology.

5. State the goals of pharmacotherapy in MDD.

6. Educate patients and caregivers on the proper use of antidepressants.


KEY CONCEPTS

image Classic views as to the cause of major depressive disorder (MDD) focus on the monoamine neurotransmitters norepinephrine (NE), serotonin (5-HT), and to a lesser extent, dopamine (DA) in terms of both synaptic concentrations and receptor functioning.

image It is not uncommon for a patient to experience only a single major depressive episode, but most patients with MDD will experience multiple episodes.

image One extremely important goal in the treatment of MDD is the prevention of suicidal attempts.

image Sexual dysfunction is common and challenging to manage and often leads to noncompliance with serotonergic medications.

image Each antidepressant has a response rate of approximately 60% to 80%, and no antidepressant medication or class has been reliably shown to be more efficacious than another.

image It is widely accepted that approximately 2 to 4 weeks of treatment are required before improvement is seen in emotional symptoms of depression, such as sadness and anhedonia. Furthermore, as long as 6 to 8 weeks of treatment may be required to see the full effects of antidepressant therapy.

image Because the typical major depressive episode lasts 6 months or longer, if antidepressant therapy is interrupted for any reason following the acute phase, the patient may relapse into the depressive episode. When treating the first depressive episode, antidepressants must be given for an additional 4 to 9 months in the continuation phase for the purpose of preventing relapse.

image Pediatric patients and young adults should be observed closely for suicidality, worsened depression, agitation, irritability, and unusual changes in behavior, especially during the initial few months of therapy or at times of dosage changes. Furthermore, families and caregivers should be advised to monitor patients for such symptoms.

image Lack of patient understanding concerning optimal antidepressant drug therapy frequently leads to partial compliance or noncompliance with therapy; thus, the primary purpose of antidepressant counseling is to enhance compliance and improve outcomes.

My spirit is broken, my days are cut short, the grave awaits me.

—Job 17:1

Contrary to popular belief, major depression is not a fleeting “bad day,” is not the result of personal weaknesses or character flaws, and does not respond to volitional efforts simply to feel better. Major depressive disorder (MDD) is a serious medical condition with a biological foundation, and it responds to biological and psychological treatments. Individuals who suffer from MDD experience significant and pervasive symptoms that can affect mood, thinking, physical health, work, and relationships. Unfortunately, suicide is often the result of MDD that has not been diagnosed and treated adequately.

The last two decades have seen improvements in the screening, diagnosis, and treatment of MDD. The willingness of general practitioners to involve themselves in the identification and treatment of MDD is noteworthy. To that end, antidepressants have become some of the most commonly prescribed drugs, and they account for 10 of the top 100 prescription drugs dispensed in the United States.1 Inadequate treatment remains a serious concern.2

EPIDEMIOLOGY

MDD is quite common; lifetime and 12-month prevalence estimates are 16.2% and 6.6%, respectively.2 Females are approximately twice as likely as males to experience MDD.2 The average age at onset is the mid-twenties.3Interestingly, MDD appears to occur earlier in life in people born in more recent decades.2 Most patients with MDD also suffer from comorbid psychiatric disorders, especially anxiety disorders and substance-use disorders.2

According to the World Health Organization (WHO), depression is the leading cause of disability (based on years lived with disability) and the fourth leading contributor to the global burden of disease (based on disability adjusted life years).4

ETIOLOGY/PATHOPHYSIOLOGY

The exact cause of MDD remains unknown, but it is probably multifactorial. Biological, psychological, and social theories abound, and many practitioners suggest that the development of depression often is predicated on the complex synthesis of genetic predisposition, psychological stressors, and biological pathophysiology. At present, there are currently no accepted unifying theories that explain these various factors adequately.


Patient Encounter 1, Part 1

PT is a 34-year-old male who was brought into the hospital by friends after telling them that he was considering taking an overdose of pain killers. He lost his job 2 months ago, followed by the loss of his home to foreclosure. In addition, he lost most of his 401-K and children’s college fund due to the downturn in the market. On questioning, he is tearful and describes overwhelming feelings of sadness and guilt. He also states that he has not been sleeping or eating and that he has experienced a 6.8 kg (15 lb) weight loss over the last 6 weeks. He states that he drinks three or four beers per night in order to relax and fall asleep

What information is suggestive of MDD?

What medical or psychiatric issues could be contributing to his symptoms?

Does he have risk factors for depression?

What additional information do you need to know before creating a treatment plan for this patient?


Genetics

First-degree relatives of MDD patients are about three times more likely to develop MDD compared with first-degree relatives of normal control individuals. Adoption studies and twin studies reveal that the familial aggregation of MDD is due to genetic influences.5

Life Stress

Depression can occur in the absence of major life stressors, and conversely, major life stressors do not invariably cause depression. Nevertheless, there is an undeniable association between life stressors and depression, and there appears to be a significant interaction between life stressors and genetic liability in causing depression.6 Although acute stressors may precipitate depression, chronic stressors have a longer risk period, cause longer episodes, and are more likely to lead to relapse and recurrence.6

Monoamine Neurotransmitter and Receptor Hypotheses

image Classic views as to the cause of MDD focus on the monoamine neurotransmitters norepinephrine (NE), serotonin (5-HT), and to a lesser extent, dopamine (DA) in terms of both synaptic concentrations and receptor functioning.The monoamine hypothesis asserts that depression is due to a deficiency of monoamine neurotransmitters. The major supporting evidence for this hypothesis is that existing antidepressants increase synaptic monoamine concentrations through various mechanisms (see Pharmacologic Therapy). One argument against the monoamine hypothesis is that depressed patients do not consistently exhibit decreased monoamine concentrations. In addition, monoamine levels are altered within hours of the initiation of antidepressant therapy, but there is a latency period of weeks before the actual antidepressant effect is typically evident.7–9

The neurotransmitter receptor hypothesis suggests that depression is related to abnormal functioning of neurotransmitter receptors. In this model, antidepressants presumably exert therapeutic effects by altering receptor sensitivity. In fact, chronic administration of antidepressants has been shown to cause desensitization, or downregulation, of β-adrenergic receptors and various 5-HT receptors. Importantly, the time required for changes in receptor sensitivity corresponds to the onset of antidepressant effects.7–9

Such models of the pathophysiology of depression are assuredly an oversimplification. Depression probably involves a complex dysregulation of monoamine systems, and these systems, in turn, modulate and are modulated by other neurobiological systems.10

Other Neurobiological Hypotheses

Various other pathophysiological hypotheses are proposed. These hypotheses include the role of nonmonoamine neurotransmitters (e.g., glutamate and γ-aminobutyric acid), neuroendocrine systems (e.g., the hypothalamic-pituitary-adrenal axis), neurosteroids (e.g., allopregnanolone), neuronal plasticity (e.g., brain-derived neurotrophic factor),11 messenger cascades, and gene expression.12


Clinical Presentation of MDD

Patients typically present with a combination of emotional, physical, and cognitive symptoms:

• Emotional

• Sadness

• Anhedonia

• Pessimism

• Feeling of emptiness

• Irritability

• Anxiety

• Worthlessness

• Thoughts of death/suicidal ideation (SI)

• Physical

• Disturbed sleep

• Change in appetite/weight

• Psychomotor changes

• Decreased energy

• Fatigue

• Bodily aches and pain

• Cognitive

• Impaired concentration

• Indecisiveness

• Poor memory

Occasionally, severely depressed patients also will present with psychotic symptoms:

• Hallucinations

• Delusions

Some patients present with “atypical features” of depression:

• Reactive mood (i.e., mood improves in response to positive events)

• Significant increase in appetite/weight gain

• Hypersomnia

• Heavy feelings in arms or legs

• Sensitivity to interpersonal rejection


CLINICAL PRESENTATION AND DIAGNOSIS

The diagnosis of a major depressive episode requires the presence of a certain number of depressive symptoms (five) for a minimum specified duration (2 weeks) that cause clinically significant effects (Table 38–1).3

HINT: In order to remember the nine diagnostic symptoms for a major depressive episode, learn the following mnemonic: Depression = SIG E CAPS (depression, sleep, interest, guilt, energy, concentration, appetite, psychomotor, suicide).

In turn, the diagnosis of MDD is based on the presence of one or more major depressive episodes during a person’s lifetime.3

Differential Diagnosis

Major depressive episodes also occur in patients with bipolar disorder. Persons with bipolar disorder also experience manic, hypomanic, and/or mixed episodes (see Chap. 39) during the course of their illness, whereas persons with MDD do not.3

The presence of a significant medical disorder can produce depressive symptoms via either psychological or physiological mechanisms. Examples include hypothyroidism, neoplasms, anemia, infections, electrolyte disturbances, cardiovascular diseases, neurologic disorders, and many others.9 Various psychiatric conditions, such as substance-use disorders and anxiety disorders, have been associated with depression as well.9 The use of CNS depressants, such as benzodiazepines and narcotics, is associated with increased propensity for depression.13 Drugs that reportedly cause depressive symptoms or depressive-like side effects include corticosteroids, contraceptives, gonadotropin-releasing hormone agonists, interferon-α, interleukin-2, mefloquine, isotretinoin, propranolol, and sotalol.14

Table 38–1 Diagnostic Criteria for Major Depressive Episode


At least five of the following symptoms have been present during the same 2-week period and represent a change from previous functioning:

• Depressed mooda

• Markedly diminished interest or pleasure in usual activitiesa

• Increase or decrease in appetite or weight

• Increase or decrease in amount of sleep

• Increase or decrease in psychomotor activity

• Fatigue or loss of energy

• Feelings of worthlessness or guilt

• Diminished ability to think, concentrate, or make decisions

• Recurrent thoughts of death, suicidal ideation, or suicide attempt

The symptoms cause clinically significant distress or impairment in functioning

The symptoms are not due to the direct physiological effects of a substance or medical condition


a One of these two symptoms must be present.

From Ref. 3.

Dysthymia is a condition that must be differentiated from depression. Many of the symptoms of dysthymia are similar to those of depression, but in dysthymia, symptoms are chronic and milder. Symptoms of dysthymia must be present for at least 2 years and may include sleep and appetite disturbances, a loss of energy, a lack of interest in things that would usually be enjoyable, and poor self-image. Patients with dysthymia often have family members with a history of depression or dysthymia. It occurs more frequently in women, and patients with dysthymia are more likely to develop major depression than the general population.3

COURSE/PROGNOSIS

Symptoms of a major depressive episode usually develop over days to weeks, but mild depressive and anxiety symptoms may last for weeks to months prior to the onset of the full syndrome. Left untreated, major depressive episodes typically last 6 months or more, but a minority of patients experience chronic episodes that last at least 2 years. Approximately two-thirds of patients recover fully from major depressive episodes and return to normal mood and full functioning, whereas the other one-third have only partial remission.3

The course of MDD varies markedly from patient to patient. image It is not uncommon for a patient to experience only a single major depressive episode, but most patients with MDD will experience multiple episodes. Some patients experience isolated episodes separated by many years, others have clusters of episodes, and still others suffer more frequent episodes as they age. The number of prior episodes predicts the likelihood of developing subsequent episodes. A patient experiencing a third major depressive episode has about a 90% chance of having a fourth one. MDD is associated with a high mortality rate because about 15% of patients ultimately commit suicide.3

TREATMENT

Desired Outcomes

The goals of therapy for the depressed patient are the resolution of depressive symptoms, a return to euthymia, and prevention of relapse and recurrence of depressive symptoms. image One extremely important goal in the treatment of MDD is the prevention of suicidal attempts. Other desired outcomes include improvement of the patient’s quality of life, normalization of functioning in areas such as work and relationships, avoidance or minimization of adverse effects, and reduction of health care costs.15

Nonpharmacologic Therapy

Interpersonal therapy and cognitive behavioral therapy are psychotherapies that have well-documented efficacy for the treatment of MDD. Psychotherapy alone is an initial treatment option for mild-to-moderate depression, and it may be useful when combined with pharmacotherapy in the treatment of more severe cases. The combination of psychotherapy and pharmacotherapy can be more effective than either treatment modality alone in severe or recurrent MDD. It may be especially helpful for patients with significant psychosocial stressors, interpersonal difficulties, or comorbid personality disorders.16


Patient Encounter, Part 2: Medical History, Physical Exam, and Diagnostic Tests

The workup on PT reveals:

PMH: Chronic back pain since motor vehicle accident 3 years ago.

PPH: Noncontributory

FH: Mother with diabetes mellitus and MDD; father is alive and well with no medical problems; brother is a recovered alcoholic

SH: Worked for a construction company, but job ended 2 months ago. For the last several months he has been drinking three to four beers per night. He denies smoking cigarettes or using illicit substances

Current Meds: Ranitidine 150 mg twice daily; oxycontin 10 mg twice daily

ROS: Decreased energy; decreased sleep; all others noncontributory

PE:

Ht 5 ft 10 in. (178 cm); wt 66 kg (146 lb); weight loss of 6.8 kg (15 lb) over last 6 weeks

MSE: Depressed mood; decreased concentration; positive SI with plan

Labs: Within normal limits

Given this additional information, what is your assessment of the patient’s condition?

Identify your treatment goals for the patient.

What nonphamacologic and pharmacologic alternatives are available for this patient?


Electroconvulsive therapy (ECT) is a highly efficacious treatment for MDD. The response rate is about 80% to 90%, and it exceeds 50% for patients who have failed pharmacotherapy.16,17 ECT may be particularly beneficial for MDD that is complicated by psychotic features, severe suicidality, refusal to eat, pregnancy, or contraindication/nonresponse to pharmacotherapy.16,17 Around 6 to 12 treatments are typically necessary with response occurring in 10 to 14 days. Once ECT is discontinued, antidepressants are initiated to help maintain the response. ECT is typically a very safe treatment alternative, but various cautions do exist. Side effects include confusion and memory impairment.16

Light therapy is an alternative treatment for depression associated with seasonal (e.g., winter) exacerbations. Side effects include eye strain, headache, insomnia, and hypomania.16,17 Potentially vulnerable patients, such as those with photosensitivity or a history of skin cancer, should be evaluated carefully prior to therapy.16,17

Vagus nerve stimulation (VNS) may be used for adult patients with treatment-resistant depression. A pulse generator is surgically implanted under the skin of the left chest, and an electrical lead connects the generator to the left vagus nerve. Stimulation of this nerve sends signals to the brain. This therapy is used along with traditional therapies such as pharmacotherapy and ECT.18 Adverse effects of VNS include alterations in patients’ voice, coughing, pharyngitis, sore throat, hoarseness, headache, nausea, vomiting, dyspnea, and paresthesias.18

Transcranial magnetic stimulation is a noninvasive and well-tolerated procedure that is FDA approved for use after one failed trial of an antidepressant.19 Some data suggest that physical exercise may reduce depressive symptoms, but well-controlled studies are needed to document efficacy.20

Pharmacologic Therapy

Clinical Distinctions

Each antidepressant has its unique blend of characteristics, and in fact, even individual drugs within the same class have important differences.21

General Pharmacology

Table 38–2 demonstrates the differing pharmacologic properties of the antidepressant medications,7–9 whereas Table 38–3 delineates the results of those pharmacologic actions.7,8 Monoamine oxidase inhibitors (MAOIs) inhibit the enzyme responsible for the intraneuronal breakdown of 5-HT, NE, and DA. Tricyclic antidepressants (TCAs) possess both 5-HT (serotonin) reuptake inhibition (SRI) and NE reuptake inhibition (NRI) properties but unfortunately also block the so-called “dirty receptors,” including α1-adrenergic, histamine-1, and muscarinic cholinergic receptors, which contribute to side effects but not efficacy. The selective serotonin reuptake inhibitors (SSRIs) are classified as such because SRI is the predominant effect. Bupropion is an NE and DA reuptake inhibitor (NDRI). Venlafaxine, desvenlafaxine, and duloxetine are 5-HT and NE reuptake inhibitors (SNRIs) but are also weak inhibitors of DA reuptake. Compared with venlafaxine and desvenlafaxine, which have primarily SRI activity, duloxetine has more balanced SRI and NRI activities and has a higher affinity for the reuptake sites. Nefazodone and trazodone are 5-HT antagonists/reuptake inhibitors. Their SRI activity is not as pronounced as that of SSRIs, but they potently block 5-HT2A receptors, which allows more 5-HT to interact at postsynaptic 5-HT1A sites. In addition, trazodone blocks histaminergic and α-adrenergic receptors, whereas nefazodone possesses weak NRI and α-adrenergic blocking properties. Finally, mirtazapine is a noradrenergic and specific serotonergic antidepressant. It blocks presynaptic α2receptors, both autoreceptors on noradrenergic neurons and heteroreceptors on serotonergic neurons, with resulting increases in NE and 5-HT synaptic concentrations, respectively. Mirtazapine also blocks various postsynaptic serotonergic receptors and histamine-1 receptors.7–9

Table 38–2 Primary Pharmacologic Actions of Antidepressants

Image

Table 38–3 Efficacy and Adverse-Effect Profiles Based on Pharmacology

Image

St. John’s wort (Hypericum perforatum) is a herbal medication that has shown some efficacy in mild-to-moderate depression but minimal efficacy for moderate-to-severe depression.20 Many patients believe that herbal medications, being “natural” products, are devoid of adverse effects and drug interactions; however, St. John’s wort can cause GI irritation, headache, fatigue, and nervousness,17 and it triggers drug interactions through induction of CYP3A4 enzymes, as well as other potential mechanisms.22 The safety and efficacy of St. John’s wort combined with standard antidepressant medications remain unknown.16

Adverse Effects

The important adverse effects of the various antidepressants are often a function of their underlying pharmacologic profiles7,8 (Table 38–3). TCAs cause problematic sedative, anticholinergic, and cardiovascular adverse effects owing to their interaction with “dirty receptors.” While these adverse effects generally are considered to be common and bothersome, they can be quite serious in some cases. For example, constipation in its extreme form can lead to paralytic ileus. The tertiary amines (e.g., amitriptyline, imipramine) are more sedative and anticholinergic than secondary amines (e.g., desipramine, nortriptyline). TCAs have a quinidine-like effect on the heart, which makes them quite toxic on overdose. The average lethal dose in a young adult is only 30 mg/kg, which is typically less than a 1 month’s supply.7,9,21,23

The adverse-effect profile of the SSRIs includes sexual dysfunction (e.g., delayed or absent orgasms), CNS stimulation (e.g., nervousness and insomnia), and GI disturbances (e.g., nausea and diarrhea).7,9,21,23image Sexual dysfunction is common and challenging to manage and often leads to noncompliance.24 Various strategies to deal with antidepressant-induced sexual dysfunction include waiting for symptoms to subside, reducing the dosage, permitting periodic “drug holidays,” prescribing adjunctive therapy, and switching antidepressants.25 However, waiting for symptoms to subside usually does not work because sexual dysfunction may very well persist throughout the duration of therapy. Reducing the dose and using drug holidays may weaken the antidepressant effects. Thus, clinicians often prescribe adjunctive therapy such as dopaminergic drugs (e.g., bupropion or amantadine), 5-HT2antagonists (e.g., cyproheptadine or nefazodone), and phosphodiesterase inhibitors (e.g., sildenafil), or simply switch to a nt ide pressants with less like lihood of causing these effects, such as bupropion, mirtazapine, or nefazodone.24,25

Bupropion causes insomnia, nightmares, decreased appetite, anxiety, and tremors, but the most concerning adverse effect is seizures. Because of the risk for seizures, patients with a CNS lesion, history of seizures, head trauma, or bulimia should not receive the drug. The daily dose of bupropion should not exceed 450 mg/day, and any single dose of the immediate-release formulation should not exceed 150 mg. Occurrences of insomnia and/or nightmares often respond to moving the last daily dose from bedtime to late afternoon.7,9,21,23

Table 38–4 Relative Incidence of Adverse Effects of Various Newer Antidepressants

Image

The adverse effects of SNRIs are similar to those of SSRIs. Nausea can be particularly troublesome with venlafaxine and desvenlafaxine, which sometimes necessitates using lower starting dosages than usual and giving the medication with food. A dose-related elevation in blood pressure can occur at higher doses, probably owing to the NRI effects. Blood pressure monitoring should be conducted for patients receiving venlafaxine and desvenlafaxine therapy. As a rule, duloxetine should not be prescribed to patients with extensive alcohol use or evidence of chronic liver disease owing to the potential for hepatic injury.9,21,26,27

Trazodone routinely causes sedation, which is why it is used far more often as an adjunct with other antidepressants for sleep than as an antidepressant. Priapism is a rare but serious adverse effect in males who take trazodone. In addition, orthostatic hypotension and dizziness are more common with trazodone than with nefazodone because the latter agent has a weaker effect at α-adrenergic receptors and also has a balancing of adrenergic effects owing to weak NRI activity. Unfortunately, nefazodone has been associated with development of hepatotoxicity, which has led to a black-box warning and a great reduction in its use. It has been discontinued in some countries.7,9,21,23

Mirtazapine can cause sedation and weight gain by virtue of blocking histamine-1 receptors. Despite being partially a serotonergic drug, it rarely causes serotonergic-related adverse effects because it blocks the various postsynaptic 5-HT receptors. Although it carries a bolded warning for neutropenia owing to a handful of cases reported during clinical trials, it is questionable whether neutropenia is any more problematic with this agent than other antidepressants.9,21,23

The relative incidence of adverse effects among some of the newer antidepressant agents are shown in Table 38–4.9,13,28

Pharmacokinetic Parameters

Pharmacokinetic parameters of the newer antidepressants are shown in Table 38–5.9,29 Several antidepressants are not highly protein-bound, and the most notable of these are venlafaxine and desvenlafaxine. The elimination half-lives of nefazodone and venlafaxine are relatively short compared with the other agents. Conversely, fluoxetine has a very long half-life (i.e., 5–9 days) with chronic dosing, and its active metabolite (norfluoxetine) has an even longer half-life. Owing to the extremely long half-life of fluoxetine and its active metabolite, a 5-week washout of fluoxetine is required before starting an MAOI. Sertraline and citalopram are the other SSRIs with active metabolites, but these metabolites (desmethylsertraline and desmethylcitalopram, respectively) are only about one-eighth as potent as the parent compounds in terms of SRI activity.

Table 38–5 Pharmacokinetic Parameters of Newer Antidepressants

Image

Drug Interactions

The major drug interactions of antidepressants are shown in Table 38–6.9,22,30 The usual pharmacodynamic drug interactions involve the “dirty receptors” blocked by some antidepressants. Hence, especially TCAs can cause significant additive effects with drugs that cause sedation, hypotension, or anticholinergic effects. Similarly, nefazodone and mirtazapine can interact with other drugs that cause hypotensive and sedative effects, respectively. By far, the most concerning pharmacodynamic interactions are hypertensive crisis and 5-HT syndrome, which are both potentially life-threatening when they occur. Hypertensive crisis is characterized by sharply elevated blood pressure, occipital headache, stiff or sore neck, nausea, vomiting, and sweating. It may result during MAOI therapy if the patient takes a sympathomimetic drug, such as ephedrine, pseudoephedrine, phenylephrine, or phenylpropanolamine, or if the patient consumes foods rich in tyramine, such as tap beers, aged cheeses, fava beans, yeast extracts, liver, dry sausage, sauerkraut, or tofu.23 There are extensive lists of foods and drinks that are permitted and not permitted during therapy with MAOIs, and these always should be provided to patients. Since many over-the-counter products contain sympathomimetics, patients always should be told to consult with their clinician and/or pharmacist prior to using these drugs. 5-HT syndrome is characterized by confusion, restlessness, fever, abnormal muscle movements, hyper-reflexia, sweating, diarrhea, and shivering.31 It may result when a serotonergic agent is added to any serotonergic antidepressant, but the MAOIs are strongly associated with severe cases of 5-HT syndrome.31 5-HT syndrome is complicated by (a) an unawareness by clinicians of the diagnosis31 and (b) the fact that many implicated drugs are not obviously serotonergic in nature, such as dextromethorphan, meperidine, and tramadol.

Several antidepressants, including most of the SSRIs, nefazodone, and duloxetine, are known to inhibit various cytochrome P450 isoenzymes, thereby elevating plasma levels of substrates for those isoenzymes and thus potentially leading to increased adverse effects or toxicity. The propensity to cause these drug interactions will vary with the particular antidepressant and the precise isoenzyme9,22,30(Table 38–6).

Dosing

Dosing is summarized in Table 38–7.13,16,17,20,29,32 The extended-release formulations of venlafaxine and bupropion allow for once-daily dosing. The delayed-release capsule of fluoxetine can be given once weekly, which can be started 7 days after the last regular-release capsule or tablet. Selegiline is available as a transdermal patch and a dose of 6 mg/24 hours can be used without the usual dietary restrictions associated with MAOI use, although patients on the higher doses (9 and 12 mg/24 hours) should follow the usual dietary restrictions. Liquid dosage forms and disintegrating tablets of various antidepressants are ideal for patients who have difficulty swallowing tablets or capsules or those who otherwise may attempt to “cheek” their medication.

The starting dose is the usual therapeutic dose for most of the SSRIs, desvenlafaxine, duloxetine, and mirtazapine, whereas there is usually need for at least some upward titration of venlafaxine, bupropion, and nefazodone. A particular disadvantage of TCAs is that the customary way of dosing them involves meticulous upward titration from a small starting dose to a wide usual therapeutic dosage range. On the contrary, one advantage of some TCAs is that plasma levels may be used to help guide dosing, especially for those that have well-defined therapeutic plasma level ranges, including nortriptyline (50–150 ng/mL or mcg/L, or 190–570 nmol/L), desipramine (100–160 ng/mL or mcg/L, or 375–600 nmol/L), amitriptyline (75–175 ng/mL or mcg/L, 255–595 nmol/L), and imipramine (200–300 ng/mL or mcg/L, or 714–1,071 nmol/L).28

Table 38–6 Drug Interactions of Antidepressantsa

Image

Table 38–7 Dosing of Antidepressants in Adult Patients

Image

Image

Efficacy of Pharmacotherapy

image Each antidepressant has a response rate of approximately 60% to 80%, and no antidepressant medication or class has been reliably shown to be more efficacious than another.7,21 MAOIs may be the most effective therapy for atypical depression, but MAOI use continues to wane because of problematic adverse effects, dietary and drug restrictions, and possibility of fatal drug interactions.21,28 There is some evidence that dual-action antidepressants, such as TCAs and SNRIs, may be more effective for inpatients with severe depression than are the single-action drugs such as SSRIs,21,28 but the more general assertion that multiple mechanisms of action confer efficacy advantages is quite controversial.33

Selection of Medication

Figure 38–1 depicts a well-known algorithm for the pharmacologic treatment of nonpsychotic MDD—the Texas Medication Algorithm Project.34 Notable aspects of this algorithm include the preferential use of newer antidepressants in the earlier stages of treatment and sequential trials of antidepressant monotherapy prior to the use of combination therapy (see Managing Partial Response or Nonresponse). It has been shown that patients undergoing treatment guided by this algorithm fared better than those who received treatment not guided by the algorithm during a 1-year period, as measured by clinician-rated symptoms, self-reported symptoms, and overall mental functioning.35 Antipsychotic medication should be combined with antidepressant medication in cases of depression with psychotic features.16

Various factors must be taken into account when selecting antidepressant therapy for a particular patient. The most reliable predictor of response is the patient’s history of response (e.g., efficacy, side effects, and overall satisfaction) to antidepressants. To a lesser extent, the history of a first-degree relative’s response to antidepressants may be used to predict a patient’s response. Adverse-effect profiles should be considered because compliance is influenced greatly by tolerability. In this regard, a frank discussion should occur with the patient in order to determine which adverse effects are acceptable and which are not and how to deal with side effects (i.e., using chewing gum, hard candy, or ice chips for dry mouth). The clinician must be careful to contemplate potential drug–drug interactions and disease-state interactions. For instance, a patient with seizure disorder would be an inappropriate candidate for bupropion therapy. The presence of comorbid psychiatric conditions can help the clinician to determine the best antidepressant to choose for a patient. For example, an SSRI can treat both MDD and panic disorder, obviating the need for separate medication therapy. The patient must be willing and able to comply with dosing schedules (e.g., upward titration of TCAs or twice-daily dosing of nefazodone) and special instructions (e.g., dietary restrictions with MAOI therapy) associated with certain antidepressants. Another patient-specific factor is the potential for accidental or intentional overdosing because certain antidepressants (e.g., TCAs) are quite toxic and potentially lethal in overdose situations. Finally, the patient should be able to comfortably afford the chosen medication or else compliance is at risk.21

Time Course of Response

Unfortunately, antidepressants do not produce a clinical response immediately. Improvement in physical symptoms, such as sleep, appetite, and energy, can occur within the first week or so of treatment. Although a recent metaanalysis suggests earlier effects of antidepressant treatment,36 image it is widely accepted that approximately 2 to 4 weeks of treatment are required before improvement is seen in emotional symptoms of depression, such as sadness and anhedonia. Furthermore, as long as 6 to 8 weeks of treatment may be required to see the full effects of antidepressant therapy.7,21,23

Managing Partial Response or Nonresponse

Approximately one-third of patients with MDD do not respond satisfactorily to their first antidepressant medication.37 In such cases, the clinician must evaluate the adequacy of antidepressant therapy, including dosage, duration, and patient compliance.17 Treatment reappraisal should also include verification of the patient’s diagnosis and reconsideration of clinical factors that could be impeding successful therapy, such as concurrent medical conditions (e.g., thyroid disorder), comorbid psychiatric conditions (e.g., alcohol abuse), and psychosocial issues (e.g., marital stress).16

A series of reports from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial revealed that remission is associated with a better overall prognosis for patients than is improvement alone. STAR*D also established that in patients with a greater level of resistance, clinicians are less likely to push the patient to achieve remission, and in addition, those patients with the greatest levels of resistance had the highest rates of relapse. In these cases, STAR*D established some successful treatment recommendations.37

For patients who have experienced a partial response, extending the medication trial and/or using higher doses within the recommended dosage range of the antidepressant may be helpful.16 Another option is to employ augmentation therapy, that is, adding another medication that generally is not used as an antidepressant.38 Augmenting agents with clear efficacy include lithium and triiodothyronine, whereas initial enthusiasm has lessened to some extent for the serotonergic drugs buspirone and pindolol owing to negative findings in controlled trials.39 Aripiprazole, a second-generation antipsychotic was recently FDA approved for augmenting partial response to antidepressants. Efficacy has been suggested for dopaminergic drugs (e.g., pramipexole), psychostimulants (e.g., methylphenidate), and atypical antipsychotics (e.g., olanzapine), whereas various other medications such as anticonvulsants (e.g., valproic acid), modafanil, and estrogen have anecdotal evidence to support their use.39 A third option is to make use of combination therapy, whereby another antidepressant, typically from a different pharmacologic class, is added to the first antidepressant medication. Examples include combining bupropion and SSRIs and combining TCAs and SSRIs.39,40

Switching to a different antidepressant is a common strategy for patients who have had no response to initial antidepressant therapy but also is acceptable in cases of partial response.16 Relative to augmentation/combination, advantages of switching include improved compliance, decreased costs, and less concern over drug–drug interactions, whereas disadvantages include loss of time (“reset the clock”) and loss of any improvement seen with the initial drug.40 When switching from one antidepressant to another, clinicians may choose to stay within the same class (e.g., sertraline to fluoxetine) or go outside of the class (e.g., paroxetine to venlafaxine).38,40

Image

FIGURE 38–1. Strategies for the treatment of nonpsychotic major depression. Redrawn with permission from the Texas Medication Algorithm Project. (AD, antidepressant; BUP, Bupropion; BUS, Buspirone; ECT, electroconvulsive therapy; Li, lithium; T3, liothyronine; LTG, lamotrigine; MAOI, monoamine oxidase inhibitor; MOA, Mechanism of action; MRT, Mirtazapine; OLZ, Olanzapine; RSP, risperidone; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; VNS, vagus nerve stimulation.

Nonpharmacologic interventions in cases of treatment nonresponse include adding or changing to psychotherapy or initiating ECT.16

Duration of Therapy

Treatment of MDD can be conceptualized as a series of three phases: acute, continuation, and maintenance7,8,16 (Fig. 38–2). During a major depressive episode, a clinician will initiate antidepressant therapy for the purpose of attaining remission of symptoms. This acute phase of treatment typically lasts 6 to 12 weeks. image Because the typical major depressive episode lasts 6 months or longer, if antidepressant therapy is interrupted for any reason following the acute phase, the patient may relapse into the depressive episode. When treating the first depressive episode, antidepressants must be given for an additional 4 to 9 months in the continuation phase for the purpose of preventing relapse. Maintenance treatment takes place after the normal course of a major depressive episode in order to prevent recurrence, which is the development of future episodes. This phase can last for years, if not for a lifetime. Whereas all patients who suffer a major depressive episode should receive both acute and continuation treatment, not all of them will require maintenance treatment. The reason for this is because not all patients experience multiple major depressive episodes, and even in many cases in which they do, many years may separate the episodes. Therefore, the clinician must consider various factors in determining whether an individual patient requires maintenance treatment. A major factor is the number of prior episodes experienced by the patient. As discussed earlier, the more episodes experienced, the more likely future episodes will occur. This has led many clinicia ns to adopt the “three strikes and you’re on” approach, whereby a patient with a history of three or more major depressive episodes is given lifelong maintenance treatment because of the very high (i.e., 90%) chance of experiencing additional episodes. Other factors to consider are the severity of previous episodes, especially if suicide attempts were made or psychotic features were present, and patient preference.16 In general, the dose of the antidepressant required in the acute phase of treatment should be sustained during the continuation and maintenance phases.16

Discontinuation of Therapy

When the clinician and patient are ready to attempt discontinuation of therapy, whether at the end of the continuation phase or during the maintenance phase, it is best to do so via gradual taper of the antidepressant. This is done for two reasons. First, almost all antidepressants can produce withdrawal syndromes if discontinued abruptly or tapered too rapidly, especially antidepressants with shorter half-lives (e.g., venlafaxine, paroxetine, and fluvoxamine).17These withdrawal syndromes can cause sleep disturbances, anxiety, fatigue, mood changes, malaise, GI disturbances, and a host of other symptoms,17and often are confused with depressive relapse or recurrence.16 In general, a tapering schedule involving a small dosage decrement (e.g., paroxetine 5 mg) every 3 to 5 days should prevent significant withdrawal symptoms.17 Second, depressive symptoms may return on taper or discontinuation of the antidepressant. If antidepressant therapy is discontinued abruptly and depressive symptoms return weeks later, then the lag time to onset of action must be observed once the antidepressant is restarted (“reset the clock”); however, if gradual tapering is carried out, then early signs of depression can be countered with a return to the original dosage and a potentially quicker response.16 Depending on the patient’s illness and the clinical circumstances, tapering of the antidepressant can be extended for weeks or even months because of the concern over relapse or recurrence.

Image

FIGURE 38–2. The course of depression and phases of treatment. (From Refs. 7, 8.)


Patient Encounter, Part 3: Creating a Care Plan

On the basis of information presented, create a care plan for PT. Your plan should include:

(a) a statement of the drug-related needs and/or problems,

(b) the goals of therapy,

(c) a patient-specific detailed therapeutic plan, and

(d) a plan for follow-up to determine whether the goals have been achieved.


Special Considerations

Pregnant/Breast-Feeding Patients

It is a common misconception that pregnancy protects against depression (i.e., the “glow” of pregnancy). Depression actually is quite common in pregnancy, especially for women with a history of recurrent depression. Both maternal and fetal well-being must be taken into account when weighing the benefits and risks of using antidepressant therapy during pregnancy.41 In general, studies have not demonstrated an increased risk of miscarriage or congenital malformations with antidepressant use,41 but the prescribing information for paroxetine was changed recently to reflect the findings of epidemiological studies in which an increased risk of congenital malformations, in particular atrial or ventricular septal defects, was seen in infants born to women taking the drug during the first trimester of pregnancy.42 Sertraline and citalopram have also been associated with causing septal heart defects when taken during the first trimester. In addition, the incidence of having a baby with a septal heart defect was four times higher for mothers taking more than one SSRI in the first trimester.43 Antidepressants have been reported occasionally to cause perinatal sequelae, such as poor neonatal adaptation, respiratory distress, feeding problems, and jitteriness.41 Data concerning the long-term neurobehavioral effects of in utero antidepressant exposure remain quite limited.41Fluoxetine, citalopram, and TCAs have the greatest reproductive safety data and should be considered first-line treatments when pharmacotherapy is indicated.41

There will be at least some drug exposure to the infant from nursing mothers taking antidepressant medications. Although there have been rare anecdotal reports of adverse effects (i.e., respiratory depression and seizure-like episodes) in infants exposed to antidepressants through breast milk, no rigorous study has confirmed adverse effects of these drugs, and it is generally accepted that the benefits of breast-feeding outweigh the risks to the infant of antidepressant exposure. However, the decision needs to be made on an individual basis.44

Geriatric Patients

It is generally agreed that depression in older adults is under-recognized and undertreated.45 Although not uncommon in community samples, MDD is particularly prevalent among those living in long-term care facilities.15,45 Barriers to recognition of geriatric depression include the tendency toward “masked” presentations, that is, complaints of physical symptoms (e.g., pain and GI problems) instead of mood symptoms, the frequent presence of medical illnesses, and the overlap of mood and cognitive symptoms with those of dementia.15,45 Age-related pharmacokinetic and pharmacodynamic changes cause geriatric patients to be more sensitive to the effects of antidepressant medications.15Thus, lower starting doses of antidepressants with slow upward titrations as tolerated are recommended for geriatric patients.13,16,45 SSRIs are chosen frequently to treat geriatric depression because of their overall favorable adverse-effect profiles and low toxicity, whereas most TCAs are avoided owing to problematic anticholinergic, cardiovascular, and sedative properties.45 Desipramine and nortriptyline are two TCAs that are more tolerable in terms of these adverse effects and thus may be used in geriatric depression.45Other newer antidepressants, such as bupropion, venlafaxine, nefazodone, and mirtazapine, are alternatives for the treatment of geriatric patients as well.45

Pediatric Patients

Antidepressant medications appear to be useful for certain children and adolescents, particularly those who have severe or psychotic depression, fail psychotherapeutic measures, or experience chronic or recurrent depression. SSRIs generally are considered the initial antidepressants of choice, although comorbid conditions may favor alternative agents. Clinicians should be aware of the possibility of “behavioral activation” with the SSRIs, including such symptoms as impulsivity, silliness, daring conduct, and agitation.46 Desipramine should be used with caution in this population because of several reports of sudden death, and a baseline and follow-up ECG may be warranted when this medication is used to treat pediatric patients.9

The FDA has warned that antidepressants increase the risk of suicidality (i.e., suicidal thinking and behavior) in children and young adults. A large analysis of clinical trials revealed that the risk of such events was 4% for antidepressant medications versus 2% for placebo, although no completed suicides occurred in the trials. Because of this increased risk, antidepressants have black-box warnings concerning the matter, and patient medication guides are required to be distributed with each prescription or refill of antidepressant medications. image Pediatric patients should be observed closely for suicidality, worsened depression, agitation, irritability, and unusual changes in behavior, especially during the initial few months of therapy or at times of dosage changes. Furthermore, families and caregivers should be advised to monitor patients for such symptoms.47

Suicidal Patients

The FDA is in the process of analyzing data to determine whether there is an increased risk of suicidality in adult patients similar to that seen in pediatric patients (see above). Even though the suicidality risk for adults taking antidepressant medications is currently unknown, similar monitoring for suicidality and clinical worsening that is mandated for pediatric patients should be followed for adult patients.48

Table 38–8 Patient Counseling

Image

The clinician should bear in mind the toxic potential for the various antidepressant medications when patients already have or develop suicidality. The TCAs and MAOIs have narrow therapeutic indices, whereas the SSRIs, SNRIs, nefazodone, and mirtazapine have wide therapeutic indices.21

Patient Counseling

Major counseling points and the clinical rationale behind them are outlined in Table 38–8.28,49 image Lack of patient understanding concerning optimal antidepressant drug therapy frequently leads to partial compliance or noncompliance with therapy; thus, the primary purpose of antidepressant counseling is to enhance compliance and improve outcomes.49

OUTCOME EVALUATION

• Review the patient’s medication profile to ensure that there are no potential/actual pharmacotherapy problems related to dosing, disease-state precautions or contraindications, drug–drug interactions, or unnecessary therapeutic duplication.

• Verify the extent of compliance with pharmacotherapy.

• Assess the response to pharmacotherapy, especially with regard to suicidality and those symptoms that cause significant subjective distress and/or functional impairment.

• Determine whether the patient is experiencing adverse effects of pharmacotherapy. Although general questioning (e.g., “Are you having any side effects?”) may reveal some problems with therapy, it is better to use direct questioning concerning adverse effects that are most common and/or most problematic (e.g., “Have you noticed any change in your sexual functioning?”).

• Provide counseling to enhance patient understanding of MDD and its pharmacotherapy.

Abbreviations Introduced in This Chapter

Image


Patient Care and Monitoring

1. Assess the patient’s severity of symptoms to determine if patient-directed therapy is appropriate or whether a psychiatrist should evaluate the patient.

2. Obtain a thorough history of prescription, nonprescription, natural, and illicit drug use. Rule out medications or medical disorders that may cause or mimic depressive symptoms.

3. Review Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria to determine an appropriate diagnosis.

4. Determine appropriate pharmacologic and psychological treatments (e.g., cognitive-behavioral therapy), including what has been helpful to the patient in the past.

5. Educate patient and/or caretaker about the disease state, lifestyle modifications, and medication therapy.

• What risk factors are present that could contribute to depression?

• What lifestyle modifications could be made to improve condition (e.g., exercise)?

• How the medication should be taken?

• What potential adverse effects may occur?

• Which drugs may interact with their therapy?

• Warning signs and prevention of suicidal and/or homicidal ideation.

6. Develop a plan to assess effectiveness of pharmacologic therapy after 4 weeks of being on a clinically effective dose.

7. Evaluate the patient for the presence of adverse drug reactions, drug allergies, and drug interactions.

8. Assess improvement in quality-of-life measures such as physical, psychological, and social functioning and well-being.

9. If the patient does not respond, determine if the patient is taking the appropriate medication and dose.

10. Recommend changes in therapy if the patient does not respond.

11. Determine long-term maintenance therapy.



image Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.


REFERENCES

1. The top 300 prescriptions for 2005 by number of U.S. prescriptions dispensed. http://www.rxlist.com/top200.htm.

2. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: Results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003;289:3095–3105.

3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Text revision. Washington, DC: American Psychiatric Association, 2000.

4. World Health Organization. Depression. http://www.who.int/mental_health/management/depression/definition/en/print.html.

5. Levinson DF. The genetics of depression: A review. Biol Psych 2006;60:84–92.

6. Tennant C. Life events, stress and depression: a review of recent findings. Aust N Z J Psychiatry 2002;36:173–182.

7. Boland RJ, Keller MB. Antidepressants. In: Tasman A, Kay J, Lieberman JA, eds. Psychiatry Therapeutics, 2nd ed. Hoboken, NJ: Wiley, 2003:292–334.

8. Stahl SM. Essential psychopharmacology: Neuroscientific basis and practical applications, 3rd ed. New York: Cambridge University Press, 2008:135–295.

9. Kando JC, Wells BG, Hayes PE. Depressive disorders. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008:1235–1255.

10. Belmaker RH, Agam G. Major Depressive Disorder. New Engl J Med 2008;358:55–68.

11. Wolkowitz OM, Reus VI. Neurotransmitters, neurosteroids, and neurotrophins: New models of the pathophysiology and treatment of depression. World J Biol Psychiatry 2002;4:98–102.

12. Vaidya VA, Duman RS. Depression—emerging insights from neurobiology. Br Med Bull 2001;57:61–79.

13. Peveler R, Carson A, Rodin G. Depression in medical patients. BMJ 2002;325:149–152.

14. Patten SB, Barbui C. Drug-induced depression: A systematic review to inform clinical practice. Psychother Psychosom 2004;73:207–215.

15. Raj A. Depression in the elderly. Tailoring medical therapy to their special needs. Postgrad Med 2004;115:26–28, 37–42.

16. Kaiser Permanente Care Management Institute. Depression Clinical Practice Guidelines Oakland (CA). Kaiser Permanente Care Management Institute, 2006; 1–196.

17. Trivedi M, Kleider BA. Algorithm for the treatment of chronic depression. J Clin Psychiatry 2001;22–29.

18. VNS therapy system. http://www.fda.gov/cdrh/mda/docs/p970003s050.html.

19. Gershon AA, Dannon PN, Grunhaus L. Transcranial magnetic stimulation in the treatment of depression. Am J Psychiatry 2003;160:835–845.

20. Sutherland JE, Sutherland SJ, Hoehns JD. Achieving the best outcome in treatment of depression. J Fam Pract 2003;52:201–209.

21. Cates M. Selecting antidepressant therapy for patients with major depression. Am J Pharm Educ 2001;65: 190–194.

22. Spina E, Scordo MG. Clinically significant drug interactions with antidepressants in the elderly. Drugs Aging 2002;19:299–320.

23. Maxmen JS, Ward NG. Psychotropic Drugs Fast Facts. 3rd ed. New York: WW Norton, 2002:95–214.

24. Cassano P, Fava M. Tolerability issues during long-term treatment with antidepressants. Ann Clin Psychiatry 2004;16:15–25.

25. Worthington JJ, Peters PM. Treatment of antidepressant-induced sexual dysfunction. Drugs Today 2003;39: 887–896.

26. Westanmo AD, Gayken J, Haight R. Duloxetine: A balanced and selective norepinephrine- and serotonin-reuptake inhibitor. Am J Health-Syst Pharm 2005;62:2481–2490.

27. Eli Lilly and Company. Manufacturer’s Information. Prozac. Indianapolis, IN, 2007.

28. Stimmel GL. Mood disorders. In: Helms RA, Quan DJ, eds. Textbook of Therapeutics: Drug and Disease Management, 8th ed. Philadelphia: Lippincott Williams & Wilkins, 2006:1416–1431.

29. Clinical Pharmacology. http://cpip.gsm.com/.

30. Devane CL. Antidepressant-drug interactions are potentially but rarely significant. Neuropsychopharmacology 2006;31:1594–1604.

31. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112–1120.

32. To SE, Zepf RA, Woods AG. The symptoms, neurobiology, and current pharmacological treatment of depression. J Neurosci Nurs 2005;37:102–107.

33. Burke WJ. Selective versus multi-transmitter antidepressants: Are two mechanisms better than one? J Clin Psychiatry 2004;65(suppl 4):37–45.

34. Texas Medication Algorithm Project—nonpsychotic depression algorithm. http://www.dshs.state.tx.us/mhprograms/disclaimer.shtm.

35. Trivedi MH, Rush AJ, Crismon ML, et al. Clinical results for patients with major depressive disorder in the Texas Medication Algorithm Project. Arch Gen Psychiatry 2004;61:669–680.

36. Posternak MA, Zimmerman M. Is there a delay in the antidepressant effect? A meta-analysis. J Clin Psychiatry 2005;66:148–158.

37. Rush JA. STAR*D: What have we learned? Am J Psych 2007;164: 201–204.

38. Klein N, Sacher J, Wallner H, et al. Therapy of treatment resistant depression: Focus on the management of TRD with atypical antipsychotics. CNS Spectr 2004;9: 823–832.

39. Fava M. Augmentation and combination strategies in treatment-resistant depression. J Clin Psychiatry 2001;62(suppl 18):4–11.

40. Nelson JC. Managing treatment-resistant major depression. J Clin Psychiatry 2003;64(suppl 1):5–12.

41. Cohen LS, Nonacs R, Viguera AC, Reminick A. Diagnosis and treatment of depression during pregnancy. CNS Spectr 2004;9:209–216.

42. FDA public health advisory—paroxetine. http://www.fda.gov/cder/drug/advisory/paroxetine200512.htm.

43. Pedersen LH, Henriksen TB, Vestergaard M, et al. Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: Population based cohort study. BMJ 2009;339:b3569.

44. Gentile S. The use of contemporary antidepressants during breastfeeding: A proposal for a specific safety index. Drug Safety 2007;30:107–121.

45. Doraiswamy PM. Contemporary management of comorbid anxiety and depression in geriatric patients. J Clin Psychiatry 2001:62(Suppl 12):30–35.

46. Ryan ND. Treatment of depression in children and adolescents. Lancet. 2005;366:933–940.

47. FDA public health advisory—suicidality in children and adolescents being treated with antidepressant medications. http://www.fda.gov/cder/drug/antidepressants/SSRIPHA200410.htm.

48. FDA public health advisory—suicidality in adults being treated with antidepressant medications. http://www.fda.gov/cder/drug/advisory/SSRI200507.htm.

49. Bollini P, Pampallona S, Kupelnick B, et al. Improving compliance in depression: A systematic review of narrative reviews. J Clin Pharm Ther 2006;31:253–260.