Table 86-5

Comparison of Selected Depression Rating Scales

Instrument Minimal Mild Moderate Severe

Hamilton (HAM-D)—17 item (clinician rated) <8 8–15 16–27 >27

Beck Depression Inventory (BDI)

BDI (clinician rated) <10 10–16 17–29 >29

BDI (patient rated) <10 10–15 16–23 >23

Quick Inventory for Depressive Symptoms (QIDS)

QIDS-C16

(clinician rated) <6 6–10 11–15 >15

QIDS-SR16

(patient rated) <6 6–10 11–15 >15

Patient Health Questionnaire (PHQ) (patient rated) <10 11–14 15–19 >19

Montgomery-Åsberg Depression Rating Scale (MADRS)

(clinician rated)

<7 7–19 20–34 >34

Nondrug Therapies for Depression

PSYCHOTHERAPY

For the treatment of mild-to-moderate depression, psychotherapy has proved to be

comparable to pharmacologic intervention and may be preferred by some patients.

There are many types of psychotherapy, and experts suggest that cognitive behavioral

therapy (CBT), behavioral activation (BA), and interpersonal psychotherapy (IPT)

are effective with CBT being preferred for monotherapy.

5 For the acute treatment of

severe depression, antidepressants appear to be more effective than psychotherapy

alone and have a more rapid onset of therapeutic action.

5,26 The beneficial effects of

psychotherapy, however, may persist longer than medication-related benefits after the

interventions have been formally discontinued. In addition, psychotherapy may be

particularly beneficial for preventing relapse among patients who previously

demonstrated a therapeutic response to antidepressants.

53 Overall, the combination of

treatments is superior to either intervention alone.

5,10

SOMATIC INTERVENTIONS

ECT is a safe, rapid-acting, and highly effective therapeutic intervention. ECT was

enormously popular during the 1940s and 1950s and was used without discretion to

treat a wide variety of psychiatric conditions. This practice waned with the advent of

effective psychotropic medications, and with the accumulation of case reports

describing fractures and severe cognitive impairment in treated patients. Since the

1950s, the ECT procedure has undergone considerable transformation and

refinement.

54 Adjunctive medications are now routinely administered to prevent

adverse effects and reduce morbidity (e.g., a short-acting barbiturate for general

anesthesia, an anticholinergic agent to prevent bradycardia and to dry excessive

airway secretions, succinylcholine to prevent fractures from tonic–clonic

contractions). The electric stimulus itself is no longer applied in one steady current

but now consists of a series of brief pulses that have been shown to decrease the

severity of postictal headaches and memory impairment.

Fundamentally, ECT features the induction of generalized seizures through an

electric current delivered by bilateral or unilateral electrode placement. Medications

that raise the seizure threshold or promote cognitive impairment (lithium) should be

discontinued before the procedure although this is not always necessary. Adverse

effects are generally minimal and consist mainly of transient anterograde amnesia

(i.e., difficulty remembering events around the time of the procedure), retrograde

amnesia, confusion, headaches, and muscle aches. Cardiovascular effects (e.g.,

ventricular arrhythmias, myocardial infarction [MI]) are the most ominous sequelae,

but these events are extremely rare.

54

ECT is recommended for patients with treatment-resistant depression, severe

vegetative depression, psychotic depression, and severe depression in pregnancy.

Overall response rates are impressive, ranging from 70% to 90%, and ECT has the

distinct advantage of inducing a therapeutic response within the first week or two of

treatments.

54–56 The recommended frequency of ECT treatments is variable. Most

institutions have used three sessions weekly to induce a therapeutic response acutely,

although evidence suggests that twice-weekly sessions are better tolerated and more

cost-effective.

57 The frequency of treatments thereafter (i.e., maintenance therapy) is

recommended that ECT be administered weekly for 1 month and less frequently

thereafter may be as effective as aggressive pharmacotherapy in preventing relapse.

58

Other somatic interventions have also been used successfully to treat depression.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive procedure

involving the application of an electrical magnetic stimulus across the scalp, which

ultimately generates an electrical field in the cerebral cortex.

59,60 Unlike ECT, rTMS

does not generate an actual seizure, and it is very well tolerated, with common side

effects consisting of transient scalp discomfort and headaches. Preliminary

investigations successfully used repetitive high-frequency techniques in depressed

subjects, and imaging studies have shown functional improvements consistent with

antidepressant properties. However, not all studies have shown efficacy, and overall

results show only a slight benefit for depression or treatment refractory

depression.

56,61,62

In 2008, the US Food and Drug Administration (FDA) decided to

allow the marketing of TMS for patients who failed a minimum of one prior

antidepressant trial.

Vagus nerve stimulation involves the surgical implantation of an electrical device

in the subcutaneous tissue below the clavicle, which sends an impulse along the left

vagal nerve into the cerebral cortex. Setting adjustments are through a telemetric

wand.

56,63

It is currently FDA-approved for the management of

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treatment-resistant depression although its effect takes time and cannot be

considered an acute therapy. Implantation of the device is an invasive procedure with

standard risks associated with this type of surgery. However, long-term safety has

been shown in both epilepsy and depression studies. It may be useful when combined

with medication treatment.

56

Light therapy or phototherapy is particularly effective for relieving the irritability

and malaise associated with seasonal affective disorder, a milder form of depression

that has been attributed to decreases in natural sunlight found with seasonal

variation.

10,64 Phototherapy is administered in the form of a light box delivering 1,500

to 10,000 lux for a period of 1 to 2 hours daily. It is extremely well tolerated.

LIFESTYLE ADJUSTMENTS

Any therapeutic approach to mood disorders should seek to reverse unhealthy or

destructive lifestyle habits and promote other activities that may relieve stress and

facilitate well-being. Alcohol and illicit drug use should be minimized (if not

prohibited) in patients suffering from depressive disorders. Sleep habits should be

evaluated and improved to ensure optimal rest. Dietary factors should be modified to

promote diverse, balanced, and nutritional eating habits.

Increased physical activity and sustained cardiovascular exertion can impart a

variety of health benefits, including improvement in depressive symptoms.

5 Although

investigations examining the effectiveness of exercise for depression have met with

mixed results, exercise can regulate appetite, improve sleep patterns, increase

energy, enhance self-esteem, and promote a return to euthymic status.

65 Exercise has

been shown to increase circulating concentrations of serotonin in the periphery and

enhance neurogenesis in the hippocampus.

66 Other activities may also serve to

relieve stress and help patients acquire insights into their emotional well-being.

These pursuits can range from daily journal writing (journaling), meditation, yoga,

and Tai chi. Classes in mindfulness-based meditation, in particular, are offered at

many medical centers, and the health benefits of this approach have been

demonstrated in a wide range of medical conditions including cancer, chronic pain

syndromes, and human immunodeficiency virus (HIV) illness.

67

MAJOR DEPRESSIVE DISORDER

CASE 86-1

QUESTION 1: A.R. is a 25-year-old female in graduate school who presents to the student health clinic for a

routine physical examination. During her visit, A.R. states, “I’ve been feeling pretty down lately and just want to

give up.” Her physical examination is unremarkable, and all laboratory tests (complete blood count with

differential, chemistry panel, and thyroid function tests) are within normal limits. A human chorionic

gonadotropin test is negative. Her medical history is noncontributory, takes no medication, uses a daily

multivitamin, and denies drinking alcohol, smoking cigarettes, or using illicit substances.

Diagnosis

When asked, A.R. states that she has had increasing periods of depressed mood

during the past few months and often finds herself crying in the morning for no

particular reason. She reports that she has no interest in her old hobbies (playing the

piano, mountain biking, gardening). During the past 6 months, her appetite has

decreased, and she has lost 15 pounds. She feels overwhelmed about all of her

academic work and job and has difficulty sleeping, often waking in the middle of the

night and being unable to fall back asleep. She has no energy during the day and finds

it difficult to concentrate or make decisions. This is clearly impacting her ability to

finish her graduate work as she is falling behind and has been getting extensions for

her project due dates.

On examination, A.R. is an appropriately dressed woman who appears sad but

who is alert, coherent, and logical. Her affect is constricted, apprehensive, and sad.

Mood is depressed, and she admits having vague suicidal ideation but she has no

specific plans. She is oriented to person, place, and time, but shows some recent

memory deficits. Her intelligence is estimated to be above average. Concentration

and abstractions (e.g., “don’t cry over spilled milk,” “a rolling stone gathers no

moss”) are satisfactory. She denies hearing voices or other hallucinations. She denies

any symptoms of mania such as increased periods of energy, rapid speech, and racing

thoughts (See Chapter 87, Bipolar Disorders). She has good insight and judgment into

her illness. A.R. is asked to complete the PHQ-9 and has a total score of 15 with five

different questions scoring 2 or more and as well as question one and two scoring 2

(i.e., moderate-to-severe symptoms). After reviewing the PHQ-9 results, a more indepth interview is conducted and A.R. is diagnosed as having MDD. What nondrug

options have shown efficacy?

From A.R.’s history, she appears to be exhibiting a dysphoric or depressed mood

1.

2.

3.

as well as anhedonia (lack of interest in hobbies or pleasurable activities). In

addition, she demonstrates frequent episodes of crying, decreased appetite (with an

unintentional 15-pound weight loss), poor concentration, low energy, suicidal

ideation, worthlessness, and inappropriate guilt. Her mental status examination is

consistent with these target symptoms, revealing a constricted, sad affect (physical

manifestation of inner emotional states), and frequent crying episodes during the

interview.

Based on the DSM-5 criteria (Table 86-4), A.R. has MDD. During the past 2

weeks, she has consistently exhibited at least five of the associated symptoms, one of

which is depression or anhedonia. It does not appear that her symptoms are the result

of any medical condition, medication, thought disorder, or uncomplicated

bereavement. These are impacting functioning because she is not able to complete her

school work assignments.

Psychotherapy has been shown to have beneficial effects on mild-to-moderate

depression. Studies have also shown that combined with medication the beneficial

effects are greater than either alone. ECT is an effective somatic treatment but

typically reserved for more refractory cases. rTMS is currently being studied but has

not been standardized yet. Lifestyle modifications such as exercise generally have

benefit, but typically are not strong enough on their own to treat clinically significant

depressed symptoms.

DRUG MANAGEMENT

Drug Selection: General Considerations

CASE 86-1, QUESTION 2: A.R. agrees to a therapeutic trial of an antidepressant. What are the drug

options available for A.R.’s depressive symptoms? What considerations should be made when selecting

antidepressant therapy?

In randomized, controlled trials (RCTs) of antidepressants, a therapeutic response

is usually apparent in 60% to 70% of subjects receiving active medication

(therapeutic response is defined as a ≥50% decline in depression rating scale

score).

5,10

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Antidepressants can be divided into different categories:

Selective serotonin reuptake inhibitors (SSRIs)

Serotonin norepinephrine reuptake inhibitors (SNRIs)

Tricyclic antidepressants (TCAs)

4.

5.

6.

Miscellaneous antidepressants (e.g., trazodone, nefazodone, mirtazapine,

bupropion)

Monoamine oxidase inhibitors (MAOIs)

Serotonin reuptake inhibitor and receptor modulators (the newest group)

When comparing the impact of antidepressants on changes in depressive

symptoms, all antidepressants are considered equal, regardless of class. It is

possible that dual-acting antidepressants (SNRIs and TCAs) may be more effective

in the severely depressed but this has not resulted in experts explicitly recommending

them over other factors such as comorbid diseases, contraindications, or drug

interactions (Tables 86-6 and 86-7)

5,10,26,68 Sertraline and escitalopram have the best

efficacy to safety/tolerability ratio.

5,10,68,69 Thus, with no other factors influencing the

selection of the medication, it may be easier to select either of these.

One of the first factors to consider is the patient’s history of response to previous

antidepressant drug therapy. If this history is unavailable (or the patient has never

received an antidepressant before), the clinician should inquire about family history.

If a first-degree relative had a successful course of antidepressant treatment with

minimal adverse effects, that specific medication (or another from the same

antidepressant class) would be a prudent choice for initial therapy. The potential

impact of an antidepressant on concurrent medical conditions or disease states is

often considered next. For example, certain antidepressants (e.g., TCA, paroxetine,

mirtazapine) can cause significant weight gain and would not be desirable choices

for obese patients, whereas bupropion should be avoided in patients with a history of

seizures. Pharmacokinetic drug interactions will also help determine the preferred

first-choice option. Among the SSRIs, fluoxetine and paroxetine have significant

inhibitory effects on CYP450 2D6, whereas citalopram, escitalopram, sertraline, and

fluvoxamine have minimally clinical inhibitory effects on 2D6. Fluvoxamine does

have a strong impact on CYP1A1/2, and fluoxetine has a weak-to-moderate impact

on 3A4 (Table 86-8).

70 Other important patient-specific factors to consider in the

selection of an agent include safety in overdose, ease of administration (once-daily

vs. divided doses), and necessity for dose titration, cost, and patient preference

(Tables 86-6–86-9).

10

Table 86-6

Factors to Consider in Selecting an Antidepressant

History of prior response (personal or family member)

Safety in overdose

Adverse effect profiles

Patient age

Concurrent medical/psychiatric conditions

Concurrent medications (e.g., potential for drug interactions)

Convenience (e.g., minimal titration, once-daily dosing)

Cost

Patient preference

Table 86-7

Pharmacology of Antidepressant Medications

Medication Serotonin Norepinephrine Dopamine

Bioavailability

(Oral)

Protein

Binding

Half-Life

(hours)

(Active

Metabolite)

Selective Serotonin Reuptake Inhibitors

Fluoxetine + + + + 0/+ 0 80% 95% 24–72 (146)

Sertraline + + + + 0/+ + >44% 95% 26 (66)

Paroxetine + + + + + 0 64% 99% 24

Citalopram + + + + 0 0 80% <80% 33

Escitalopram + + + + 0 0 80% 56% 27–32

Serotonin Norepinephrine Reuptake Inhibitors

Venlafaxine + + + + + + + 0 92% 25%–29% 4 (10)

Desvenlafaxine + + + + + + 0 80% 30% 11 (0)

Duloxetine + + + + + + + + 0 50% >90% 12 (8–17)

Levomilnacipran + + + + + 0 92% 22% 12

Dopamine/Norepinephrine Reuptake Inhibitors

Bupropion 0/+ + ++ >90% 85% 10–21

Tricyclic Antidepressants

Desipramine + + + + + 0/+ 51% 90% 12–28

Nortriptyline + + + + + 0 46%–56% 92% 18–56

Amitriptyline + + + + + + + + 0 37%–49% 95% 9–46 (18–56)

Imipramine + + + + + 0/+ 19%–35% 95% 6–28 (12–28)

Doxepin + + + + 0 17%–37% 68%–85% 11–23

Others

Mirtazapine + + + + + + + 0 50% 85% 20–40

Nefazodone + + + + 0 20% 99% 5

Vilazodone + + + + 0 0 72% 98% 25

Vortioxetine + + + + 0 0 75% 99% 60

0, negligible; +, very low; + +, low; + + +, moderate; + + + +, high.

Source: Practice guideline for the treatment of patients with major depressive disorder. 3rd ed. Arlington, VA:

American Psychiatric Association; 2010; Deardorff WJ, Grossberg GT. A review of the clinical efficacy, safety

and tolerability of the antidepressants vilazodone, levomilnacipran and vortioxetine. Expert Opin Pharmacother.

2014;15(17):2525–2542.

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Table 86-8

Drug Interactions of the Cytochrome P-450 System

Relative Rank CYP1A2 CYP2C9/19 CYP2D6 CYP3A4

Strong Fluvoxamine Fluvoxamine

Fluoxetine

Nefazodone

Paroxetine

Moderate Duloxetine

Bupropion

Fluoxetine Fluoxetine

Weak Venlafaxine Fluvoxamine

Sertraline Sertraline Sertraline Sertraline

Escitalopram

Paroxetine Paroxetine Paroxetine

Fluvoxamine

Fluoxetine Citalopram

Nefazodone

Treatment Expectations

A similar delayed pattern of therapeutic response has been observed with all

antidepressant medications. Patients often begin to show signs of clinical response

during the first 1 or 2 weeks of active treatment and maximum improvement may not

be evident until weeks 6-8.

5,26,71 The pattern of patient response can also be

generalized, with neurovegetative symptoms often the first to subside (e.g., altered

sleep or appetite, decreased energy, excessive worrying and irritability). Cognitive

symptoms are slower to respond, and 3 to 4 weeks or more may elapse before

improvements are evident. These symptoms include excessive guilt or pessimism,

poor concentration, hopelessness or sadness, and decreased libido.

Selective Serotonin Reuptake Inhibitors

ADVERSE EFFECTS

There is a delay in onset of full efficacy, but side effects will occur soon after

starting the medication. Common side effects of SSRIs are related to the fact that

despite their neurotransmitter specificity to increasing the amount of serotonin in the

synapse there are at least 14 different serotonin receptors having different effects.

15

Distinct side effect profiles have emerged, consisting of gastrointestinal (GI)

complaints, CNS disturbances, and sexual dysfunction.

All of these medications may induce nausea, but this tends to be a transient effect

that diminishes after the first week of treatment. Typically, SSRI-induced nausea

occurs 1 to 2 hours after oral administration. Nausea with SSRIs can be a local effect

but is also mediated centrally through the extra serotonin-stimulating serotonin

receptors (5-HT3

) that activate the chemoreceptor trigger zone.

72 SSRIs may also

cause transient and bothersome increases in GI motility. This diarrhea is generally

limited to the first few weeks of treatment and is also related to the extra serotoninstimulating 5-HT3

receptors along the GI tract. As with nausea, this diminishes in the

first few weeks of treatment unless the dose is increased. In contrast, paroxetine

possesses a relatively mild anti-muscarinic effect that can manifest as constipation,

dry mouth, or urinary hesitancy. Although this effect is mild, paroxetine use is often

discouraged in patients with preexisting constipation or those where any

anticholinergic effects are to be avoided such as the elderly.

SSRIs can have myriad effects on the CNS, with disturbances in sleep being a

primary concern. SSRIs can have significant but highly variable effects on sleep

architecture. In sleep studies, SSRIs have been shown to increase sleep latency and

decrease sleep efficiency, often resulting in morning sleepiness or malaise. Many

patients also notice that their dreams become more vivid and memorable, which may

be an undesirable experience. REM stage sleep may be prolonged, resulting in less

fitful sleep.

73

It should be emphasized, however, that sleep may eventually improve

once the antidepressant properties of the medications are apparent and baseline

depressive symptoms are relieved (e.g., midnocturnal insomnia).

The deleterious effects of SSRI on sexual function can often lead to medication

nonadherence.

74 The reported incidence of sexual dysfunction ranges from 1.9% to

75%, reflecting the difficulty in appropriately measuring this adverse event.

75 The

actual incidence of SSRI-induced sexual dysfunction is approximately 30% to 50%,

and it appears to be slightly more common in men, but the severity may be worse in

women.

75 Delayed orgasm is the most common sexual complaint attributed to SSRIs

or SNRIs, and should be distinguished from decreases in desire or libido, which are

considered to be an aspect of the psychopathology of depression itself. This

iatrogenic effect on orgasms has actually been used to clinical advantage in treating

men by delaying premature ejaculation, but most patients find it undesirable.

75 All

SSRIs are at risk for causing sexual dysfunction, because it is due to the increased

serotonin-stimulating 5-HT2c

receptors. Paroxetine has a higher rate than the others

because it also inhibits nitric oxide synthase, reducing nitric oxide levels.

75

It also

appears that this is a dose-dependent phenomenon, which may respond favorably to a

decrease in daily dosage. Unlike the GI and CNS side effects reported with SSRIs,

sexual dysfunction is not usually a transient adverse effect and must be addressed by

clinicians if patients are to continue pharmacotherapy.

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Table 86-9

Dosage Ranges of Commonly Prescribed Antidepressant Medications

Medication Starting Dose (mg/day) Usual Dosage (mg/day)

Selective Serotonin Reuptake Inhibitors

Fluoxetine 20 20–60

Sertraline 50 50–200

Paroxetine 20 20–60

Paroxetine ER 12.5 25–75

Citalopram 20 20–60

Escitalopram 10 10–20

Serotonin Norepinephrine Reuptake Inhibitors

Venlafaxine, IR 37.5 75–375

Venlafaxine, ER 37.5 75–375

Desvenlafaxine 50 50

Duloxetine 60 60–120

Levomilnacipran 20 40–120

Dopamine Reuptake Inhibitors

Bupropion, IR 150 300–450

Bupropion, SR 150 300–400

Bupropion, ER 150 300–450

Tricyclic Antidepressants

Imipramine 25–50 100–300

Desipramine 25–50 100–300

Amitriptyline 25–50 100–300

Nortriptyline 25 50–200

Others

Mirtazapine 15 45

Nefazodone 50 150–300

Serotonin Reuptake Inhibitors and Receptor Modulators

Vilazodone 10 20–40

Vortioxetine 10 20

Source: Practice guideline for the treatment of patients with major depressive disorder. 3rd ed. Arlington, VA:

American Psychiatric Association; 2010; Deardorff WJ, Grossberg GT. A review of the clinical efficacy, safety

and tolerability of the antidepressants vilazodone, levomilnacipran and vortioxetine. Expert Opin Pharmacother.

2014;15(17):2525–2542.

The detection and proper management of SSRI-induced sexual dysfunction can be

one of the most important factors in ensuring medication adherence. Clinicians may

be uncomfortable asking patients about their sexual activities and satisfaction, but the

high incidence of this side effect (and low likelihood of patients volunteering this

information) necessitates a thoughtful and direct approach. Some patients

acknowledge sexual dysfunction but decide that improvements in mood and overall

health outweigh limitations in sexual performance; however, others simply stop the

medication if the side effect is never addressed.

It may be wise to advise patients that sexual function may change over time,

depending on the type and etiology of sexual dysfunction experienced. Depression

itself is associated with a decreased libido in 70% to 90% of untreated patients.

76

This symptom will most likely subside with a successful course of antidepressant

treatment. Delayed ejaculation or anorgasmia, however, may be caused by SSRIs and

SNRIs, often persisting and jeopardizing treatment.

Ordinarily, one of the first options in managing sexual dysfunction is to reduce the

dosage, but this may induce a return in symptoms because increasing the dose

initially was likely due to

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lack of full effect. It is also possible to introduce drug holidays. Small open-label

studies with short-acting SSRIs (e.g., paroxetine) suggested that if patients skipped

their doses on Friday and Saturday, sexual function would return to normal on the

weekends.

77,78 Although this method was reported to be successful, it may also

promote nonadherence with medication and lead to increased risk of relapse and

withdrawal symptoms and is therefore not recommended.

If the patient has had a therapeutic response to the antidepressant, the next option in

this setting is to consider antidotes to SSRI-induced sexual dysfunction. One option is

to add the antidepressant bupropion. Clinical reports and controlled investigations

suggest that the addition of bupropion can be helpful for restoring sexual desire and

may relieve delayed orgasm or anorgasmia in approximately 50% of patients.

5,79–82

This therapeutic effect has been demonstrated in depressed and nondepressed

patients alike. A common dosing technique is to start with 150 mg of bupropion

daily. If unsuccessful, the dose can be increased to 150 mg of bupropion sustained

release (SR) twice daily after several days (or 300 mg of the extended-release [XL]

preparation). The mechanisms of SSRI-induced sexual dysfunction, and bupropion

relief, are not well understood, but likely due to the pro-sexual effects of increasing

DA.

83

Other remedies have been prescribed for SSRI-induced sexual dysfunction. A

large randomized, controlled trial examined the impact of sildenafil on male patients

suffering from this side effect.

84 Overall, 54% of patients randomly assigned to

sildenafil found it to be effective compared with a 4% response rate with placebo.

Open-label trials of sildenafil in women experiencing SSRI-induced anorgasmia

have also reported improvements. Tadalafil has also shown similar efficacy

suggesting a class effect.

85

Amantadine, buspirone, and yohimbine also have been used successfully to

reverse delayed ejaculation or decreased libido, but the evidence for efficacy is

limited.

86–88 One small double-blind study compared the effects of amantadine with

buspirone or placebo among depressed patients experiencing sexual dysfunction on

antidepressants.

89 All three study treatments improved sexual dysfunction to a

comparable extent, and the only statistically significant finding was related to an

increase in energy reported among patients receiving amantadine (vs. placebo). An

open-label trial of Ginkgo biloba in men and women with sexual dysfunction

reported very high success rates, but mixed results have been reported in clinical

practice.

90 Mirtazapine is capable of blocking postsynaptic 5-HT2

receptors and has

been shown to have less sexual dysfunction than SSRIs.

91 The 5-HT and histamine

receptor antagonist cyproheptadine has been shown to alleviate this adverse event.

However, due to its broad effect on all 5-HT receptors, depression relapse and

serotonin withdrawal can occur resulting in it not being recommended. Finally,

stimulants such as methylphenidate or dextroamphetamine may increase libido in

SSRI-treated patients, but the potential for dependence and abuse discourages their

routine administration.

92

All antidepressants have a black box warning regarding the possibility of an

increase in suicidal thinking, specifically in persons 24 years old and younger. In

regard to completed suicide, the rate is less in adult and pediatric patients treated

with antidepressants than those who are not treated.

5,26,93,94 However, studies have

shown a rate in suicidal thinking among children and young adults of 4% in the

medication arms compared to 2% in placebo arms.

94 Therefore, in order to protect

the patient, it is recommended that when an antidepressant is initiated in a child or

adolescent, the patient should visit with the clinician every week in the first month,

every 2 weeks in the second month, and then monthly for the next month. Adults

should also be monitored frequently, and weekly visits initially have shown

increased adherence rates. However, other factors may play a role in monitoring such

as access to care and distance the patient needs to travel for the appointment.

Therefore, it is recommended to at least speak with the adult patient (e.g., via

telephone) at least every 1 to 2 weeks in the acute phase (initial 12 weeks) of

treatment to assess suicidality but also to check for side effects and adherence.

5,10

SSRIs are dramatically safer in overdose compared to tricyclic antidepressants and

are preferred for those with suicidal thinking or comorbidities that put them at risk

for impulsive acts of self-harm such as substance misuse.

In addition to GI, CNS, and sexual side effects, a variety of other, less-common

adverse sequelae have occurred with SSRIs. Headache can occur with SSRIs at a

rate of approximately 10% to 15% with all agents similar and slightly greater than

placebo, with discontinuations due to headache very low at 1% to 3%.

95 This may be

due to the effects of serotonin on 5-HT1b and 1d

receptors. It is important to note that

SSRIs are actually recommended for migraine prophylaxis as a second-line agent.

96,97

Increased sweating has also been reported with SSRIs and can be particularly

uncomfortable or embarrassing.

98 A dosage reduction may help relieve this adverse

effect and should be tried first. Adjunctive treatment of α-blockers (e.g., terazosin,

prazosin), cyproheptadine, and the anticholinergic benztropine has shown some

success if a dose reduction is not possible.

99,100 Bruxism, or teeth grinding, can also

be a consequence of SSRI treatment, leading to chipped or cracked teeth and

generally poor dentition.

101 Often, patients may not be aware of this nocturnal effect

and complain merely of a dull, persistent headache during the morning hours. This,

too, may be a dose-dependent side effect of all SSRIs, and several antidotes have

been prescribed (e.g., buspirone, benzodiazepines, gabapentin).

102,103

In small

retrospective studies and several case reports, SSRIs have been linked to dilutional

hyponatremia or syndrome of inappropriate antidiuretic hormone (SIADH).

104,105 All

SSRIs and SNRIs have been associated with this phenomenon, and elderly patients

appear to be uniquely at risk.

SSRIs have been rarely associated with extrapyramidal side (EPS) effects,

consisting of akathisia, dystonias, and parkinsonian symptoms that are qualitatively

identical to those seen with antipsychotics.

106–108 Although EPS reactions have been

documented with all SSRIs, most case reports have correlated with aggressive

dosing, often in a patient currently using a DA antagonistic medication, and during the

first 1 to 4 weeks of initiation. The theory is that these EPS effects are mediated

through the indirect influence of serotonergic neurons on dopaminergic activity.

107

In

certain areas of the brain, serotonin and dopamine appear to have an inverse

relationship, whereby central stimulation of serotonin receptors results in a net

decline in dopaminergic transmission. Management of EPS effects induced by SSRI

is identical to that of those precipitated by antipsychotics. Dystonias and

parkinsonian side effects can be treated with anticholinergic agents and subsequent

SSRI dosage reduction. Akathisia usually responds to a reduction in SSRI dosage

and/or administration of low-dose β-blockers.

108

The long-term effects of SSRIs on body weight are variable and difficult to

predict. A problem with accurate measurement is because decreased appetite is one

of the most common depressive symptoms and that a small weight gain after an

antidepressant course may actually be viewed as a therapeutic effect of successful

treatment. Conversely, early reports of weight loss with fluoxetine generated much

optimism for the use of SSRIs in obesity, but longitudinal studies found this to be a

brief, transient phenomenon.

109 All the SSRIs have been reported to cause significant

weight gain in long-term use, but it is a rare phenomenon believed to be mediated by

genetic markers that have not been conclusively identified. The exception is

paroxetine, which has been implicated much more often than other SSRIs as a cause

of weight gain. One long-term RCT compared the effects of fluoxetine, sertraline, and

paroxetine on total body weight.

110 After 7 months of SSRI

p. 1822

p. 1823

use, 25% of the patients receiving paroxetine gained a clinically significant amount

of weight (defined as a >7% increase in total body weight) compared with 7% with

fluoxetine and 4% with sertraline.

110 Long-term studies with citalopram and

escitalopram suggest that 3% to 5% of patients will experience a significant weight

gain. The risk of SSRI weight gain is minimal (except with paroxetine) and typically

irrelevant, but because appetite changes are part of depression, it is best to monitor

weight closely during long-term treatment for both disease- and drug-related reasons.

Epidemiologic studies have also linked SSRIs and SNRIs with an increased risk

for upper GI hemorrhage, with a number needed to harm of 3,177.

111,112 Recent trials

suggest that the risk is modest but can be increased significantly by concurrent

ingestion of NSAIDs lowering the number needed to harm of 881.

112–114 Alcohol use

can also increase the risk of bleeding.

113,114 The mechanism for SSRI-induced GI

hemorrhage has been attributed to effects on decreasing platelet activation and

aggregation. SSRIs and SNRIs should be avoided in patients with active GI bleeds,

and the concurrent use of high-dose NSAID should be discouraged.

DOSAGE TITRATION

CASE 86-1, QUESTION 3: AR and the clinician agree to start escitalopram 10 mg QAM. What is

considered the standard of care and expected outcomes for dosing and efficacy?

It is very important to establish realistic expectations for treatment with

antidepressants from the beginning of therapy. Patients should be informed of the

anticipated course of treatment and that the onset of side effects usually precedes that

of therapeutic effects. Also, patients should be advised that, although antidepressants

may relieve acute depressive symptoms and prevent relapse, they do not abolish

environmental stressors such as an abusive relationship or an oppressive work

setting.

After receiving the medication for 2 weeks, most improvement in A.R. is likely

due to the support she is getting by being involved in treatment as placebo patients

show a reduction in symptoms during this period. Medication will start to separate

from placebo typically at the 2-week monitoring period and continue to enlarge that

separation from placebo up until week 8. A.R. should be reminded that the optimal

effects of antidepressants may not be evident for another 4 to 6 weeks. Therefore, a

reasonable recommendation would be to continue with the current daily dose of 10

mg and to re-evaluate the medication’s effects when she returns to clinic in 2 weeks.

If there is no clear improvement at 4 weeks, then switching the medication is

necessary. If there is a 25% or more improvement, then the clinician could continue

for another 4 weeks (for 8 weeks of treatment) and decide whether the response is

acceptable. If the improvement is small, such as just 25% to 30%, then one can

increase the dose at this 4-week point and continue to monitor for another 8

weeks.

5,10,26

DURATION OF TREATMENT

According to the guidelines issued by the Agency for Health Research and Quality,

antidepressant treatment can be broken down into three stages (Table 86-10).

115 The

first stage, acute treatment, lasts approximately 12 weeks; during this time, the

clinician attempts to resolve the presenting symptoms and induce remission which is

defined as no impairing symptoms of depression and a score of ≤7 on the HAMD17

or ≤10 on the MADRS.

5,10 The second stage is commonly called continuation

treatment because the patient continues to receive the same antidepressant regimen

that induced the initial treatment response, and the clinician attempts to keep the acute

symptoms in remission. The duration of continuation treatment is variable (4–9

months after initial treatment or response), but it is recommended that all patients

suffering from major depression complete these first two stages. Therefore, the

minimum duration of treatment is 7 months. Alternatively, others have advocated that

the minimum duration of treatment should be for 6 months after the complete

resolution of symptoms.

5

Table 86-10

Duration of Antidepressant Treatment

Acute treatment phase 3 months

Continuation treatment phase 4–9 months

Maintenance treatment phase Variable

Acute and continuation treatment recommended for all patients with major depressive disorder (MDD) (i.e.,

minimal duration of treatment = 7 months)

Decision to prescribe maintenance treatment is based on the following:

Number of previous episodes

Severity of previous episodes

Family history of depression

Patient age (worse prognosis if elderly)

Response to antidepressant

Persistence of environmentalstressors

Indefinite maintenance treatment is recommended if any one of the following criteria is met:

Three or more previous episodes (regardless of age)

Two or more previous episodes and age older than 50 years

One or more and age older than 60 years

The third stage of treatment, maintenance treatment or prophylaxis, is not indicated

for all patients, and the necessity of continuing medication beyond the first 6 to 7

months depends on many patient-specific factors. One must consider the number of

previous episodes, family history of depression, patient’s age, severity of presenting

symptoms, response to therapy, and persistence or anticipation of environmental

stressors. There are specific populations for whom indefinite pharmacologic

treatment is advocated: (a) individuals with three or more previous episodes of

major depression, (b) individuals older than 50 years with two or more previous

episodes, and (c) individuals older than 60 years with one or more previous

episodes.

5,10 Continued antidepressant usage in the elderly is recommended to

prevent relapse.

116