Antidepressants

Our principal focus in this chapter is drugs used to treat major depression. In addition, we consider four somatic (nondrug) therapies. We begin the chapter by discussing depression itself and the basic approach to treatment. After that, we discuss the antidepressant drugs and the somatic therapies.

Major depression: clinical features, pathogenesis, and treatment overview

Depression is the most common psychiatric disorder. In the United States, about 30% of the population will experience some form of depression during their lives. At any given time, about 5% of the adult population is depressed. The incidence in women is twice that in men. The risk of suicide among depressed people is high. Unfortunately, depression is underdiagnosed and undertreated: Only 30% of depressed individuals receive treatment. This is especially sad in that treatment can help many people: About 40% of those given antidepressants achieve full remission; another 20% to 30% achieve at least a 50% reduction in symptom severity.

Clinical features

Diagnostic criteria for a major depression are summarized in Table 32–1. As indicated, the principal symptoms are depressed mood and loss of pleasure or interest in all or nearly all of one’s usual activities and pastimes. Associated symptoms include insomnia (or sometimes hypersomnia); anorexia and weight loss (or sometimes hyperphagia and weight gain); mental slowing and loss of concentration; feelings of guilt, worthlessness, and helplessness; thoughts of death and suicide; and overt suicidal behavior. For a diagnosis to be made, symptoms must be present most of the day, nearly every day, for at least 2 weeks.

TABLE 32–1

DSM-5 Diagnostic Criteria for Major Depression

Diagnostic Criteria for Major Depression

A Presence of a single Major Depressive Episode (as described below)

B The Major Depressive Episode is not better accounted for by Schizoaffective Disorder and is not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified.

C There has never been a Manic Episode or a Hypomanic Episode. (Note: This exclusion does not apply if all of the manic-like or hypomanic-like episodes are due to a substance (eg, drug of abuse, medication) or the direct physiologic effects of a general medical condition.)

Criteria for a Major Depressive Episode

A At least five of the following criteria must be present for 2 weeks or more, and must represent a change from previous functioning. Furthermore, at least one symptom must be (1) depressed mood or (2) loss of interest or pleasure. (Note: Do not include symptoms that are clearly due to a medical condition.)

1. Depressed mood most of the day, nearly every day. (Note: In children and adolescents, can be irritable mood.)

2. Markedly diminished interest or pleasure in all or almost all activities.

3. Significant weight loss or weight gain without dieting or decrease or increase in appetite. (Note: In children, consider failure to make expected weight gain.)

4. Insomnia or hypersomnia.

5. Psychomotor agitation or retardation (observable by others, not merely subjective feelings of restlessness or being slowed down).

6. Fatigue or loss of energy.

7. Feelings of worthlessness or excessive or inappropriate guilt.

8. Diminished ability to think or concentrate or indecisiveness.

9. Recurrent thoughts of death, recurrent suicidal ideation, a suicide attempt, or a specific suicide plan.

B The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

C The episode is not due to the direct physiologic effects of a substance (eg, drug of abuse, medication).

Modified from the proposed diagnostic criteria for Major Depression and a Major Depressive Episode, to be published in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Washington, DC: American Psychiatric Association. Expected publication date: May 2013. Copyright © American Psychiatric Association. The proposed criteria are from the DSM-5 web site—www.DSM5.org—accessed on November 11, 2011.

It is important to distinguish between major depression and normal grief or sadness. Whereas major depression is an illness, grief or sadness is not. Rather, grief and sadness are appropriate reactions to a major life stressor (eg, death of a loved one, loss of a job). In most cases, grief and sadness resolve spontaneously over several weeks and do not require medical intervention. However, if symptoms are unusually intense, and if they fail to resolve within an appropriate time, a major depressive episode may have been superimposed. If this occurs, treatment is indicated.

Pathogenesis

The etiology of major depression is complex and incompletely understood. For some individuals, depression seems to descend “out of the blue”; otherwise healthy people—unexpectedly and without apparent cause—find themselves feeling profoundly depressed. For many others, depressive episodes are brought on by stressful life events, such as bereavement, loss of a job, or childbirth (Box 32–1). Since depression does not occur in everyone, it would appear that some people are more vulnerable than others. Factors that may contribute to vulnerability include genetic heritage, a difficult childhood, and chronic low self-esteem.

BOX 32–1 SPECIAL INTEREST TOPIC

POSTPARTUM DEPRESSION

The vast majority of women (about 80%) experience depressive symptoms after giving birth. For most, the symptoms are mild and transient, reflecting a condition known as the “baby blues.” For others, symptoms are severe and persistent, reflecting true postpartum depression, a condition that merits rapid medical attention.

An estimated 60% to 70% of women get the postpartum blues. Symptoms include tearfulness, sadness, nervousness, irritability, and anxiety, along with difficulty eating and sleeping. The new mom may feel overwhelmed, vulnerable, weak, and alone. She may cry for no clear reason. Her self-esteem and self-confidence may decline, and she may feel unqualified to care for her baby. Fortunately, all of these symptoms pass quickly: As a rule, they develop a few days after delivery and are gone by day 10. Because the baby blues are so common, they’re considered a normal postpartum event. Treatment is neither necessary nor recommended.

True postpartum depression is different. The condition is much less common than the baby blues, but much more serious. Left untreated, postpartum depression typically lasts for months, and is likely to become worse as time passes. Not only is the condition detrimental to the mother, it can adversely affect the child, preventing secure attachment and impairing cognitive, emotional, and behavioral development. Accordingly, immediate intervention is indicated.

Just what is postpartum depression? Simply put, it’s an episode of major depression that starts after giving birth. Otherwise, the diagnostic criteria are the same as for all other episodes of major depression (see Table 32–1). According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), for a depressive episode to qualify as having postpartum onset, symptoms must begin within 4 weeks of delivery. However, most clinicians who study the disorder use a different criterion: To them, depression is considered postpartum if it begins within 3 months of delivery—not just within 4 weeks.

Who is likely to suffer postpartum depression? Sometimes the condition occurs in first-time mothers, and sometimes it doesn’t strike until a second, third, or fourth child is born. Among first-time mothers, the incidence is between 8% and 15% (about 1 in 8). For women with a history of the disorder, the risk increases to 33% (1 in 3). In addition to a prior history of the disorder, risk factors include a history of depression unrelated to childbirth, a history of premenstrual dysphoric disorder (ie, severe premenstrual syndrome), and major stress related to family, work, or residence (eg, death of a loved one, loss of a job, moving away from a familiar town or city).

The underlying cause of postpartum depression is unknown, but several factors are thought to contribute. Heading the list is the sharp drop in estrogen and progesterone levels that occurs after delivery. (Levels of these hormones increase 10-fold during pregnancy, and then return to baseline after the placenta is expelled.) However, since hormone levels fall in all women, but only some get postpartum depression, other factors—physical, emotional, and social—must be involved. The birthing process leaves women feeling weak and fatigued. Caring for a baby, who needs round-the-clock attention and feeding, exacerbates tiredness and exhaustion. Emotional and social factors may also play a role. Feelings of loss are common: Women experience loss of freedom, loss of control, and even loss of identity. In addition, they may feel loss of attractiveness. Stress increases substantially, owing to increased workload and responsibilities, coupled with feelings of self-doubt and inadequacy, and compounded by a self-imposed (albeit highly unrealistic) expectation to be a “perfect” mom. Stress can be made even worse by financial insecurity and inadequate support from one’s partner, family, and friends. Thyroid insufficiency may also contribute: Levels of thyroid hormone often decline after delivery, thereby causing symptoms that can mimic depression. Accordingly, thyroid levels should be checked and, if indicated, replacement therapy should be implemented.

Screening for postpartum depression can be accomplished with a quick test: the Edinburgh Postnatal Depression Scale. The test is administered 6 to 8 weeks after delivery and contains the following short statements:

1. I have been able to laugh and see the funny side of things.

2. I have looked forward with enjoyment to things.

3. I have blamed myself unnecessarily when things went wrong.

4. I have been anxious or worried for no good reason.

5. I have felt scared or panicky for no very good reason.

6. Things have been getting on top of me.

7. I have been so unhappy that I have had difficulty sleeping.

8. I have felt sad or miserable.

9. I have been so unhappy that I have been crying.

10. The thought of harming myself has occurred to me.

Each statement has four possible responses, such as these for statement 10: (1) yes, quite often, (2) sometimes, (3) hardly ever, and (4) never. When taking the test, the mother simply underlines the option that best reflects her feelings during the previous week. If her responses indicate she probably has postpartum depression, she should undergo clinical evaluation to establish a definitive diagnosis.

Treatment of postpartum depression is much like treatment of major depression unrelated to pregnancy. The goal is to normalize mood, and optimize maternal and social functioning. The principal treatment modalities are psychotherapy and antidepressant drugs, both of which can be effective. In addition, the woman should be encouraged to nurture herself as well as her baby: She should:

• Reduce isolation (by going out for at least a short time each day)

• Ensure adequate rest (by doing only what’s really needed and letting the rest go)

• Spend time alone with her partner.

Other beneficial measures include joining a support group for new mothers and recruiting family members and friends to assist with household and baby-related chores.

Although antidepressants are clearly appropriate, there are few published data to guide selection. In one study of women with postpartum depression, fluoxetine [Prozac], a selective serotonin reuptake inhibitor (SSRI), was compared with psychotherapy. Both treatments were equally effective, and both were superior to placebo. Efficacy has also been demonstrated for sertraline [Zoloft], venlafaxine [Effexor], and certain tricyclic antidepressants (TCAs). For initial therapy, an SSRI is an attractive choice. Why? Because these drugs are effective and well tolerated, and present little risk of toxicity if taken in overdose. However, if a woman has responded to an antidepressant from a different class in the past, that drug should be tried first. To minimize side effects, dosage should be low initially (50% of the usual starting dosage) and then gradually increased. To reduce the risk of relapse, treatment should continue for at least 6 months after symptoms have resolved. Unfortunately, even then the relapse rate is high: Between 50% and 85% of patients experience at least one more depressive episode. With each succeeding episode, the risk of another recurrence increases. Accordingly, long-term prophylactic therapy should be considered.

Which antidepressants can be taken safely while breast-feeding? All of these drugs can be detected in breast milk—but levels of some are much lower (safer) than levels of others. Sertraline, for example, appears very safe. Studies show that drug activity in breast-fed infants is extremely low, and no adverse reactions have been observed. The TCAs (eg, nortriptyline, desipramine) also appear safe: Levels are too low for detection in breast-fed infants, and follow-up studies have found no developmental deficits. In contrast to sertraline and the TCAs, fluoxetine appears unsafe: The drug and its metabolites reach therapeutic levels in breast-fed infants; potential consequences include colic and impaired weight gain.

Clinical observations made in the 1960s led to formulation of the monoamine-deficiency hypothesis of depression, which asserts that depression is caused by a functional deficiency of monoamine neurotransmitters (norepinephrine, serotonin, or both). Findings that support the hypothesis include (1) induction of depression with reserpine, a drug that depletes monoamines from the brain; (2) induction of depression with inhibitors of tyrosine hydroxylase, an enzyme needed for monoamine transmitter synthesis; and (3) relief of depression with drugs that intensify monoamine-mediated neurotransmission. Although these observations lend support to the monoamine-deficiency hypothesis, it is clear that the hypothesis is too simplistic. However, despite its shortcomings, the monoamine-deficiency hypothesis does provide a useful conceptual framework for understanding antidepressant drugs.

Treatment overview

Depression can be treated with three major modalities: (1) pharmacotherapy, (2) depression-specific psychotherapy (eg, cognitive behavioral therapy or interpersonal psychotherapy), and (3) somatic therapies, such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation. For patients with mild to moderate depression, drug therapy and psychotherapy can be equally effective. For those with more severe depression, a combination of drug therapy and psychotherapy is better than either intervention alone. Electroconvulsive therapy can be used when a rapid response is needed, or when drugs and psychotherapy have not worked. For all patients, aerobic exercise and resistance training can improve mood.

Drugs used for depression

Drugs are the primary therapy for major depression. However, benefits are limited mainly to patients with severe depression. In patients with mild to moderate depression, antidepressants have little or no beneficial effect.

Available antidepressants are listed in Table 32–2. As indicated, these drugs fall into five major classes: selective serotonin reuptake inhibitors (SSRIs), serotonin/norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and atypical antidepressants. All of these classes are equally effective, as are the individual drugs within each class. Hence, differences among these drugs relate mainly to side effects and drug interactions.

TABLE 32–2

Antidepressant Classes and Adult Dosages

Generic Name	Trade Name	Initial Dose*^,^† (mg/day)	Maintenance Dose* (mg/day)
Selective Serotonin Reuptake Inhibitors (SSRIs)
Citalopram	Celexa	20	20–60
Escitalopram	Lexapro, Cipralex	10	10–20
Fluoxetine	Prozac	20	20–60
Fluvoxamine^‡	Luvox	50	50–300
Paroxetine	Paxil, Pexeva	12.5–20	20–50
Sertraline	Zoloft	50	50–200
Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs)
Desvenlafaxine	Pristiq	50	50
Duloxetine	Cymbalta	60	40–120
Venlafaxine	Effexor XR	37.5	75–375
Tricyclic Antidepressants (TCAs)
Amitriptyline	generic only	25–50	100–300
Clomipramine^‡	Anafranil	25	100–250
Desipramine	Norpramin	25–50	100–300
Doxepin	Sinequan^§	50	75–300
Imipramine	Tofranil	25–50	100–300
Maprotiline	generic only	75	100–225
Nortriptyline	Aventyl, Pamelor	25	50–200
Protriptyline	Vivactil	10–20	20–60
Trimipramine	Surmontil	25–50	75–300
Monoamine Oxidase Inhibitors (MAOIs)
Isocarboxazid	Marplan	10–20	30–60
Phenelzine	Nardil	15	45–90
Selegiline (transdermal)	Emsam	6	6–12
Tranylcypromine	Parnate	10	30–60
Atypical Antidepressants
Amoxapine	generic only	50	200–400
Bupropion	Wellbutrin, others	150	300–450
Mirtazapine	Remeron	15	15–45
Nefazodone	generic only	50	150–300
Trazodone	generic only	150	150–600
Vilazodone	Viibryd	10	40

^*Doses listed are total daily doses. Depending on the drug and the patient, the total dose may be given in a single dose or in divided doses.

^†Initial doses are employed for 4 to 8 weeks, the time required for most symptoms to respond. Dosage is gradually increased as required.

^‡Fluvoxamine and clomipramine are not approved for major depression.

^§Doxepin is also available in a low-dose formulation, sold as Silenor, for treating insomnia.

Selective serotonin reuptake inhibitors (SSRIs)

The SSRIs were introduced in 1987 and have since become our most commonly prescribed antidepressants, accounting for over $3 billion in annual sales. These drugs are indicated for major depression as well as several other psychologic disorders (Table 32–3). Characteristic side effects are nausea, agitation/insomnia, and sexual dysfunction (especially anorgasmia). The SSRIs can interact adversely with MAOIs and other serotonergic drugs, and hence these combinations must be avoided. In addition, when used late in pregnancy, SSRIs can lead to a withdrawal syndrome and persistent pulmonary hypertension in the infant. Like all other antidepressants, SSRIs may increase the risk of suicide. Compared with the TCAs and MAOIs, SSRIs are equally effective, better tolerated, and much safer. Death by overdose is extremely rare.

TABLE 32–3

Therapeutic Uses of Selective Serotonin Reuptake Inhibitors

	Therapeutic Use*^,^†
Drug	Major Depression	OCD	Panic Disorder	Social Phobia	GAD	PTSD	PMDD	Bulimia Nervosa
Citalopram [Celexa]	A	U	U	U	U	U	U
Escitalopram [Lexapro]	A	A	U		A	U
Fluoxetine [Prozac]	A	A	A	U	U	U	A	A
Fluvoxamine [Luvox]	U	A	U	A	U	U	U	U
Paroxetine [Paxil]	A	A	A	A	A	A	A
Sertraline [Zoloft]	A	A	A	A	U	A	A

^*A = approved use, U = unlabeled use.

^†GAD = generalized anxiety disorder, OCD = obsessive-compulsive disorder, PMDD = premenstrual dysphoric disorder, PTSD = post-traumatic stress disorder.

Fluoxetine

Fluoxetine [Prozac, Prozac Weekly, Sarafem, Selfemra], the first SSRI available, will serve as our prototype for the group. At one time, this drug was the most widely prescribed antidepressant in the world, and its commercial success led Fortune magazine to call it one of the “Products of the Century.”

Mechanism of action

The mechanism of action of fluoxetine and the other SSRIs is depicted in Figure 32–1. As shown, SSRIs selectively block neuronal reuptake of serotonin (5-hydroxytryptamine, or 5-HT), a monoamine neurotransmitter. As a result of reuptake blockade, the concentration of 5-HT in the synapse increases, causing increased activation of postsynaptic 5-HT receptors. This mechanism is consistent with the theory that depression stems from a deficiency in monoamine-mediated transmission—and hence should be relieved by drugs that can intensify monoamine effects.

It is important to appreciate that blockade of 5-HT reuptake, by itself, cannot fully account for therapeutic effects. Why? Because clinical responses to SSRIs (relief of depressive symptoms) and the biochemical effect of the SSRIs (blockade of 5-HT reuptake) do not occur in the same time frame. That is, whereas SSRIs block 5-HT reuptake within hours of dosing, relief of depression takes several weeks to fully develop. This delay suggests that therapeutic effects are the result of adaptive cellular changes that take place in response to prolonged reuptake blockade. Fluoxetine and the other SSRIs do not block reuptake of dopamine or norepinephrine (NE). In contrast to the TCAs (see below), fluoxetine does not block cholinergic, histaminergic, or alpha₁-adrenergic receptors. Furthermore, fluoxetine produces CNS excitation rather than sedation.

Therapeutic uses

Fluoxetine is used primarily for major depression. In addition, the drug is approved for bipolar disorder (see Chapter 33), obsessive-compulsive disorder (see Chapter 35), panic disorder (see Chapter 35), bulimia nervosa, and premenstrual dysphoric disorder (see Chapter 61). Unlabeled uses include post-traumatic stress disorder, social phobia, alcoholism, attention-deficit/hyperactivity disorder, migraine, Tourette’s syndrome, and obesity.

Pharmacokinetics

Fluoxetine is well absorbed following oral administration, even in the presence of food. The drug is widely distributed and highly bound to plasma proteins. Fluoxetine undergoes extensive hepatic metabolism, primarily by CYP2D6 (the 2D6 isozyme of cytochrome P450). The major metabolite—norfluoxetine—is active, and later undergoes metabolic inactivation, followed by excretion in the urine. The half-life of fluoxetine is 2 days and the half-life of norfluoxetine is 7 days. Because the effective half-life is prolonged, about 4 weeks are required to produce steady-state plasma drug levels—and about 4 weeks are required for washout after dosing stops.

Adverse effects

Fluoxetine is safer and better tolerated than TCAs and MAOIs. Death from overdose with fluoxetine alone has not been reported. In contrast to TCAs, fluoxetine does not block receptors for histamine, NE, or acetylcholine, and hence does not cause sedation, orthostatic hypotension, anticholinergic effects, or cardiotoxicity. The most common side effects are sexual dysfunction (70%), nausea (21%), headache (20%), and manifestations of CNS stimulation, including nervousness (15%), insomnia (14%), and anxiety (10%). Weight gain can also occur. Fluoxetine and most other SSRIs appear safe for use during pregnancy. Paroxetine is the principal exception (see below).

Sexual dysfunction.

Fluoxetine causes sexual problems (impotence, delayed or absent orgasm, delayed or absent ejaculation, decreased sexual interest) in nearly 70% of men and women. The underlying mechanism is unknown.

Sexual dysfunction can be managed in several ways. In some cases, reducing the dosage or taking “drug holidays” (eg, discontinuing medication on Fridays and Saturdays) can help. Another solution is to add a drug that can overcome the problem. Among these are yohimbine, buspirone [BuSpar], and three atypical antidepressants: bupropion [Wellbutrin, others], nefazodone, and mirtazapine [Remeron]. Drugs like sildenafil [Viagra] can also help: In men, these drugs improve erectile dysfunction, as well as arousal, ejaculation, orgasm, and overall satisfaction; in women, they can improve delayed orgasm. If all of these measures fail, the patient can try a different antidepressant. Agents that cause the least sexual dysfunction are the same three atypical antidepressants just mentioned.

Sexual problems often go unreported, either because patients are uncomfortable discussing them or because patients don’t realize their medicine is the cause. Accordingly, patients should be informed about the high probability of sexual dysfunction and told to report any problems so they can be addressed.

Weight gain.

Like many other antidepressants, fluoxetine and other SSRIs cause weight gain. When these drugs were first introduced, we thought they caused weight loss. Why? Because during the first few weeks of therapy patients do lose weight, perhaps because of drug-induced nausea and vomiting. However, with long-term treatment, the lost weight is regained. Furthermore, about one-third of patients continue putting on weight—up to 20 pounds or more. Although the reason for weight gain is unknown, a good possibility is decreased sensitivity of 5-HT receptors that regulate appetite.

Serotonin syndrome.

By increasing serotonergic transmission in the brainstem and spinal cord, fluoxetine and other SSRIs can cause serotonin syndrome. This syndrome usually begins 2 to 72 hours after treatment onset. Signs and symptoms include altered mental status (agitation, confusion, disorientation, anxiety, hallucinations, poor concentration) as well as incoordination, myoclonus, hyperreflexia, excessive sweating, tremor, and fever. Deaths have occurred. The syndrome resolves spontaneously after discontinuing the drug. The risk of serotonin syndrome is increased by concurrent use of MAOIs and other drugs (see below under Drug Interactions).

Withdrawal syndrome.

Abrupt discontinuation of SSRIs can cause a withdrawal syndrome. Symptoms include dizziness, headache, nausea, sensory disturbances, tremor, anxiety, and dysphoria. These begin within days to weeks of the last dose, and then persist for 1 to 3 weeks. Resumption of drug use will make symptoms subside. The withdrawal syndrome can be minimized by tapering the dosage slowly. Of the SSRIs in use today, fluoxetine is least likely to cause a withdrawal reaction. Why? Because fluoxetine has a prolonged half-life. Hence, when dosing is stopped, plasma levels decline slowly. When SSRIs are discontinued, it is important to distinguish between symptoms of withdrawal and return of depression.

Neonatal effects from use in pregnancy.

Use of fluoxetine and others SSRIs late in pregnancy poses a small risk of two adverse effects in the newborn: (1) neonatal abstinence syndrome (NAS) and (2) persistent pulmonary hypertension of the newborn (PPHN). NAS is characterized by irritability, abnormal crying, tremor, respiratory distress, and possibly seizures. The syndrome can be managed with supportive care and generally abates within a few days. PPHN, which compromises tissue oxygenation, carries a significant risk of death, and, among survivors, a risk of cognitive delay, hearing loss, and neurologic abnormalities. Treatment measures include providing ventilatory support, giving oxygen and nitric oxide (to dilate pulmonary blood vessels), and giving IV sodium bicarbonate (to maintain alkalosis) and dopamine or dobutamine (to increase cardiac output, and thereby maintain pulmonary perfusion). Infants exposed to SSRIs late in gestation should be monitored closely for NAS and PPHN.

Teratogenesis.

Do fluoxetine and other SSRIs cause birth defects? Probably not. And if they do, the risk appears to be very low. Two SSRIs—paroxetine and fluoxetine—may cause septal heart defects. But even with these agents, the absolute risk is very low.

Suicide risk.

As discussed above, antidepressants may increase the risk of suicide in depressed patients, especially during the early phase of treatment. The risk of antidepressant-induced suicide is greatest among children, adolescents, and young adults.

Extrapyramidal side effects.

SSRIs cause extrapyramidal symptoms (EPS) in about 0.1% of patients. This is much less frequent than among patients taking antipsychotic medications (see Chapter 31). Among patients taking SSRIs, the most common EPS is akathisia, characterized by restlessness and agitation. However, parkinsonism, dystonic reactions, and tardive dyskinesia can also occur. EPS typically develop during the first month of treatment. The risk is increased by concurrent use of an antipsychotic drug. The underlying cause of SSRI-induced EPS may be alteration of serotonergic transmission within the extrapyramidal system. For a detailed discussion of EPS, refer to Chapter 31.

Bruxism.

SSRIs may cause bruxism (clenching and grinding of teeth). However, since bruxism usually occurs during sleep, the condition often goes unrecognized. Sequelae of bruxism include headache, jaw pain, and dental problems (eg, cracked fillings).

How do SSRIs cause bruxism? One theory is that they inhibit release of dopamine, a neurotransmitter that suppresses activity in certain muscles, including those of the jaw. By decreasing dopamine availability, SSRIs could release these muscles from inhibition, and excessive activity could result. This same mechanism may be responsible for SSRI-induced EPS.

How can bruxism be managed? One option is to reduce the SSRI dosage. However, this may cause depression to return. Other options include switching to a different class of antidepressant, use of a mouth guard, and treatment with low-dose buspirone (5 to 10 mg 1 to 3 times a day).

Bleeding disorders.

Fluoxetine and other SSRIs can increase the risk of bleeding in the GI tract and at other sites. How? By impeding platelet aggregation: Platelets require 5-HT for aggregation, but can’t make it themselves, and hence must take 5-HT up from the blood; by blocking 5-HT uptake, SSRIs suppress aggregation. The SSRIs cause a threefold increase in the risk of GI bleeding. However, the absolute risk is still low (about 1 case for every 8000 prescriptions). Caution is advised in patients with ulcers or a history of GI bleeding, in patients older than 60, and in patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) or anticoagulants.

Fluoxetine and other SSRIs have been associated with an increased risk of hemorrhagic stroke. However, a causal relationship has not been established.

Hyponatremia.

Fluoxetine can cause hyponatremia (serum sodium below 135 mEq/L), probably by increasing secretion of antidiuretic hormone. Most cases involve older patients taking thiazide diuretics. Accordingly, when fluoxetine is used in older patients, sodium should be measured at baseline and periodically thereafter.

Other adverse effects.

Fluoxetine may cause dizziness and fatigue; patients who experience intense dizziness and fatigue should be warned against driving and other hazardous activities. Skin rash, which can be severe, has occurred in 4% of patients; in most cases, rashes readily respond to drug therapy (antihistamines, glucocorticoids) or to withdrawal of fluoxetine. Other common reactions include diarrhea (12%) and excessive sweating (8%).

Drug interactions

MAOIs and other drugs that increase the risk of serotonin syndrome.

MAOIs increase 5-HT availability, and hence greatly increase the risk of serotonin syndrome. Accordingly, use of MAOIs with SSRIs is contraindicated. Because MAOIs cause irreversible inhibition of monoamine oxidase (MAO; see below), their effects persist long after dosing stops. Therefore, MAOIs should be withdrawn at least 14 days before starting an SSRI. Because fluoxetine and its active metabolite have long half-lives, at least 5 weeks should elapse between stopping fluoxetine and starting an MAOI. For other SSRIs, at least 2 weeks should elapse between treatment cessation and starting an MAOI.

Other drugs that increase the risk of serotonin syndrome include the serotonergic drugs listed in Table 32–4, drugs that inhibit CYP2D6 (and thereby raise fluoxetine levels), tramadol (an analgesic), and linezolid (an antibiotic that inhibits MAO).

TABLE 32–4

Drugs That Promote Activation of Serotonin Receptors

Drug	Mechanism
Selective Serotonin Reuptake Inhibitors (SSRIs)
Citalopram [Celexa] Escitalopram [Lexapro, Cipralex] Fluoxetine [Prozac] Fluvoxamine [Luvox] Paroxetine [Paxil] Sertraline [Zoloft]	Block 5-HT reuptake and thereby increase 5-HT in the synapse
Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs)
Desvenlafaxine [Pristiq]	Same as SSRIs
Duloxetine [Cymbalta]
Venlafaxine [Effexor]
Tricyclic Antidepressants (TCAs)
Amitriptyline	Same as SSRIs
Clomipramine [Anafranil]
Doxepin [Sinequan]
Imipramine [Tofranil]
Trimipramine [Surmontil]
Monoamine Oxidase Inhibitors (MAOIs)
Desipramine [Norpramin] Isocarboxazid [Marplan] Phenelzine [Nardil] Selegiline [Emsam]	Inhibit neuronal breakdown of 5-HT by MAO, and thereby increase stores of 5-HT available for release
Atypical Antidepressants
Mirtazapine [Remeron]	Promotes release of 5-HT
Nefazodone	Same as SSRIs
Trazodone [Oleptro]	Same as SSRIs
Analgesics
Meperidine [Demerol]	Same as SSRIs and MAOIs
Methadone [Dolophine]	Same as MAOIs?
Tramadol [Ultram]	Same as SSRIs
Triptan Antimigraine Drugs
Almotriptan [Axert] Eletriptan [Relpax] Frovatriptan [Frova] Rizatriptan [Maxalt] Sumatriptan [Imitrex] Zolmitriptan [Zomig]	Cause direct activation of serotonin receptors
Others
St. John’s wort	Same as SSRIs and MAOIs
Linezolid [Zyvox]	Same as MAOIs