Introduction

This article focuses on the medications used in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. This was the largest and longest study on the effectiveness of treatments for depression and led to the best evidence-based treatment for depression to date. Table 1 outlines the side effects of some of the more commonly used antidepressants that were studied in STAR*D including potential augmenting (adjuvant) medications for improving antidepressant efficacy (eg, adding bupropion up to 400 mg to a selective serotonin reuptake inhibitor [SSRI] in a patient with less than a remission response to their SSRI).The STAR*D study showed that on first exposure to an antidepressant, only 28% to 33% of patients will go into full remission. Total remission of depressive symptoms (not just response, ie, an amelioration of depressive symptoms) is now the aim of modern antidepressant psychopharmacology.¹

Typically, SSRIs are the first agents used to treat depression in clinical practice due to their safety and low incidence of serious side effects. Table 1 provides a list of side effects common with most SSRIs (listed for the two prototypic SSRIs used in the STAR*D study, namely citalopram and sertraline).² One of the important findings of the STAR*D study is that antidepressant efficacy is often improved with the addition of various antidepressant adjuvant (augmenting) medications (eg, triiodothyronine [T₃] or lithium, with T₃ causing fewer side effects).³ Primary care physicians (PCPs) will need to familiarize themselves with the switch and augmentation strategies tested in the STAR*D study. Readers should note that there are other antidepressants and adjuvant medications available that do not appear in Tables 1 or 2. Nortriptyline is the prototypic tricyclic antidepressant (TCA) that was used in the STAR* D study, just as citalopram and sertraline were the stand-in SSRIs. However, TCAs are rarely used now as a first-line antidepressant in treating depression.

When medications are combined, the potential for side effects can increase, and it can become difficult to differentiate which agent is responsible for the side effect(s). Hence, the primary antidepressant should be introduced first and the adjuvant agent added at a later time to analyze the etiology of potential future side effects. Augmentation of citalopram with either bupropion sustained release (SR) or buspirone was found in the STAR*D study to be useful. However, augmentation with bupropion SR did have certain advantages, including a greater reduction in the number and severity of symptoms and fewer side effects.² If the dosing strategies in Table 1 are adhered to, the incidence of adverse side effects should be diminished.

Medication side effects or adverse events can range from less serious annoyances to very serious, life-threatening situations (Table 2). The more side effects that a patient experiences, the less adherent patients are likely to be. Whether serious or not, it is important to manage the side effects experienced by the patient.

Minor Side Effects

Headache

Headaches can range from mild to severe, and may not be related to the antidepressant being used by the patient. Many studies of SSRIs show prevalences of headache to be greater in the placebo group than in the active drug groups. However, there is still a minority of patients who appear to get headaches on SSRIs. They typically respond to analgesics such as acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), or to an ice pack on the headache area.

Fatigue

Complaints of fatigue, lethargy, and tiredness are common, especially during the early weeks of antidepressant treatment. Possible antidotes include taking a brief nap during the day or getting some mild exercise such as walking. Sometimes, the medication can be taken 1–2 hours before bedtime so that the side effect can be put to use by helping the patient fall sleep. (Insomnia is a common problem in patients with depressive disorders.)

Sedation

It should be standard practice to educate or warn patients that antidepressants have potential sedative effects and could impair judgment, thinking, and motor skills, as well as their ability to drive, use machines, or perform tasks that require alertness, coordination, or physical dexterity. Interventions for fatigue can also be beneficial for counteracting antidepressant-induced sedation. Some clinicians try moderate doses of modafinil or other stimulants (eg, methylphenidate, dextroamphetamine/amphetamine composite medication) to counteract the sedation induced by antidepressants.

Sexual Side Effects

SSRIs are associated with delayed orgasm or an inability to achieve orgasm (anorgasmia). This can occur in both men and women perhaps more than half the time at regular or higher therapeutic doses. Most cases of sexual dysfunction stop after 1–3 days of the medication being stopped.

Possible remedies include dose lowering or trying to schedule sexual activity before taking medication for the day. Clinicians can also switch to an antidepressant less associated with these side effects. These antidepressants include bupropion or mirtazapine. If erectile dysfunction is an issue, agents such as sildenafil, vardenafil, tadalafil, or alprostadil (the latter given by injection into the side of the penis) may be considered.

Clinicians may try stopping medication for only the day that sexual activity will occur (or lower the dose on that day, returning to regular higher dose the other days of the week (this may not work so well for antidepressants with half-lives >24 hours, such as fluoxetine). However, this intervention of stopping SSRIs before planned sexual acttivity can cause an SSRI discontinuation syndrome (especially for SSRIs with a shorter half-life).

Insomnia

Insomnia occurs because some antidepressants cause stimulation that can interfere with sleep. To counteract this effect, medication can be taken in the morning. (In fact, SSRIs are typically first tried as an AM dose.) Lower-dose mirtazapine is quite sedating and might be best for patients with severe insomnia. Stimulation associated with antidepressants can be a negative side effect when taken at night, but a positive experience when taken in the morning, with the medication providing a needed energy boost. Antidepressant-induced insomnia can be dealt with by giving the antidepressant with a sedating medication (eg, a benzodiazepine or trazodone) at bedtime. To avoid insomnia, medications such as bupropion are never dosed at bedtime.
Patients should be encouraged to practice good sleep hygiene, including avoiding caffeinated drinks before bedtime, getting regular exercise at least 4–5 hours before bedtime, and developing a relaxing bedtime routine.

Gastrointestinal Side Effects

Nausea is one of the most common reasons people stop taking antidepressants. Nausea typically begins within 1 week of starting treatment and often goes away on its own within a few weeks. Anecdotally, this common side effect has been reduced by taking antidepressants with food or with an antacid (there are no studies to the authors’ knowledge supporting this intervention for nausea). If available, a slow-release form of an antidepressant might lessen gastric upset and nausea, or the dosage might be decreased and the upward dose titration slowed.

Constipation

To treat or prevent constipation (much more common with the TCAs), patients should increase fiber and fluid intake as well as mobility (ie, physical activity).

Weight Gain

Overall, SSRIs (except paroxetine) are thought to have no or only slight weight-inducing effects (although there are no doubt exceptions to this). Hence, with the SSRIs, it is prudent to carefully monitor patients’ weight, since the amelioration of depressive symptoms can be associated with improved appetite and weight gain. Mirtazapine can also be associated with weight gain, while bupropion is associated with potentially problematic weight loss in already underweight patients.

SSRI Discontinuation Syndrome

Not all patients taking antidepressants experience SSRI discontinuation syndrome, but for those who do the syndrome often presents with flu-like symptoms such as headache, diarrhea, nausea, vomiting, chills, dizziness, fatigue, and insomnia. Symptoms can even include agitation, impaired concentration, vivid dreams, depersonalization, irritability, and suicidal thoughts. Symptoms last anywhere from one to several weeks and vary in intensity.³

In order to avoid this syndrome, clinicians should educate patients to not suddenly stop taking SSRIs. Patients can use a pill splitter to more slowly taper off their SSRIs. Another option is to switch to the liquid form of the medication so that patients can reduce their dosages more slowly to avoid discomfort when they discontinue an SSRI. Another option is for patients to switch from their shorter-acting SSRI to fluoxetine for the final discontinuation. Fluoxetine has a 9.3 day half-life (which is longer than the 24-hour or so half-lives of many other SSRIs) and usually has the mildest discontinuation effects of all the SSRIs.⁴ Antidepressants with shorter half-lives (eg, paroxetine or fluvoxamine) have a higher risk of SSRI discontinuation syndrome.

Serious Side Effects

SSRI-Induced Mania/Hypomania

Estimates are that 3% to 10% of depressed individuals may be at risk for developing hypomania or mania when treated with antidepressants. Patients with underlying bipolar disorder seem susceptible to antidepressant-induced mania/hypomania. There is a high rate of instances when bipolar depression is misdiagnosed as unipolar depression.^5,6 The rate of antidepressant-induced hypomania in patients with major depressive disorder (MDD) is thought to correspond with the rate of misdiagnosis of bipolar depression as unipolar depression. Besides the induction of mania/hypomania by antidepressants, there can be “dysphoric” hypomanic/manic (“mixed”) states that can be difficult to differentiate from depression, or the more subtle induction of “rapid cycling” of manic and depressive episodes (ie, increasing the number of depressive and hypomanic/manic episodes peer year) that fade after discontinuation of antidepressants. It should be noted that some clinicians and researchers view these states as having a high-risk suicide potential.^7,8 If the PCP is concerned about having precipitated mania in a patient, he or she should seek consultation with a mental health colleague.

Agitation, Jitteriness, Restlessness, and Anxiety/Panic

Agitation, restlessness, and anxiety can result from the stimulating effect of some antidepressants. Patients might not be able to relax or sit still. Clinicians should be alert for racing or impulsive thoughts along with high energy, as they may be signs of antidepressant-induced hypomania or mania.

Patients with a history of panic disorder (Table 3) or anxiety who are being treated with antidepressants should have a gradual escalation in dosage to minimize these side effects, typically seen during the initial days of treatment with antidepressants. It may be difficult to place patients back on an antidepressant after they have experienced an antidepressant-induced panic anxiety state. It has also been shown that the presence of agitation and anxiety in a patient with depression is a risk factor for suicide. It is this latter fact which makes this constellation of side effects potentially serious.^9,10

To prevent the inadvertent precipitation of a panic attack when using an antidepressant, it may be useful to inquire about the symptoms (Table 3) and then recommend using a low dose of an antidepressant at initiation of therapy, with very slow upward titration. Education about this potential paradoxical increase in anxiety/panic while being introduced to an antidepressant is likely to improve adherence with medication. A benzodiazepine can often be employed to prophylax/treat antidepressant-induced panic or anxiety.

Increased Risk of Suicide

Whether or not the SSRIs increase suicide rates—especially in adolescents—has been a matter of contention, but the Food and Drug Administration has come down on the side of accepting the notion that SSRIs can increase suicide rates during the initial few months of a course of drug therapy or at times of dose changes (either increases or decreases; Table 4).¹¹

During treatment with antidepressants, patients should be asked at every visit ( there should be more frequent visits in the early months of treatment) about their suicidal thoughts (Table 5). Any patient being treated for depression should have a “suicide prevention plan” in case suicidal ideation emerges or re-emerges. This plan could include going to the nearest emergency room, calling suicide hot lines, encouraging family education about depression and suicide, providing Internet sites for patients with suicidal ideation,^12,13 and ways to contact their mental healthcare workers if suicidal ideation emerges. The “suicide prevention plan” provides alternative behaviors to suicidal behaviors.^10,14-17

Hyponatremia/SIADH

SSRIs may lead to the syndrome of inappropriate antidiuretic hormone secretion (SIADH), characterized by hyponatremia, a potentially fatal condition that is typically asymptomatic until it becomes severe. It is a relatively infrequent but serious complication of SSRI use. (One author estimated its occurrence with fluoxetine in approximately 6.3 cases out of 1,000.¹⁸) Risk factors for the development of SIADH/hyponatremia with SSRIs include older age, female gender, concomitant use of diuretics, low body weight, and lower baseline serum sodium concentrations. Baseline serum sodium levels should be obtained in those at higher risk who are going to start on an SSRI. Mental status changes are frequently the earliest manifestation of SIADH/hyponatremia.^19,20

Following discontinuation of the offending SSRI, the serum sodium concentration should normalize within approximately 2 weeks. Switching to another SSRI might still result in SIADH, hence plasma sodium concentrations must be monitored not only in the first weeks of treatment but throughout the full course of patients switched to another SSRI after a bout of SSRI-induced SIADH. The clinician might also consider use of a non-SSRI such as the aminoketone bupropion.

Serotonin Syndrome

Serotonin syndrome can be mild (in which case it may not be detected) or dramatic and life threatening.²¹ An often-cited differential point for differentiating neuroleptic malignant syndrome (NMS) from serotonin syndrome involves abnormal reflexes, where there will be hyperreflexia and clonus in serotonin syndrome versus bradyreflexia in NMS. Information from a recently released Food and Drug Administration warning related to serotonin syndrome and various antidepressants can be found in Tables 6 and 7.²²

Prevention of serotonin syndrome with the avoidance of drug interactions that might cause it should be the mainstay of treating serotonin syndrome. Clinicians should also remember that single SSRIs (especially in high dose and overdose) can result in serotonin syndrome.²³ Patients who are going to be placed on SSRIs, especially those who are going to be on other serotonergic medications (such as triptans for migraines) along with their SSRIs, should be educated about this syndrome in order to make them partners in the early detection of this rare side effect.²⁴

The most important treatment is to discontinue the offending agents. The syndrome usually resolves within 24 hours after the withdrawal of the offending medications.^25-27

Seizures

Four out of every 1,000 people who receive bupropion in doses <450 mg/day experience seizures. When doses exceed 450 mg/day, the risk increases 10-fold. Bupropion should not be used in patients with epilepsy and other conditions that lower the seizure threshold (eg, alcohol withdrawal, active brain tumors). Seizures are a very rare event in patients taking SSRIs.⁴

Upper Gastrointestinal Bleeding and SSRIs

Serotonin enhances platelet activation that is induced by adenosinediphosphoric acid and thrombin in whole blood.²⁸ The depletion of serotonin from platelets, subsequent to reuptake blockade, would therefore be expected to diminish hemostasis. Upper gastrointestinal bleeding (UGIB) has been a concern in SSRI treatment following the publication of numerous case reports.^29-31 Studies employing large patient databases have been useful in examining the relationship between SSRI use and subsequent UGIB. A recent study in the Danish population found that users of SSRIs were hospitalized with UGIB at a rate 3.6 times greater than age- and sex-matched controls.²⁹ Yuan and colleagues³⁰ concluded that the evidence supporting increased UGIB in the context of SSRI use in the general population is limited. However, there is greater evidence that SSRI use is associated with increased UGIB in the elderly,³¹ concomitant NSAID use, and patients with a past history of UGIB. Clinicians should therefore be aware of this potential serious adverse event of SSRIs.

Birth Defects and Breastfeeding in Patients Taking SSRIs

The treatment of maternal depression during pregnancy is an important clinical issue. The fetal safety of SSRIs was an early concern after the introduction of fluoxetine in the 1980s as a result of the high-reported prevalence of depression among women (up to 20%) and the fact that >50% of all pregnancies are unplanned.³² An early study raised concerns that fluoxetine use during pregnancy was associated with perinatal complications and minor malformations,³³ although this association may have been more directly related to the severity of depression. A prospective controlled study³² comparing 267 women who contacted one of nine “teratology information service centers” because of concerns regarding SSRI use during pregnancy and 267 women exposed to nonteratogenic agents failed to find differences on several important outcome measures, including major malformations, spontaneous and elective abortions, stillbirths, birth weight, and gestational age. The women were contacted 6–9 months after delivery.

A study of 1,403 pregnant women identified in a population-based registry in Quebec³⁴ suggested that a paroxetine dose >25 mg/day during the first trimester of pregnancy may be associated with increased risk of major congenital and cardiac abnormalities relative to other antidepressants. Thus, a dose-related effect of paroxetine during first-trimester exposure on cardiac malformations may exist. The impression that paroxetine is distinguished from other SSRIs in terms of a heightened association between its use during early pregnancy and infant cardiovascular defects, notably ventricular and atrium septum defects, emerged in a study of the Swedish Medical Birth Registry of 6,481 women who used SSRIs in early pregnancy between July 1, 1995 through the end of 2004.³⁵ This study did not find any support for a postulated association of maternal use of SSRIs during pregnancy and craniostenosis or omphalocele. Another large meta-analytic study of published obstetrical outcomes of women exposed to SSRIs during pregnancy did not find any association with heightened risk for major cardiovascular or minor malformations; however, there was a significantly increased risk of spontaneous abortion.36 Based on a retrospective study of 3,581 pregnant women drawn from two United States managed care insurance databases that excluded concurrent first-trimester use of known teratogens (eg, lithium, valproic acid, carbamazepine), paroxetine use during the first-trimester was associated with a 1% increase in the absolute risk for congenital malformations over the baseline rate of occurrence.³⁷ Various organ systems were affected and the most common cardiovascular malformations were ventricular septal defects. This study was conducted by GlaxoSmithKline, the manufacturer of paroxetine, and led to the issuance of an FDA warning regarding risk of major congenital malformations (Table 8).^37,38

Congenital malformations do not appear to occur more frequently with maternal use of most SSRIs during pregnancy (paroxetine may be an exception); however, these medications do cross the placenta, appear in umbilical cord blood at birth, and are associated with metabolic effects and emergence of serotonin syndrome in the neonate.³⁹ Serotonin syndrome due to SSRI administration is well-described in adults and includes changes in mental state, myoclonus, hyperreflexia, tremor, and fever, among other symptoms.²¹ It is not clear that long-term sequelae are associated with the emergence of serotonin syndrome in neonates. However, SSRI exposure during pregnancy does have metabolic and clinical consequences, albeit often subtle, for the neonate. Thus, the risk to the developing infant and mother of untreated maternal MDD, panic disorder, or obsessive-compulsive disorder during pregnancy must be weighed against potential risk to the fetus. With the availability of other antidepressants, paroxetine use should be avoided in pregnant women in need of treatment with an SSRI.

Breastfeeding and SSRIs

Postpartum depression occurs in approximately 10% to 15% of women, many of whom may require antidepressants while breastfeeding.⁴⁰ Of all the SSRIs, citalopram and fluoxetine are associated with the highest exposures to nursing infants, which are usually significantly <10% of the maternal dose per body weight. Studies of maternal/infant pairs of plasma and serum samples suggest that infant levels of nortriptyline, paroxetine, fluvoxamine, and sertraline are often undetectable, whereas levels of fluoxetine and citalopram were found to exceed 10% of the maternal levels in a high percentage of nursing infants.^41,42 Data suggest that serious adverse side effects with clinical consequences are not usually encountered in the infant during breastfeeding by mothers treated with SSRIs; thus, breastfeeding need not be discouraged.⁴⁰ However, fluoxetine and citalopram are not the preferred SSRIs for the treatment of nursing mothers.

Conclusion

Though antidepressants help alleviate the potentially impairing syndrome of depression, it is important to recognize their side effects to more effectively help maintain compliance. PCPs should also be aware that some symptoms in a patient treated with an SSRI might be an adverse event associated with high morbidity and even fatality, such as SIADH and serotonin syndrome, the latter of which can present with symptoms (eg, agitation, anxiety, twitching, confusion) interpreted as worsening depression. However, the PCP should not get scared off from using these life-saving medications. An increased awareness of the side effects of the most current and commonly used antidepressants should improve the PCP’s confidence to treat the most common disabling illness in this country. These mediations can typically be used with great tolerance and benefit in the majority of depressed patients. PP

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