CURRENT THERAPY

ELIAS A. KHAWAM, MD GEORGIA LAURENCIC, MD DONALD A. MALONE JR., MD Louis Stokes Cleveland VA Medical Center; Department of Psychiatry and Psychology, Head, Section of Adult Primary Services, Senior Instructor, Department of Psychiatry, Cleveland Clinic Department of Psychiatry and Psychology, Case Western Reserve University Cleveland Clinic

Side effects of : An overview

■ ABSTRACT URRENT are C effective and generally well tolerated, but Adverse effects of antidepressant drugs can decrease noncompliance remains worrisome. Up to 70% compliance and delay recovery. It is therefore crucial to of patients taking antidepressants are noncom- consider potential side effects when choosing an pliant,1,2 as a result of either missed doses or antidepressant. Although there is no perfect premature discontinuation. According to Lin antidepressant that works quickly and is completely free et al,1 28% of patients stopped taking antide- of adverse reactions, newer antidepressants are safer, pressants in the first month of treatment, and better tolerated, and associated with a lower rate of 44% discontinued by the third month. Several noncompliance. reasons were identified for premature discon- tinuation, with side effects the most common. ■ KEY POINTS Dropout rates in studies of antidepres- sants varied from 7% to 44%; in studies of sero- Although side effects can be idiosyncratic, most can be tonin reuptake inhibitors, the dropout rates explained by the drug’s mechanism of action. were 7% to 23%.3,4 Physicians should educate and reassure Most antidepressant side effects subside within the first their patients about potential side effects. Benign and transient side effects are more few days to weeks of therapy. common than dangerous or irreversible effects, especially with the newer antidepres- is a side effect of all sants. This knowledge can help in reducing reuptake inhibitors, , and . the rate of medication discontinuation, which and have the lowest risk for is important because even after a medication sexual side effects. has produced the desired benefit, it needs to be continued to prevent relapses. The risk of may be increased during the first This article will focus on the adverse month or so of antidepressant therapy; physicians, effects of antidepressants, with the goal of patients, and family members should be vigilant for signs helping physicians to recognize and under- of suicidal thoughts and behavior. stand them, so that patients can undergo effective treatment.

In elderly patients, serotonin reuptake inhibitors seem to ■ SIDE EFFECTS ARE USUALLY PREDICTABLE be safer and better tolerated than tricyclic antidepressants. The choice should be made on the basis Medications are the mainstay of treatment of of side effect profile and drug interactions. moderate to severe , often com- bined with psychotherapy.5 In addition, anti- depressants are used to treat other psychiatric PATIENT INFORMATION illnesses and even medical illnesses (TABLE 1). If you need an antidepressant, page 363 Although some side effects of antidepres-

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TABLE 1 Mechanism of serotonin reuptake inhibitors Serotonin reuptake inhibitors selectively Other indications for antidepressant drugs block serotonin reuptake at the presynaptic disorders: phobic disorders, , nerve terminal. obsessive-compulsive disorder, generalized , and have the post-traumatic stress disorder most selective effect on serotonin reuptake, with little inhibitory effect on norepinephrine Attention deficit and disruptive behavior disorders and reuptake and a low affinity for Eating disorders: anorexia and bulimia alpha 1 adrenergic receptors, muscarinic Gastrointestinal disorders: irritable bowel syndrome cholinergic receptors, and histamine H1 receptors.11,12 Genitourinary disorders: enuresis Other serotonin reuptake inhibitors have Pain syndromes: , other chronic pain conditions similar profiles, except that has some anticholinergic properties, Psychotic disorders: schizoaffective disorder weakly inhibits norepinephrine reuptake, and Sleep disorders: insomnia, night terrors, sleep apnea, narcolepsy, weakly inhibits norepinephrine and functional enuresis dopamine reuptake.7–9,11

Pharmacokinetics of serotonin reuptake inhibitors sant drugs are idiosyncratic, most can be Serotonin reuptake inhibitors differ in their explained by their effects at the synaptic level . Fluoxetine has the longest (TABLE 2).6,7 Antidepressants typically block half-life, and its active metabolite (norfluoxe- the reuptake of certain neurotransmitters tine) has a half-life of 7 to 15 days.11 Paroxetine (norepinephrine, serotonin, and dopamine) and fluvoxamine have relatively short half-lives back into the nerve ending and block some of (21 and 15 hours, respectively). the other neurotransmitter receptors.7–10 The All serotonin reuptake inhibitors are Serotonin most clinically relevant receptor blockade metabolized in the by the cytochrome P- reuptake occurs at muscarinic (acetylcholine), hista- 450 system.11 Because they competitively minic (H1), alpha-1 adrenergic, dopaminer- inhibit these hepatic enzymes, serotonin reup- inhibitors are gic (D2), and possibly serotonergic (5- take inhibitors can increase the levels of other metabolized HT2A) receptors. medications metabolized by these enzymes, Side effects are not always a disadvantage. possibly leading to toxic effects. The greater by the P-450 For example, a patient with insomnia may the P-450 inhibition, the greater the possibili- system benefit from a sedating antidepressant given at ty of drug interactions. For example, giving bedtime. (a ) with a serotonin such as fluoxetine ■ SEROTONIN REUPTAKE INHIBITORS can lead to as much as a fourfold increase in the plasma level of desipramine, which could Serotonin reuptake inhibitors have replaced lead to increased anticholinergic effects, seda- the tricyclic antidepressants as the first-line tion, , and cardiotoxicity. Fluoxetine treatment for depression and now account for might interact with , with the possibil- most prescriptions for antidepressants in the ity of an increased anticoagulant effect and an United States. Fluoxetine (Prozac) was intro- increased risk of bleeding. duced in 1988 and was followed by sertraline (Zoloft), paroxetine (Paxil), fluvoxamine Side effects (Luvox), citalopram (Celexa), and escitalo- of serotonin reuptake inhibitors pram (Lexapro). All but fluvoxamine are Serotonin reuptake inhibitors are generally approved by the US Food and Drug well tolerated. However, approximately 15% Administration (FDA) for treating depres- of patients cannot tolerate certain side effects sion; fluvoxamine is approved for obsessive- and therefore may stop taking the drug. compulsive disorder. Sexual dysfunction. Although psychi-

352 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 4 APRIL 2006 Downloaded from www.ccjm.org on September 23, 2021. For personal use only. All other uses require permission. atric illnesses in themselves can affect sexual TABLE 2 desire and performance, so can the drugs used to treat the illness. Sexual dysfunction is the Adverse effects of antidepressant most common side effect of all serotonin reup- drugs, based on mechanism of action take inhibitors. Delayed ejaculation, anorgas- Norepinephrine transporter blockade mia, and decreased can occur in up to Anxiety 60% of patients,13,14 and the effects continue Augmentation of pressor effects of sympathomimetic amines as long as the drug is taken. Diaphoresis The stimulation of serotonin 5-HT2 and 5-HT3 receptors is a proposed mechanism for the occurrence of sexual dysfunction due to Serotonin reuptake inhibition serotonin reuptake inhibitors, so it has been Anorexia early in the treatment and weight gain later suggested that adding medications that block Dose-dependent increase or decrease in anxiety those receptors might help with this adverse Ejaculatory disturbances, anorgasmia, and decreased libido effect. The most common medications for Extrapyramidal side effects counteracting this fall into three Interaction with monoamine oxidase inhibitors and groups: alpha-2 adrenergic receptor antago- Nausea, vomiting, and . nists, serotonin 5-HT2 or 5-HT3 receptor Sedation or insomnia antagonists (eg ), and dopaminer- gic agents. Other strategies include decreasing Dopamine reuptake inhibition the dose; adding bupropion, , cypro- Activation and aggravation of heptadine, or ; or switching to Parkinsonism another antidepressant that has few sexual side Psychomotor activation effects, such as bupropion, mirtazapine, or Alpha-1 adrenergic receptor blockade nefazodone.2,14 Postural hypotension and dizziness Gastrointestinal effects. Sertraline and Potentiation of the antihypertensive effect of other medications fluvoxamine may cause more gastrointestinal Reflex tachycardia side effects than other serotonin reuptake Dopamine D2 receptor blockade inhibitors. Nausea and diarrhea are dose-relat- Extrapyramidal side effects: , dystonia, parkinsonism, ed and usually resolve within the first 2 weeks tardive dyskinesia of treatment. Starting the medication at a low Endocrine effects; prolactin elevation dose and giving it with food usually alleviates nausea. Histamine H1 receptor blockade Drowsiness and dry mouth tend to be Falls in the elderly more common with paroxetine because of its anticholinergic activity.6 Sedation Anorexia is most common with fluoxe- Weight gain tine and occurs early in the treatment.8,14 It is probably related to activation of 5-HT2C Muscarinic acetylcholine receptor blockade 8 Blurred vision receptors. However, with time this suppres- Central effects: memory and cognitive impairment, sant effect on appetite is lost. Indeed, sero- delirium in severe cases tonin reuptake inhibitors have the potential Gastrointestinal effects: decreased salivation, dry mouth, to cause weight gain, possibly due to desensi- decreased peristalsis, constipation tization and down-regulation of the serotonin Precipitation of narrow-angle receptors associated with appetite control. Sinus tachycardia Central nervous system side effects Urinary hesitancy and retention include anxiety, insomnia, sedation, night- ADAPTED FROM RICHELSON E. INTERACTION OF ANTIDEPRESSANTS WITH NEUROTRANSMITTER mares,6,14 and extrapyramidal symptoms. TRANSPORTERS AND RECEPTORS AND THEIR CLINICAL RELEVANCE. J CLIN PSYCHIATRY 2003; 64(SUPPL 13):5–13; Patients may experience increased anxiety, AND RICHELSON E. OF ANTIDEPRESSANTS. most commonly early in treatment. MAYO CLIN PROC 2001; 76:511–527. Sleep disturbances, either insomnia or , have been reported in about

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25% of patients taking serotonin reuptake L-tryptophan. Therefore, it is mandatory to inhibitors. Fluoxetine is more likely to cause wait at least 2 weeks after stopping a serotonin insomnia than is paroxetine, which is more reuptake inhibitor before starting a mono- likely to cause sedation. Others tend to lead amine oxidase inhibitor, and at least 5 weeks if equally to somnolence or insomnia. Insomnia switching from fluoxetine, in view of this can be treated with , benzodi- drug’s long half-life. azepines, or other sedative medications.14 Discontinuation syndrome can occur if a Headache, nightmares, and vivid dreams serotonin reuptake inhibitor with a short half- have been reported in a minority of patients. life such as paroxetine or fluvoxamine is These side effects often resolve within a few abruptly stopped.14,15,20 Patients may experi- weeks and rarely lead to a change in medica- ence dizziness, nausea, weakness, insomnia, tion. anxiety, irritability, and headache. These In rare cases, serotonin reuptake inhibitors symptoms tend to be transient and resolve can cause extrapyramidal side effects, includ- spontaneously within a week. Slowly tapering ing akathisia (motor restlessness; constant serotonin reuptake inhibitors over a couple of movement).6 Such adverse effects are not due weeks can help prevent this syndrome. to dopamine receptor blockade but rather to Fluoxetine is less likely to cause this syndrome increased serotonin at the synaptic levels, because of its long half-life. Indeed, fluoxetine mediating inhibition of the release of has been used to treat the discontinuation dopamine through one of the presynaptic sero- syndrome caused by other serotonin reuptake tonin receptor subtypes. The rate of seizures inhibitors. with serotonin reuptake inhibitors is 0.1% to 0.2%, which is not significantly different from ■ VENLAFAXINE that with placebo.15,16 Orthostatic hypotension is unlikely in Venlafaxine (Effexor) was first released in an patients treated with serotonin reuptake immediate-release form. An extended-release inhibitors because they do not block alpha-1 form (Effexor XR) was approved by the FDA Serotonin adrenergic receptors significantly.6,15 in 1997. reuptake These drugs have minimal effects on hist- Venlafaxine inhibits serotonin and norepi- amine H1 receptors and therefore they are less nephrine reuptake and is a weak inhibitor of inhibitors sedating than tricyclic antidepressants. dopamine reuptake.8 It is not active at the mus- should be Bleeding. Serotonin reuptake inhibitors carinic, nicotinic, histaminergic, or adrenergic inhibit platelet function and may prolong receptors. tapered to bleeding. Several reports have indicated an The most common side effects are nausea, avoid the association between the use of these drugs and dizziness, insomnia, somnolence, and dry discontinuation bleeding disorders ranging from bruising and mouth. Gastrointestinal side effects are less epistaxis to more serious conditions such as common with the XR preparation. syndrome gastrointestinal bleeding.17 Sexual dysfunction can occur, as with has been reported in rare serotonin reuptake inhibitors.13 cases.18 Discontinuation syndrome, with nau- Serotonin syndrome is serious.15,19 sea, somnolence, insomnia, and anxiety, can Resulting from hyperstimulation of serotonin result if venlafaxine is abruptly stopped.21 receptors, it is characterized by nausea, diar- To prevent this syndrome, venlafaxine XR rhea, restlessness, extreme agitation, hyper- should be tapered over several days to reflexia, autonomic instability, myoclonus, weeks. hyperthermia, rigidity, delirium, , and Hypertension can occur with venlafaxine status epilepticus. In severe cases, it can XR,22 especially in higher doses. Physicians result in cardiovascular collapse, coma, and should be cautious when prescribing this med- death. ication to patients with preexisting hyperten- This syndrome can occur when a sion. Blood pressure should be monitored reg- monoamine oxidase inhibitor is given with a ularly, especially when using venlafaxine XR serotonin reuptake inhibitor, , or at doses of 225 mg or more per day.

356 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 4 APRIL 2006 Downloaded from www.ccjm.org on September 23, 2021. For personal use only. All other uses require permission. ■ MIRTAZAPINE sea are common side effects of bupropion. Increased irritability and agitation may also Mirtazapine (Remeron) is a presynaptic alpha occur. 2 adrenergic receptor antagonist and a potent Seizures. The extended-release formula- antagonist of serotonin 5-HT2 and 5-HT3 tion carries a seizure risk of about 0.4% at a receptors.8,23 It has very little effect on 5-HT1 dose of 400 mg per day. Physicians should receptors. Therefore, mirtazapine directly avoid prescribing this medication to patients increases norepinephrine release and, indi- with a history of seizure, epileptiform dis- rectly, serotonin release. It also blocks hista- charges on electroencephalography, heavy mine receptors and has minimal affinity for use, or eating disorders; or with ben- muscarinic and alpha-1 adrenergic receptors. zodiazepine withdrawal, head trauma, or Sedation is the most common side effect. organic brain syndrome. Giving the medication at bedtime can mini- Bupropion does not cause orthostatic mize sedation. Nighttime sedation could be an hypotension, daytime drowsiness, or anti- advantage in depressed patients with sleep dis- cholinergic side effects. turbances, but on the other hand, undesirable Caution should be used in patients with daytime sedation could occur. renal or liver diseases because these condi- Weight gain. Mirtazapine can increase tions could result in elevated plasma levels of appetite and carbohydrate craving.14 This bupropion. may lead to significant weight gain if not monitored closely. It may also increase choles- ■ DULOXETINE terol and triglyceride levels. Patients should be educated and advised to monitor their Duloxetine (Cymbalta), the newest approved weight and to exercise regularly at the time of antidepressant, is an inhibitor of serotonin prescribing this medication. and norepinephrine reuptake and a less Liver function tests, especially alanine potent inhibitor of dopamine reuptake.24 It aminotransferase, can be mildly elevated. has no significant affinity for adrenergic, Neutropenia has developed in rare cases cholinergic, or histaminergic receptors. Nighttime in patients treated with mirtazapine.15 This The most common side effects reported in sedation hematologic condition is more likely to occur placebo-controlled clinical trials were nausea, in patients with other risk factors for neu- dry mouth, constipation, fatigue, decreased may be tropenia. appetite, and sweating.24 The overall dropout desirable in Dizziness, dry mouth, constipation, rate due to side effects was 10%, with nausea increased appetite, and disturbing dreams as the most common adverse event. depressed have also been reported. Sexual dysfunction was more common patients with Mirtazapine does not tend to cause sexual with duloxetine than with placebo.25 sleep dysfunction.14 However, the rate appears to be less than with serotonin reuptake inhibitors. disturbances ■ BUPROPION Initial insomnia, irritability, anxiety, nervousness, and restlessness were also Bupropion (Wellbutrin) is a unique antide- reported. pressant that has few sexual side effects and Duloxetine was associated with an tends not to cause an increase in appetite or increased risk of and should be used weight gain.2,13,14 Besides depression, it is used with caution in controlled narrow-angle glau- in smoking cessation. coma. Bupropion is thought to work by inhibit- Treatment with duloxetine was associated ing norepinephrine reuptake and dopamine with increased blood pressure. Therefore, neurotransmission. It also has an active one should measure blood pressure before metabolite that mediates antidepressant effi- starting duloxetine and periodically monitor cacy by blocking reuptake of norepinephrine it throughout treatment.26 and dopamine.8 Duloxetine should not be used in combi- Insomnia, headache, , and nau- nation with monoamine oxidase inhibitors

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and can be used only at least 14 days after Drug interactions are significant. stopping one of these drugs. Serotonin reuptake inhibitors may raise the If duloxetine is stopped, it should be plasma levels of tricyclic antidepressants. tapered gradually to avoid discontinuation There is a possibility that levels side effects. increase with tricyclic coadministration. Valproic acid can increase levels of , ■ TRICYCLIC AND TETRACYCLIC and may decrease them. ANTIDEPRESSANTS ■ MONOAMINE OXIDASE INHIBITORS Tricyclic antidepressants were introduced shortly after monoamine oxidase inhibitors. Monoamine oxidase inhibitors are very effec- They were the drugs of choice for depression tive antidepressants, but dietary restrictions and in the 1980s, but they are not as widely used the risk of hypertensive crises limit their use. now because less toxic and more selective These drugs irreversibly inactivate the medications are available. enzyme monoamine oxidase in the central These medications block reuptake of nor- nervous system, platelets, liver, and gastroin- epinephrine and serotonin. They are also com- testinal tract, the last of which may cause an petitive antagonists at the muscarinic, hista- increase in tyramine absorption. minergic, and alpha 1 and 2 adrenergic recep- Monoamine oxidase inhibitors were discov- tors, which results in their characteristic side ered in the early 1950s. The first drug of this effect profile.8 , , and class was , but serious side effects, par- have the most anticholinergic activi- ticularly hypertensive crisis and hepatic necro- ty, whereas and desipramine are sis, prevented its use.15,29 Currently available are less anticholinergic.6,15 (Nardil), (Marplan), Anticholinergic side effects include dry (Parnate), and mouth, constipation, urinary retention, (Eldepryl). Reversible monoamine oxidase blurred vision, confusion, and delirium. inhibitors require few dietary restrictions but are Renal or liver Narrow-angle glaucoma can be aggravated. not available in the United States; these include diseases can Cardiac effects. Tricyclic antidepressants (Manerix) and befloxatone. may slow cardiac conduction, causing intra- Orthostatic hypotension, the most fre- elevate ventricular conduction delay, atrioventricular quent side effect, is secondary to alpha-1 adren- bupropion block, flattened T waves, depressed ST seg- ergic blockade. The exact mechanism is not ments, and prolonged QT intervals.27 All tri- known but likely involves elevated norepineph- levels cyclic antidepressants can cause tachycardia, rine at presynaptic alpha-2 receptors. Dizziness which is one of the most common reasons for and reflex tachycardia may also occur. stopping them. Nortriptyline is the least likely Antihistaminergic activity might lead to to cause orthostatic hypotension. weight gain and sedation. Because of cardiotoxicity, an overdose of Hypertensive crises are usually induced as little as 1 week’s worth of medication can be by consuming food rich in tyramine or by fatal. medications with sympathomimetic activity. Sedation is the most common side effect of Headache, stiff neck, sweating, nausea, and tricyclic antidepressants and is a result of anti- vomiting characterize the prodromal phase. cholinergic and antihistaminergic effects.28 This could be followed by autonomic instabil- Doxepin has the highest antihistaminergic ity, elevated blood pressure, cardiac arrhyth- activity among tricyclic antidepressants. mia, coma, and death. Weight gain and sexual side effects are Sexual dysfunction, hepatotoxicity, and also common.14 pyridoxine deficiency have been reported. A discontinuation syndrome28 is mostly Drug interactions are numerous, includ- related to cholinergic and serotonergic ing problems with over-the-counter medica- rebound. After prolonged treatment, tricyclic tions such as pseudoephedrine. Serotonin syn- antidepressants should be tapered gradually drome can occur when monoamine oxidase over several weeks. inhibitors are combined with serotonin reup-

358 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 4 APRIL 2006 Downloaded from www.ccjm.org on September 23, 2021. For personal use only. All other uses require permission. take inhibitors, tricyclic antidepressants, or The risk was identified in a combined carbamazapine. Coadministration with opi- analysis of short-term (lasting up to 4 months), oids, especially meperidine, may lead to auto- placebo-controlled trials of the serotonin reup- nomic instability, delirium, and death. take inhibitors fluoxetine, citalopram, paroxe- Caution should be taken when using tine, fluvoxamine, and sertraline, as well as monoamine oxidase inhibitors with antihy- bupropion, nefazodone, mirtazapine, and ven- pertensive agents, due to an increased likeli- lafaxine XR, in children and adolescents with hood of hypotension. major depressive disorder and other psychiatric disorders.32 The analysis showed a twofold ■ TRAZODONE greater risk of suicidal thoughts and behavior during the first few months of treatment in Trazodone is effective in treating depression, those receiving antidepressants—an average of but it is not often used for this indication 4%—compared with the rate with placebo. because other antidepressants with a more Of note: although this analysis suggests benign side effect profile are available. that the incidence of suicide may be higher in Trazodone is a weak inhibitor of serotonin patients taking serotonin reuptake inhibitors, reuptake and a potent antagonist of serotonin no definitive link has been made. There were 5-HT2A and 5-HT2C receptors.8 The side no reported cases of suicide in these studies.32 effects of trazodone are mostly attributed to If there is an increased risk of suicide, a antihistaminic and alpha-1 adrenergic block- possible explanation is that serotonin reup- ade. take inhibitors and some other antidepres- Sedation. Trazodone has been often used sants can cause anxiety, agitation, and activa- for treating insomnia because it has sedative tion, particularly at the start of treatment. In qualities. However, in a recent review, someone with lowered mood, new aversive Mendelson30 found that data are lacking to symptoms might further worsen mood and support its use in this way. increase the risk of suicide.33 Trazodone can cause significant orthosta- The FDA recognizes that depression and hypotension, dizziness, and headache. In other psychiatric disorders can have signifi- Tricyclic rare cases, it can cause priapism in the cant consequences if not appropriately treat- antidepressants absence of sexual stimuli. This serious side ed. The new warning does not prohibit the effect usually occurs during the first 4 weeks of use of antidepressants, but it warns of the risk can cause treatment, and it is not dose-dependent. of suicidal thoughts and behavior and encour- tachycardia ages clinicians to balance this risk with clini- ■ ANTIDEPRESSANTS AND SUICIDE RISK cal need and to closely monitor patients, espe- cially at the start of treatment. This issue The relationship between antidepressants, remains a concern and a topic of continuing especially serotonin reuptake inhibitors, and scientific debate. suicidal ideation and behavior has received Suicide is a significant public health prob- considerable public attention lately. The use lem. Each year there are approximately 30,000 of these drugs in children and adolescents has in the United States and 1 million been of particular concern.31 worldwide.34,35 Suicide is the eighth leading In October 2004, the FDA issued a cause of death in the United States, and major warning about the increased risk of suicidal depression is a factor in about 50% of suicides.36 thoughts and behavior in children and ado- The suicide rate has actually been declin- lescents being treated with antidepressant ing over the last 10 to 15 years, coinciding medications. The agency has asked phar- with the introduction of serotonin reuptake maceutical manufacturers to add a “black inhibitors and increases in antidepressant pre- box” warning statement to the label for all scriptions.37–39 Furthermore, most of those antidepressant medications to describe the who commit suicide and carry the diagnosis of risk and emphasize the need for close mon- major depressive disorder at the time of death itoring of patients started on these medica- are either untreated or receiving subtherapeu- tions. tic doses of antidepressants,37,39 indicating the

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need for better recognition and adequate in the elderly. The choice of antidepressant in treatment of patients at risk. the elderly should be based on its side effect It is important to educate patients about profile and drug interactions.41 their illness and available treatment options. Serotonin reuptake inhibitors appear to They should be informed about the current be safer and better tolerated than tricyclic controversy regarding the use of serotonin antidepressants. Common side effects of sero- reuptake inhibitors as a part of the process of tonin reuptake inhibitors in the elderly are obtaining informed consent. They need to be nausea, insomnia, and sedation. Citalopram instructed to watch for any signs of activation, and sertraline have the fewest, if any, drug agitation, or suicidal ideation, and inform the interactions. Paroxetine can cause more seda- prescribing physician immediately. tion and anticholinergic side effects. It is also reasonable to schedule more fre- Tricyclic antidepressants should be start- quent follow-up visits at the beginning of ed with very low doses. Alpha-1 adrenergic treatment to monitor more closely for emer- blockade leads to orthostatic hypotension, gence of these side effects. Patients at higher which can cause dizziness and falls in the risk for suicide may be given limited amounts elderly. Histaminic effects can cause sedation of the medication, just enough until the next and weight gain. Blood levels of tricyclic anti- follow-up visit. Any reports of suicidal depressants should be monitored, as should ideation need to be taken seriously, and hospi- their electroencephalographic, blood pressure, talization should be considered. and cardiac effects. Patients need to be referred for psychiatric Mirtazapine may be a useful alternative to consultation if one or more antidepressants fail tricyclic antidepressants in the elderly because it or produce only a partial response, or if they promotes sleep and causes minimal orthostasis. have major depression with psychotic features. ■ IMPORTANCE OF PATIENT EDUCATION ■ ANTIDEPRESSANTS IN THE ELDERLY Education and reassurance of patients about side The risk of Medication dosages need to be altered in older effects will enhance compliance and improve suicide during age because of physiological changes. Aging and treatment outcome. Providing patients with concomitant medical problems affect the phar- contact information might decrease their anxi- antidepressant macodynamics and pharmacokinetics of med- ety and help in reporting any adverse event. It is therapy ications. In addition, many elderly patients use a also very helpful to provide patients with litera- number of medications, and caution should be ture explaining the potential side effects. remains a topic given to potential drug interactions.40 Patients should be encouraged to contact their of debate No important differences in efficacy have provider about any troublesome side effect that been found between classes of antidepressants does not resolve. ■ REFERENCES Application. New York, NY: Cambridge University Press. Second edition; 1. Lin EH, Von Korff M, Katon W, et al. The role of the primary care physician 2000. in patients’ adherence to antidepressant therapy. Med Care 1995; 9. Stahl SM. Basic psychopharmacology of antidepressants, pt 1: antidepres- 33:67–74. sants have seven distinct mechanisms of action. J Clin Psychiatry 1998; 2. Zajecka JM. Clinical issues in long term treatment with antidepressants. J 59(suppl):5–14. Clin Psychiatry 2000; 61(suppl l2):20–25. 10. Nierenberg AA. 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