CURRENT DRUG 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 antidepressants: An overview ■ ABSTRACT URRENT ANTIDEPRESSANT DRUGS 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 tricyclic 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- Sexual dysfunction is a side effect of all serotonin sants. This knowledge can help in reducing reuptake inhibitors, venlafaxine, and duloxetine. the rate of medication discontinuation, which Bupropion and nefazodone 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 suicide 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 depression, 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- CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 4 APRIL 2006 351 Downloaded from www.ccjm.org on September 23, 2021. For personal use only. All other uses require permission. ANTIDEPRESSANTS KHAWAM, LAURENCIC, AND MALONE TABLE 1 Mechanism of serotonin reuptake inhibitors Serotonin reuptake inhibitors selectively Other indications for antidepressant drugs block serotonin reuptake at the presynaptic Anxiety disorders: phobic disorders, panic disorder, nerve terminal. obsessive-compulsive disorder, generalized anxiety disorder, Citalopram and escitalopram 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 dopamine 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: migraine headache, other chronic pain conditions similar profiles, except that paroxetine has some anticholinergic properties, fluoxetine Psychotic disorders: schizoaffective disorder weakly inhibits norepinephrine reuptake, and Sleep disorders: insomnia, night terrors, sleep apnea, narcolepsy, sertraline 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 pharmacokinetics. 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 liver 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. desipramine (a tricyclic antidepressant) with a serotonin reuptake inhibitor 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, seizures, and cardiotoxicity. Fluoxetine treatment for depression and now account for might interact with warfarin, 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 libido 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 Tachycardia 5-HT3 receptors is a proposed mechanism for Tremor 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 adverse effect fall into three Interaction with monoamine oxidase inhibitors and tryptophan groups: alpha-2 adrenergic receptor antago- Nausea, vomiting, and diarrhea. nists, serotonin 5-HT2 or 5-HT3 receptor Sedation or insomnia antagonists (eg mirtazapine), and dopaminer- Serotonin syndrome gic agents. Other strategies include decreasing Dopamine reuptake inhibition the dose; adding bupropion, sildenafil, cypro- Activation and aggravation of psychosis heptadine, or buspirone; 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