740 Treating Depression With SSRIs Mayo Clin Proc, July 2001, Vol 76 Table 1. Currently Available Selective Serotonin Reuptake Inhibitors Dose Initial

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1 Mayo Clin Proc, July 2001, Vol 76 Treating Depression With SSRIs 739 Concise Review for Clinicians Treating Depression With Selective Serotonin Reuptake Inhibitors: A Practical Approach SHIRLENE M. SAMPSON, MD Depression is a common disorder that is becoming better understood as an illness that can be chronic, recurrent, and refractory to treatment. Depression can produce substantial suffering and profoundly affect a patient s selfesteem, relationships, and functional capacity. The improved adverse-effect profile and safety from overdose of selective serotonin reuptake inhibitors (SSRIs) have led to treatment of milder forms of depression and thus increased treatment of depression overall. This article synthesizes several previously published reviews and psychopharmacology resources and addresses practical issues related to initiating, monitoring, continuing, and discontinuing SSRIs. Precautions related to SSRI use and important considerations for various types of depression are discussed. Mayo Clin Proc. 2001;76: MAOI = monoamine oxidase inhibitor; MDD = major depressive disorder; OCD = obsessive-compulsive disorder; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant Depression is a common illness with a lifetime prevalence of 10% to 25% for women and 5% to 12% for men. 1 Depression is becoming better understood as an illness that can be chronic, recurrent, and refractory to treatment. 2 With respect to global disease burden, depression is expected to be the second most serious illness by the year In 1990, 11 million Americans suffered a depressive disorder at an estimated cost of $44 billion. 4 As well as being a major cause of lost productivity, depression can produce substantial suffering and profoundly affect relationships. Many people suffer because they are unable to seek help. This can be due to signs and symptoms of the depression (eg, lack of insight, reduced energy/motivation), stigma related to depression, or presentation with less typical features of depression. For instance, elderly patients usually present with unexplained somatic complaints or anxiety and anhedonia rather than complaints of sadness. 5 Before the advent of selective serotonin reuptake inhibitors (SSRIs), the primary antidepressant medications used were tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Because these medications have serious adverse effects, treatment was primarily reserved for moderate to severe major depression. Since the development of SSRIs, antidepressant medications are now be- From the Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minn. A question-and-answer section appears at the end of this article. Address reprint requests and correspondence to Shirlene M. Sampson, MD, Department of Psychiatry and Psychology, Mayo Clinic, 200 First St SW, Rochester, MN ing used to treat milder forms of depression (mild major depression and dysthymia) and anxiety disorders (generalized anxiety disorder and social phobia). Other advantages likely driving the increased use of SSRIs include the potential for improved medication compliance with once-a-day dosing schedules (all except fluvoxamine), reduced cardiovascular effects compared with TCAs, and increased safety from overdose. CURRENT SSRIS The 5 currently available SSRIs, initial dose, dose range, and form are listed in Table 1. Although all have antidepressant efficacy, only citalopram, fluoxetine, paroxetine, and sertraline have received approval from the Food and Drug Administration for use as an antidepressant. Fluvoxamine has been approved for treating obsessive-compulsive disorder (OCD) but not depression. Adverse Effects Some of the more well-known adverse effects of SSRIs are discussed subsequently. A detailed list has been published previously. 6 Gastrointestinal. Nausea is the most common adverse effect and generally decreases over time. Vomiting can occur. Both diarrhea and constipation have been reported. Dry mouth tends to be less severe than that with TCAs. All SSRIs can produce weight gain, and transient weight loss has been reported with fluoxetine. Central Nervous System. Tension headaches can occur, and migraines can worsen. Both sedation and activation/insomnia can occur early in treatment. Tremors, increased anxiety, and akathisia have also been noted, as Mayo Clin Proc. 2001;76: Mayo Foundation for Medical Education and Research

2 740 Treating Depression With SSRIs Mayo Clin Proc, July 2001, Vol 76 Table 1. Currently Available Selective Serotonin Reuptake Inhibitors Dose Initial Generic Trade range dose name name (mg) (mg) Form Citalopram Celexa Tablet, 20, 40 mg; elixer, 10 mg/5 ml (peppermint) Fluoxetine Prozac Capsule, 10, 20, 40 mg; tablet, 10 mg; elixer, 20 mg/5 ml (mint) Fluvoxamine Luvox Tablet, 25, 50, 100 mg Paroxetine Paxil Tablet, 10, 20, 30, 40 mg; elixer, 10 mg/5 ml (orange) Sertraline Zoloft Tablet, 25, 50, 100 mg; elixer, 100 mg/5 ml (menthol) have increased dreaming and nightmares. All SSRIs can precipitate mania or hypomania. Endocrine. All SSRIs can produce secretion of inappropriate antidiuretic hormone, and risk increases with age and female sex. Increased prolactin, galactorrhea, and decreased fasting glucose level (up to 30%) have also been reported. Sexual. Decreased libido, delayed ejaculation, and anorgasmy can occur. Approaches to treatment include decreasing medication dose, changing medication, or treating symptoms. Medication options for sexual adverse effects include amantadine, cyproheptadine, buspirone, bupropion, mirtazepine, nefazodone, methylphenidate, yohimbine, and sildenafil. Other. Other adverse effects are rash, increased sweating, dizziness, impaired balance, and bradycardia (rare reports of tachycardia, palpitations, and hypertension). Initiation of Drug Because adverse effects occur with the onset of medication use but the antidepressant response can take 3 to 4 weeks to occur (assuming the medication will produce a beneficial response), optimizing medication tolerance is key. Beginning with a subtherapeutic dose can help to improve initial tolerance. This generally involves using half the lowest therapeutic dose for a few days (3-7 days) before increasing the dose into the therapeutic range. Conservative initial doses are 10 mg for fluoxetine, paroxetine, and citalopram and 25 mg for sertraline. After this initial period, the dose of fluoxetine, paroxetine, and citalopram can be increased to 20 mg as tolerated by the patient. The dose of sertraline can be increased to 50 mg. For patients with a history of extreme sensitivity to medications, liquid forms can be used to titrate lower doses. For geriatric patients or those with hepatic or renal failure, a therapeutic trial of the lower dose should be used because of the risk of reduced medication clearance. For patients with pronounced anxiety or somatic symptoms, low doses should be used initially to enhance tolerability even though patients with comorbid anxiety symptoms often need higher doses over time for optimal treatment. Providing educational materials on depression and medication adverse effects can be helpful because patients are often anxious and have reduced concentration or memory; thus, they may not recall the details of an initial visit. Medication compliance is an important issue for patients with depression because of the associated stigma and difficulties with memory/concentration. Strategies for optimizing treatment compliance include (1) providing education on the symptoms of depression; (2) targeting discussion to reduce the stigma associated with depression (ie, depression as a biologic disease process); (3) identifying the target symptoms for treatment (customized for each patient); (4) helping patients identify an existing daily habit to connect with taking their medication; (5) encouraging patients to call before discontinuing medications on their own; and (6) helping patients understand that they have some control in choosing to treat their depression. This last-mentioned issue is especially important as the symptoms of depression often make patients feel that they have lost control of their lives. Monitoring the Drug Efforts to provide increased support early are particularly helpful in optimizing medication compliance and helping patients tolerate adverse effects before any beneficial response occurs. This can be facilitated by having the patient return in 2 weeks or by setting up a day that the patient should call to give feedback on medication tolerance. This can be a brief interaction that is supportive for the patient.

3 Mayo Clin Proc, July 2001, Vol 76 Treating Depression With SSRIs 741 Figure 1. Mood log for patients to self-monitor their particular features of depression. Identification of the particular target symptoms for a patient is helpful for monitoring the patient s progress. Charting patient data has been done for years in mood disorders research. 7 The mood log (Figure 1) is a modified form of a life chart used in research studies. A mood log helps patients self-monitor their particular features of depression and become aware of subtle improvements and enhances reliability regarding the degree of their progress. It can also save time during subsequent evaluations because a substantial amount of information can be summarized in an easy-to-read format. Patient charting of symptoms is useful to circumvent difficulties related to reduced memory. Self-charting can help patients monitor for early symptoms of hypomania or mania that may be precipitated by antidepressants and possibly aid with early intervention. Of importance, the clinician should ask patients about specific adverse effects of medications because it is often difficult for patients to initiate discussion of sensitive issues, particularly sexual adverse effects. Identifying the cause of sexual adverse effects can be difficult because

4 742 Treating Depression With SSRIs Mayo Clin Proc, July 2001, Vol 76 both depression and antidepressant medications can reduce libido. Sexual adverse effects may diminish over time. If sexual adverse effects remain pronounced, the dose can be reduced or an alternative antidepressant with a lower incidence of sexual adverse effects can be used (eg, bupropion, nefazodone, or mirtazepine). Another approach is to add 75 to 150 mg of bupropion to the patient s medical regimen. 8,9 In the evaluation of the antidepressant response and the need for a dose increase, antidepressants should be given for at least 4 weeks when treating depression (vs 6-12 weeks for OCD) before the trial is considered a failure or the dose is considered inadequate. Even though it can be difficult to wait 4 weeks before increasing the dose when patients are suffering, the benefit of waiting is to use the minimal effective dose and attempt to minimize the potential for adverse effects. If at 4 weeks symptoms have improved partially, the dose should not be increased for another 2 weeks. 9 If at 4 weeks the patient has been able to tolerate the antidepressant but has had no substantial benefit, the dose can be increased to 30 to 40 mg for fluoxetine, paroxetine, or citalopram and to 100 mg for sertraline. Antidepressant doses can then be increased over 4-week intervals to the upper dose ranges of 80 mg for citalopram and fluoxetine, 50 mg for paroxetine, and 200 mg for sertraline in an effort to optimize treatment based on clinical response. Discontinuation of Drug Patients should continue taking antidepressants for at least 6 months after successful treatment of the first and possibly second episode of depression. The full therapeutic dose should be maintained, and patients must be educated that the risk of recurrence is increased if medications are discontinued before this time frame. Exceptions include patients with bipolar disorder for whom the risk-benefit ratio of prolonged antidepressant medication use would warrant shorter-term treatment or patients in other situations with altered risk-benefit ratios (eg, those wanting to become pregnant). After the first episode of depression, the probability of a second and third episode is 50% and greater than 90%, respectively. Antidepressant maintenance therapy for prophylaxis is highly recommended after a third episode of depression. The World Health Organization recommends maintenance treatment after 2 episodes within a 5-year period. When the decision is made to discontinue antidepressant medications, tapering the dose is the best approach to prevent a serotonin withdrawal syndrome. Symptoms associated with this syndrome are generally described by patients as flulike and can include nausea, diarrhea, insomnia, malaise, muscle aches, anxiety, irritability, dizziness, vertigo, and vivid dreams. Patients have also described electric shocklike sensations. This withdrawal syndrome was initially noted with paroxetine but can occur with other SSRIs. It is most likely to occur within 24 to 48 hours after abrupt discontinuation of SSRIs. In tapering SSRI doses to avoid symptoms of withdrawal, the half-life of the medication, the amount being taken, and the length of time it has been taken must be considered. After prolonged use, SSRIs should be withdrawn gradually. Because of the long halflife of fluoxetine and its active metabolite (6-7 days), withdrawal symptoms are least likely with this drug, and it has been used to treat SSRI withdrawal symptoms. No single approach exists for discontinuing SSRIs, and patient tolerance for the tapering schedule ultimately determines the time frame in which the medication can be discontinued. Precautions Although SSRIs are safer and often better tolerated than TCAs and MAOIs, complications can arise. Clinicians should remember the following issues when they prescribe SSRIs. Serotonin Syndrome. The serotonin syndrome is a potentially fatal hypermetabolic reaction that can occur when serotonergic medications are combined (eg, SSRIs and MAOIs). Because of this, SSRIs are not to be combined with an MAOI. When switching from an SSRI to an MAOI, allowing a washout of 5 half-lives of the SSRI is recommended. The washout is 1 to 2 weeks for citalopram, fluvoxamine, paroxetine, and sertraline and 4 to 5 weeks for fluoxetine. When switching from an MAOI to an SSRI, the washout period is 10 days. Symptoms of serotonin syndrome include lethargy, restlessness, confusion, flushing, diaphoresis, tremor, and myoclonic jerks. As the syndrome progresses, hyperthermia, hypertonicity, myoclonus, and death can occur. Serotonergic medications should be discontinued and medical support provided as needed. Cytochrome P-450 Inhibition. Fluoxetine, fluvoxamine, and paroxetine inhibit metabolism and elevate other drugs also metabolized by the P-450 system. Sertraline may inhibit the P-450 system at higher doses (>100 mg/d). Citalopram is the least likely to inhibit this system. Thus, sertraline and citalopram have become the preferred SSRIs for medically ill patients taking multiple medications. Apathy Syndrome. Distinguishing apathy syndrome from loss of response to a previously effective SSRI dose is important because treatment differs. The treatment for loss of response to a previously effective dose is to increase the dose, whereas apathy syndrome can be treated by decreasing the SSRI dose. Apathy syndrome can occur months or years after effective treatment with an SSRI. It is characterized by loss of motivation, passivity, lethargy, and flatness. Apathy is distinguished from a recurrence of depres-

5 Mayo Clin Proc, July 2001, Vol 76 Treating Depression With SSRIs 743 sion by the absence of sadness, tearfulness, decreased concentration, hopelessness, worthlessness, or suicidality. If dose reduction is not helpful, a stimulant can be added. Safety From Overdose. Although SSRIs are much safer, at least 1 death from fluoxetine overdose has been reported, and 6 deaths have been reported due to overdose with citalopram. 10 All but 1 death due to citalopram occurred in combination with other medications. SSRIs and Pregnancy. Data are limited concerning use of SSRIs during pregnancy. Thus far, no increase in major fetal malformations has been noted; however, all 5 SSRIs are category C. 11,12 Of all the SSRIs, fluoxetine has been studied the most. Using fluoxetine in the third trimester has been reported to increase risk of perinatal complications. 13 One long-term neurodevelopmental study on fluoxetine use showed no negative outcomes related to fetal exposure. 14,15 Less information is available for paroxetine, fluvoxamine, sertraline, and citalopram. Electroconvulsive therapy is a good option for treating severe depression during pregnancy. TYPES OF DEPRESSION AND TREATMENT CONSIDERATIONS Major Depressive Disorder For major depressive disorder (MDD) to be diagnosed, a patient must have 5 of the following for at least 2 weeks: decreased mood and/or anhedonia (must have 1 of these), pronounced weight change, sleep disturbance, psychomotor change (retardation or agitation), decreased energy, worthlessness or guilt, decreased concentration, or recurrent thoughts of death. Symptoms must produce clinically meaningful distress or impairment in function. Episodes are characterized by severity, single vs recurrent, presence of psychosis, and remission. All SSRIs are equally effective in treating MDD. For patients taking multiple medications in whom drug interactions are a concern, citalopram or sertraline should be considered. Bipolar Depression Patients with bipolar disorder can have episodes of depression and are at increased risk for antidepressant-induced mania or hypomania. A mood stabilizer should be considered before antidepressant therapy is initiated. Limited data suggest that bupropion may be less likely to induce mania. Depression Secondary to a General Medical Condition If a patient has depression secondary to a general medical condition, eg, stroke, hypothyroidism, or B 12 or folate deficiency, the first-line treatment is to address any reversible causes of depression. If this is not possible (eg, after a stroke), treat as if the patient had MDD. Depression Secondary to a Substance When a patient has depression secondary to a substance, eg, alcohol or corticosteroids, the first step is to discontinue the substance that may be precipitating depression. If this is not possible, treat as if the patient had MDD. Postpartum Depression Onset of depression within 4 weeks postpartum (coded as MDD with a postpartum specifier) should to be distinguished from postpartum blues, which is common (50%- 85%) and resolves without medication during the first 2 weeks postpartum. 16 Postpartum depression lasts longer and occurs in 10% to 26% of women at any time frame up to 1 year postpartum. 16 Breast-feeding should be recommended with caution for women treated with SSRIs because there are no long-term studies of exposure risk through breast milk. Limited data show no adverse effects in infants whose mothers were taking fluoxetine, sertraline, or citalopram. 8 Dysthymic Disorder Dysthymic disorder is defined as a decreased mood for most of the day or for more days than not during a 2-year period. For this diagnosis, the patient must have 2 or more of the following: change in appetite, sleep disturbance, decreased energy, low self-esteem, poor concentration or indecisiveness, or hopelessness. Although antidepressant medications can be helpful, patients often receive substantial benefit from individual therapy alone or in combination with medications. Medications are clearly indicated for patients with double depression (MDD and dysthymia). Bereavement Depression as a reaction to the death of a loved one is termed bereavement. Individual psychotherapy is often sufficient; however, consider MDD and the possible need for antidepressant medications if symptoms are severe (eg, suicidal, marked functional impairment). Depression Not Otherwise Specified Examples for use of this coding are premenstrual dysphoric disorder, minor depressive disorder (2 weeks but fewer than 5 symptoms), recurrent brief depression (2 days to 2 weeks), and inability to determine whether depression is primary or secondary. Consider antidepressant medications if functional impairment is pronounced. All SSRIs except fluvoxamine have been shown to be effective in treating premenstrual dysphoric disorder. CONCLUSIONS Clearly, the improved tolerability, dosing, and safety profile of SSRIs have substantially affected treatment of de-

6 744 Treating Depression With SSRIs Mayo Clin Proc, July 2001, Vol 76 pression. This is a brief review, and some questions on the approach to treating depression with SSRIs likely remain unanswered. Clinicians are referred to 2 psychopharmacology handbooks for more information, 6,9 both of which are excellent resources for quick use in the office. REFERENCES 1. Blazer DG II. Mood disorders: epidemiology. In: Sadock BJ, Sadock VA, eds. Kaplan & Sadock s Comprehensive Textbook of Psychiatry. Vol 1. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2000: Frank E, Thase ME. Natural history and preventative treatment of recurrent mood disorders. Annu Rev Med. 1999;50: Kupfer DJ. Research in affective disorders comes of age [editorial]. Am J Psychiatry. 1999;156: Hall RC, Wise MG. The clinical and financial burden of mood disorders: cost and outcome. Psychosomatics. 1995;36:S11-S Gallo JJ, Rabins PV. Depression without sadness: alternative presentations of depression in late life. Am Fam Physician. 1999;60: Bezchlibnyk-Butler KZ, Jeffries JJ, eds. Clinical Handbook of Psychotropic Drugs. 10th rev ed. Seattle, Wash: Hogrefe & Huber Publishers; Roy-Byrne P, Post RM, Uhde TW, Porcu T, Davis D. The longitudinal course of recurrent affective illness: life chart data from research patients at the NIMH. Acta Psychiatr Scand Suppl. 1985; 317: Woodrum ST, Brown CS. Management of SSRI-induced sexual dysfunction. Ann Pharmacother. 1998;32: Arana GW, Rosenbaum JF. Handbook of Psychiatric Drug Therapy. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; Edwards JG, Anderson I. Systematic review and guide to selection of selective serotonin reuptake inhibitors [published correction appears in Drugs. 1999;58: ]. Drugs. 1999;57: Masand PS, Gupta S. Selective serotonin-reuptake inhibitors: an update. Harv Rev Psychiatry. 1999;7: Misri S, Burgmann A, Kostaras D. Are SSRIs safe for pregnant and breastfeeding women? Can Fam Physician. 2000;46: , Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med. 1996;335: Koren G, Nulman I, Addis A. Outcome of children exposed in utero to fluoxetine: a critical review. Depress Anxiety. 1998;8(suppl 1): Nulman I, Rovet J, Stewart DE, et al. Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med. 1997; 336: Stowe ZN, Calhoun K, Ramsey C, Sadek N, Newport J. Mood disorders during pregnancy and lactation: defining issues of exposure and treatment. CNS Spectrums. 2001;6:156, Questions About Treating Depression With SSRIs 1. Which one of the following is not a common early adverse effect of SSRIs? a. Nausea b. Headaches c. Anxiety d. Apathy e. Constipation 2. Which one of the following percentages is true regarding the likelihood that a patient will have a second episode of depression? a. 10% b. 30% c. 50% d. 70% e. >90% 3. Which one of the following medication groups should not be combined with an SSRI? a. β-blockers b. Antipsychotics c. TCAs d. MAOIs e. Benzodiazepines 4. Which one of the following medications is least likely to inhibit the cytochrome P-450 system? a. Fluoxetine b. Paroxetine c. Citalopram d. Fluvoxamine e. Sertraline 5. Which one of the following is the minimum time an SSRI should be taken before it is considered a failure? a. 1 week b. 2 weeks c. 3 weeks d. 4 weeks e. 6 weeks Correct answers: 1. d, 2. c, 3. d, 4. c, 5. d