What are the best treatments? Description of Condition Depression is a common medical condition with a lifetime prevalence in the United States of 15% among adults. Symptoms include feelings of sadness, hopelessness, or guilt; diminished interest or pleasure in usual activities; decreased ability to think or concentrate; and disruptions in sleep or appetite. Clinically important depression is also known as major depressive disorder, which differs from ordinary sadness. The diagnosis is based on the presence of characteristic symptoms that are sufficient to interfere with functioning or wellbeing, which occur most days for 2 weeks or more. Depression tends to come in episodes, usually lasting for months, which may resolve spontaneously. However, recurrence is common: there is a 60% chance of remission after one episode, 70% after two episodes. Nonprescription Interventions and When to Seek Help The major treatment options for depression are psychotherapy and antidepressant medications. Other options include the herbal preparation known as St. John s wort (Hypericum perforatum) for cases of mild depression, and electroconvulsive therapy, which has been shown to be relatively safe and effective for cases of severe, refractory depression. There is some evidence that aerobic exercise reduces the symptoms of depression and may help to prevent relapse, particularly in elderly persons. Not all forms of psychotherapy (talk therapy) have been shown to be effective in the treatment of depression. However, cognitive behavioral therapy, problem-solving therapy, and interpersonal psychotherapy are of established benefit and may be considered first-line treatments for outpatients with mild-to-moderate depression. Because depression is potentially debilitating and highly treatable, patients with depressed mood or other characteristic symptoms lasting 2 weeks or longer should seek professional advice. Patients with severe symptoms or persistent suicidal thoughts should obtain immediate psychiatric attention. Categories of Prescription Pharmaceutical Treatments (i.e., Drug Classes) The major drug classes available for the treatment of depression are the first-generation antidepressants (e.g., amitriptyline, imipramine, nortriptyline) and the newer, second-generation antidepressants (e.g., fluoxetine, sertraline, venlafaxine). Both first- and second-generation drugs treat depression effectively, although the second-generation agents are associated with fewer side effects and a lower risk of suicide when taken in overdose. Another group of first-generation antidepressants, monoamine oxidase inhibitors, are rarely used in general practice because of drug-drug and drug-food interactions. The relative costs of firstand second-generation antidepressants and other treatments are shown in the Table. Intraclass Comparisons Overall treatment effects among the second-generation antidepressants appear similar. Differences, where they exist, are relatively minor: Mirtazapine may have a faster onset of action than fluoxetine, paroxetine, and sertraline. Based on limited data, venlafaxine may be associated with a higher response rate than fluoxetine and sertraline. Page 1
Second-generation antidepressants are similar in terms of overall tolerability and safety. Differences in side-effect profiles are relatively minor but may be clinically important in some patients: Bupropion and nefazodone may be associated with fewer sexual side effects as compared with other second-generation antidepressants. However, nefazodone is no longer a first-line agent owing to concerns about liver toxicity (approximately one case of severe liver failure or death per 250,000 patient-years of exposure). Compared with other second-generation antidepressants, venlafaxine may cause more nausea and be associated with an increased risk of seizures in overdose. Mirtazapine and paroxetine may lead to greater weight gain as compared with bupropion, fluoxetine, and sertraline. The likelihood that sudden cessation of antidepressant therapy will lead to withdrawal symptoms (including dizziness, nausea, paresthesias, and headache) is inversely related to the half-life of the drug. Paroxetine is more often associated with withdrawal symptoms than are sertraline and fluoxetine. In general, second-generation antidepressants appear to have similar efficacy and side effects in the elderly and younger adults. The use of antidepressants in children and adolescents is controversial. A black box warning cautions that in short-term studies antidepressants increased the risk of suicidal thinking and behavior among patients in this age group. Ethnic differences in the effectiveness and safety of second-generation antidepressants have not been adequately studied. First- and second-generation antidepressants taken during pregnancy have not been associated with an increased risk of major congenital malformation. However, information on the long-term neurobehavioral effects of these medications is limited, and withdrawal syndromes among infants have been observed. Based on pharmacokinetic studies and clinical follow-up, nortriptyline, paroxetine, and sertraline may be the preferred choices in women who breast-feed. Interclass Comparisons Psychotherapy (especially cognitive behavioral therapy, problem-solving therapy, and interpersonal psychotherapy) and antidepressant medications are both effective first-line treatments for patients with mild-moderate depression. Cognitive behavioral therapy and second-generation antidepressants are equally effective in the shortterm treatment of postpartum depression. The combination of psychotherapy plus an antidepressant medication is more effective than either alone in patients with severe depression. Neither pharmacotherapy nor psychotherapy act immediately to reduce the symptoms of depression. Both take several weeks or more for maximal effect. Page 2
Conclusions Clinically important depression is common and treatable. Second-generation antidepressants and certain forms of psychotherapy are safe and effective treatments for adults with mild-moderate depression. Prolonged treatment (6 months or more) is necessary to reduce the risk of relapse. Methods Note This scientific reference guide is a product of the Prescription Drug Information Project, a collaborative venture between the University of California and the California HealthCare Foundation. This summary is based on a report on the effectiveness and safety of second-generation antidepressants performed by the Drug Effectiveness Review Project (DERP). The DERP report is based on a rigorous method of systematic literature reviews, ensuring inclusion of relevant studies of high quality. Another team of researchers, at the University of California (UC), Davis, prepared a supplementary report on other drug and nondrug treatments for depression. Both reports (DERP and UC Davis) were reviewed by two outside experts and subsequently evaluated by a panel of highly regarded physicians and pharmacists from the University of California. These reports are available at www.chcf.org. Page 3
Relative Costs of First- and Second Generation Antidepressants and Other Treatments Drug Name (generic) Cost + Low ($1-50) Medium ($51-100) High ($101 +) First Generation Tricyclic and tetracyclic agents Amitriptyline* $11 Amoxapine* $36 Clomipramine* $40 Desipramine* $22 Doxepin* $10 Imipramine* $10 Tofranil-PM (Imipramine pamoate) $175 Maprotiline* $31 Nortriptyline* $13 Trazodone* $21 Surmontil (Trimipramine) $118 MAOIs Isocarboxazid Marplan $25 Phenelzine Nardil $40 Tranylcypomine Parnate $50 Second Generation SSRIs/SNRIs Bupropion* $67 Wellbutrin SR (Bupropion SR) $120 Wellbutrin XL (Bupropion XL) $110 Celexa (Citalopram) $72 Cymbalta (Duloxetine) $99 *Generic + Approximate Cost Per One Month Supply. MAOI, monoamine oxidase inhibitor; SNRI, selective norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor. Prices are from drugstore.com (February 2005). Page 4
Relative Costs of First- and Second Generation Antidepressants and Other Treatments (cont.) Drug Name (generic) Cost + Low ($1-50) Medium ($51-100) High ($101 +) Second Generation (cont.) SSRIs/SNRIs (cont.) Lexapro (Escitalopram) $67 Fluoxetine tablets* $40 Fluoxetine capsules* $16 Prozac weekly (Fluoxetine weekly) $82 Fluvoxamine* $63 Remeron (Mirtazapine) $92 Nefazodone* $45 Paroxetine* $75 Paxil CR (Paroxetine CR) $89 Zoloft (Sertraline) $75 Effexor (Venlafaxine) $55 Effexor XR (Venlafaxine XR) $95 Complementary/Herbal Therapy St. John s wort* $10 *Generic + Approximate Cost Per One Month Supply. MAOI, monoamine oxidase inhibitor; SNRI, selective norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor. Prices are from drugstore.com (February 2005). Page 5