Technology Review New Antidepressants and the Treatment of Depression Barry H. Guze, MD, and Michael Gitlin, MD Los Angeles, California Depression is a common and significant health problem antidepressant drugs, the new agents are generally safer associated with impairment in a patient’s ability to than traditional medications used to treat depression: function. The development of new antidepressant med­ they are well tolerated and, in case of overdose, less ications represents progress in its treatment. These new harmful than tricyclic antidepressants. agents work through the selective blockade of the re­ uptake of serotonin into the presynaptic neuron, thereby increasing the availability of this neurotrans­ Key words. Serotonin antagonists; antidepressants; de­ mitter at the synaptic cleft and enhancing its effective­ pression; antidepressive agents, tricyclic. ness. While no more effective than traditional tricyclic ( / Fam Pratt 1994; 38:49-57) Depression is a common condition.1 Among the nonin- probability of relapse include the severity of the initial stitutionalized elderly, the prevalence of clinically signif­ episode, the number of prior episodes, the response to icant depression is about 15%.2 With a lifetime preva­ prior treatment, and a history of chronic depression.10 lence of 6% and associated risks such as suicide, major Other important factors include comorbid conditions, depression is an important public health concern in the such as chronic medical conditions, and the degree of United States.3 In 1979 and still in 1989, suicide was the psychosocial perturbation. Because recurrence is so com­ fourth leading cause of death for white Americans.4 mon, early and aggressive treatment of depression has The economic impact of depression in the United been recommended.12 States has been estimated at more than $16 billion, only Depression is usually treated by primary care physi­ S2.1 billion of which is spent on diagnosis and treat­ cians. Major depression has been reported to be more ment.5’6 The balance is associated with lost productivity. common than hypertension in primary care practice,13 Major depression produces impairment in functioning and the presence of a psychiatric diagnosis is found in close in magnitude to that of chronic heart disease7 and 11% to 36% of patients in general practice.14 The recog­ exceeding that of many other chronic diseases. The risk nition of major psychiatric illness is poor, however, with of disability in minor depression is IV times that of 2 estimated rates for failure to detect depression ranging asymptomatic individuals; for major depression, it is 472 from 45% to 90%.15’16 In a study of nursing home times.8 patients, only 12.5% of major depression cases were The chronic nature of depression is exemplified by recognized and even fewer treated by staff physicians. An the high rate of recurrence among patients experiencing accurate differential diagnosis of mood disorder is the key an initial episode.9-11 Approximately 50% of patients to appropriate treatment. Diagnosis of a major depres­ who recover from an initial bout with depression will sive episode is appropriate when at least five of the have at least one subsequent episode during the follow­ symptoms listed in Table 1 are present nearly every day ing 2 years.11 The factors associated with a heightened for at least 2 weeks.17 One of these symptoms must be “depressed mood” or “loss of interest or pleasure in most Submitted, revised, September 8, 1993. or all activities.” from the Department o f Psychiatry and Biobehavioral Sciences, School o f Medicine, and Not all physicians are taking advantage of new de­ the Neuropsychiatric Institute and Hospital, University of California, Los Angeles. velopments in effective treatments to decrease the mor­ Requests for reprints should be addressed to Barry H. Guze, M D, UCLA NPI, 760 Westwood Plaza, Los Angeles, CA 90024. bidity and mortality associated with depression.18 Con- © 1994 Appleton & Lange ISSN 0094-3509 The Journal of Family Practice, Vol. 38, No. 1 (Jan), 1994 49 Guze and Gitlin New Antidepressants Table 2. Dosage and Administration of Three Selective Table 1. Symptoms of Depression__________ Serotonin Reuptake Inhibitors Depressed mood most of the day Range, Loss of interest or pleasure in most or all activities Usual Daily mg Comments Significant change in weight or appetite Medication Dosage, mg Insomnia or hypersomnia Paroxetine 20 10-50 N o active metabolites Psychomotor retardation or agitation Sertraline 50 50-200 No active metabolites Fatigue or loss of energy Fluoxetine 20 5-80 Active metabolite with Feelings of worthlessness or of excessive or inappropriate guilt long half-life Diminished ability to think or concentrate, or indecisiveness Recurrent thoughts of death, recurrent suicidal ideation, or suicide attempt ____________ _ Note: Diagnosis o f a major depressive episode is appropriate when a m inim um offive symptoms, one o f which is “depressed mood ” or “loss o f interest or pleasure in most or all antidepressants, and offer the same side-effect profile and activities,’’ are present nearly every day for at least 2 weeks. efficacy as tricyclic antidepressants.26 Selective serotonin reuptake inhibitors, the new an­ scientious long-term care, coupled with attention to tidepressant agents that recently have become available in patient compliance with treatment, can substantially re­ the United States, are no more effective than traditional duce the suicide rate among patients with mood disor­ agents, but their side-effect profiles often present impor­ ders. When proper recognition and pharmacologic treat­ tant clinical advantages, such as lower incidence of side ment of depression occurs, suicide rates can be effects compared with standard tricyclic and tetracyclic lowered,19'20 as exemplified by a two-session educational antidepressant drugs25 (Table 3). The mildness of their program on treating depression that was provided to side effects makes them particularly well suited for treat­ general practitioners on the Swedish island of Gotland. ing moderately depressed outpatients or the elderly.27 This program reduced the suicide rate by 71% as com­ The SSRIs also are used to treat conditions other than pared with the general rate in Sweden,21 suggesting that depression, including bulimia nervosa,28 personality dis­ increased recognition of depression and knowledge re­ orders,29 and obsessive-compulsive disorder.30 Treat­ garding its treatment can have an impact on mortality. ment of these conditions requires higher dosages than Depressive disorders can be divided into five cate­ the dosages to treat depression. gories: major depression, dysthymia, bipolar-disorder It has been estimated that 75% to 80% of patient depression, cyclothymia, and depressive disorder not taking tricyclic antidepressants receive subtherapeutic otherwise specified.17 Major depression itself can be fur­ doses because of the intolerable side effects associated ther subtyped into groups with and without psychotic with higher dosages.31 Thus, side effects may limit the features (delusions and hallucinations). Psychosis is clinical effectiveness of traditional antidepressant medica­ present in 10% to 25% of patients with major depres­ tions. In addition to subtherapeutic dosing, side effects sion.22 The presence of psychotic features often results in associated with tricyclic antidepressants often result in a different approach to treatment.23 Electroconvulsive long titration trials, premature discontinuation of ther therapy is thought by many to be the most effective apy, or lack of patient compliance, along with overdose treatment for this form of depression. The other ap­ fatalities.32 In clinical trials, twice as many patients have proach is the combination of a tricyclic antidepressant discontinued tricyclic antidepressants as have discontin­ and a neuroleptic.23 In most cases of depression, treat­ ued fluoxetine.32 ment with antidepressant medication alone is inadequate. Traditional tricyclic antidepressant side effects in- Choice of an Antidepressant Table 3. Common Side Effects of Selective Serotonin Pharmacotherapy is the most effective treatment for Reuptake Inhibitors (SSRIs) moderate to severe nonpsychotic depression,24 with tra­ Nausea ditional antidepressants being effective in approximately Somnolence 60% to 85% of patients.25 Current treatment options Weakness include traditional tricyclic antidepressants, monoamine Dizziness Insomnia oxidase inhibitors (MAOIs), tetracyclic antidepressants Sexual dysfunction (eg, maprotiline), and selective serotonin reuptake inhib­ Sweating iting (SSRI) antidepressants (Table 2). Tetracyclic com­ Tremor Decreased appetite pounds predominantly affect norepinephrine neurotrans­ Nervousness mission, are pharmacologically similar to the tricyclic Note: SSRIs may interact with AIAOIs to produce serotonin syndrome. 50 The Journal of Family Practice, Vol. 38, No. l(Jan), 199- yew Antidepressants Guze and Gidin dude orthostatic hypotension, alterations in cardiac con­ Selective Serotonin Reuptake duction, overdose fatality, dry mouth, constipation, Inhibitors blurred vision, urinary hesitancy, and memory impair­ ment,26 none of which are associated with SSBJs.25 Typ­ Paroxetine, sertraline, and fluoxetine are members of the ical side effects of the SSRIs include gastrointestinal SSRI group that are currently marketed in the United upset, such as nausea and diarrhea; restlessness or akathi- States. Fluvoxamine and citralopram are not currendy