Psychopharmacologic Treatment Strategies for Depression, Bipolar Disorder, and Schizophrenia

Patients with major psychiatric illnesses are often treated first, and sometimes exclusively, by family physicians and internists. Because the diagnosis and treatment of these disorders have changed profoundly in two decades, it may be difficult for specialists outside of psychiatry to keep informed (1-3). This, in turn, could lead to underdiagnosis and undertreatment. We therefore provide an updated synopsis for three important psychiatric disorders: major depression, bipolar disorder, and schizophrenia. Much of this information is not covered in consensus guidelines (4-6) or comprehensive reviews of these disorders (7), which are circulated minimally outside psychiatry and are not usually followed even when available (8). We describe updates in the diagnosis of each disorder and, most important, illness characteristics and treatment principles that underlie current strategies for short- and long-term psychopharmacologic treatment. These differ markedly from past strategies because they incorporate new interventions and medications on the basis of data from controlled studies (Table 1). In the short term, this means assessing a new patient and clarifying the diagnosis while rapidly initiating treatment to relieve symptoms. In the long term, this means reviewing current patient status to avoid relapse and to maintain the patient at the highest level of functioning possible. While our article focuses on psychopharmacology, it is now established that medications combined with individual and family psychotherapeutic interventions are helpful. We will not cover details of drug selection, dosing, or underlying biology, all of which are discussed in textbooks and consensus guidelines (4-6). For each condition, preferred medications (Table 2) and algorithms (Figures 1, 2, 3, 4, and 5) reflect general principles of drug management. Table 1. Characteristics of Psychiatric Illnesses and Indicated Treatment Principle Table 2. Drugs Used in Depression, Bipolar Disorder, and Schizophrenia Figure 1. Strategies for the treatment of major depressive disorder without psychotic features. Figure 2. Strategies for the treatment of major depressive disorder with psychotic features. Figure 3. Strategies for the treatment of manic/hypomanic episodes. Figure 4. Strategies for the treatment of major depressive episodes. Figure 5. Strategies for the treatment of psychosis. Depression Updates in Definition and Diagnosis Current research in the diagnosis of depression has focused on special populations and on identifying subtypes that may respond differently to treatment. Major depression is defined as having at least five symptoms during the same 2-week period, with marked change in function. At least one of the symptoms must be depressed mood or loss of interest or pleasure. In addition, changes in at least three of the following must be observed: weight, sleep, activity level, energy, ability to think or concentrate, or suicidal ideation (9). Subtypes being investigated include depression associated with psychotic symptoms, atypical features, or seasonal patterns (which may respond to bright-light therapy). A major diagnostic task is differentiating major depression from depressed states secondary to life stress, alcohol or drugs, medical illness, or bereavement (although depressive symptoms must be treated regardless of cause). Careful history, including family history, helps clarify the differential diagnosis, but clinicians should remember that depression is not a rare disorder. Lifetime prevalence is estimated at 15% and at perhaps 25% in women. Updates in Short-Term Strategies Choice of treatment for depression has changed substantially over the past two decades (Table 2). Formerly, all but the most severe cases of depression were treated first with psychotherapy alone. Currently, only mild to moderate depression may be treated with psychotherapy alone; even then, antidepressants may be equally effective (10). Psychotherapy itself has shifted from psychoanalytic to more short-term, cognitivebehavioral, or dynamic supportive therapy (11), the effects of which may outlast discontinuation of treatment. The short-term treatment of depression changed dramatically as new medications became available. In part because older tricyclic antidepressants were dangerous in overdose, physicians were reluctant to treat depression with medication. Although new medications are much safer in overdose, allowing earlier and more aggressive treatment, depression continues to be underrecognized and undertreated (1). Short-term antidepressant therapy has several goals. The first is to relieve suffering. While antidepressants may take weeks to achieve maximum benefit, improvements in sleep, anxiety, and agitation may occur earlier. A second goal is to instill hope. Prescribing an antidepressant may in itself send the message that patients have a treatable illness. Most patients regard this as positive; others, however, may resist the implication that they are mentally ill. A third goal is to improve functioning. Because a latency of response is seen with all antidepressants, this may take 4 weeks or longer. If no response occurs after 4 weeks of therapy with a therapeutic dose, the dose is usually increased. This strategy may be useful even with serotonin reuptake inhibitors (SSRIs), which were considered to have a flat doseresponse curve (12). Titration to two thirds of the maximum dose can be reasonable if tolerated by the patient. No response at a higher dose should prompt consideration of switching antidepressants. In the past, little evidence supported changing from one tricyclic antidepressant to another; now, better evidence indicates that switching to another class of agents may result in a 50% or greater response (13). Serotonin reuptake inhibitors are chemically heterogeneous, and data suggest justification for switching from one to another. Despite general agreement in the clinical community that 4 weeks is an adequate trial for an antidepressant, it is important to support this with research. Some studies recommend 6 to 8 weeks at full dose (14). Recent data on fluoxetine, however, do not indicate that a fixed-dose trial exceeding 4 weeks significantly improved response (15). One could conclude that 4 weeks at a therapeutic dose is probably adequate but that higher doses may improve response rate (12). Newer strategies in choosing antidepressants consider both patient and drug variables. Patient variables include sex, age, and depression subtype. Sex can affect response to different classes of antidepressants. Large meta-analyses show that men may have better response to and tolerance of tricyclic antidepressants (16) and that women may better respond to and tolerate select SSRIs (17). Advancing age can affect hepatic metabolism and renal clearance, increasing the risk for toxicity to all antidepressants, particularly tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs). Geriatric patients are especially sensitive to anticholinergic effects of such tricyclic antidepressants as amitriptyline and often cannot tolerate MAOIs because of orthostatic hypotension. Older patients often take several medications that can interact. Although serious interactions are less likely with newer agents, most SSRIs competitively inhibit the CYP2D6 isoenzyme that metabolizes class 1C antiarrhythmics, increasing serum levels and potentially producing toxicity. Fluoxetine, which has broader interactions than other SSRIs, has a metabolite whose long half-life makes it a threat even after discontinuation. Prevailing clinical opinion of the controlled data suggests that all antidepressants have equal efficacy, approximately 60% to 70% in any given trial. In subtypes of depression, however, real differences are discernible. Atypical depression with mood reactivity, hypersomnia, and hyperphagia responds better to MAOIs than to tricyclic antidepressants (18). For premenstrual mood symptoms, SSRIs are more effective than tricyclic antidepressants (19). Psychotic depression had only a 30% to 40% response rate to tricyclic antidepressants in several trials but may have a 70% response rate to the tetracyclic amoxapine (20). However, its metabolite is a neuroleptic that may cause tardive dyskinesia. In standard treatment, a neuroleptic is combined with an antidepressant and electroconvulsive treatment is used as a backup. New atypical antipsychotics (serotonindopamine antagonists), particularly olanzapine, are promising as monotherapy (21). Drug-related variables include safety in overdose, a safe side effect profile, and cost (22). Because tricyclic antidepressants and MAOIs are available in generic forms and are less expensive, third-party payers formerly insisted that they be tried first. However, the total cost of antidepressant treatment is complex. Tricyclic antidepressants require screening electrocardiography in older patients, serum level evaluations, and possibly more frequent office visits for side effects and premature discontinuation of drug therapy. A tricyclic antidepressant overdose is prohibitively expensive in both economic and human terms. With these costs included, tricyclic antidepressants seem more costly than newer antidepressants (23). Updates in Long-Term Strategies The long-term goal in treating depression is preventing relapse and recurrence. Concepts undergoing revision include how long to continue medication treatment and when to augment it. Overwhelming evidence now shows that major depression tends to recur, often within 2 years; in at least 75% of patients, it recurs within 10 years. Premature termination of medical therapy apparently increases risk for relapse. Evidence suggests that a minimum course of 6 months reduces this risk. However, depressive disorders are characterized by heterogeneity of outcome. Some patients may not have recurrences after their first depressive episode, a fact worth remembering for the clinician cons