Francis M. Mondimore
Clinically significant depressions often go undetected and undiagnosed in the ambulatory medical setting (1). As a consequence, patients with untreated depression may receive costly and misdirected diagnostic procedures and symptomatic therapies instead (2). Undiagnosed depressions exact a substantial toll on patients and families in the form of severe and persistent functional impairments (3). This chapter outlines the public health consequences of depressive conditions, describes the spectrum of mood disorders that afflict patients, and provides an approach to the treatment of these disorders for the generalist.
Public Health Impact of Mood Disorders
By any measurement, depressive conditions are major public health problems. In one medical outcome study, the poor functioning uniquely associated with depressive symptoms was comparable to or worse than that associated with eight major chronic medical conditions: arthritis, current advanced coronary artery disease (CAD) (recent myocardial infarction [MI]), current angina, current back problems, current severe lung problems, current gastrointestinal (GI) disorders (ulcers or inflammatory bowel disorders), diabetes, and hypertension (4). Depressed subjects ranked fourth in impairment in physical functioning, third in impairment in role functioning, second (behind advanced coronary disease) in the number of bed days, and worst in social functioning and sense of well-being about their current health.
Excess deaths attributed to depression are primarily from suicides. Studies of populations of depressed patients show that over 2% eventually die by suicide (5). Suicide was the eleventh leading cause of death in the United States in 2003, and the third leading cause of death among 15- to 24-year-olds. Illicit substance abuse is thought to account for a dramatic rise in suicide rates between the mid-1950s and the mid-1990s among male adolescents. The suicide rate for white males age 15 to 24 years peaked in the mid-1990s and appears now to be dropping, a trend attributed to the passage of laws designed to keep firearms out of the hands of adolescents and also to the increased treatment of adolescent depression with selective serotonin reuptake inhibitors (SSRIs) (6). In the Old Order Amish population, where there is very little if any drug and alcohol abuse, more than 90% of all suicides between 1880 and 1980 were by people with major depression or bipolar disorder (7). Several studies have shown that the incidence and outcome of other medical disorders are affected adversely by depression. The incidence of MI is increased about fourfold in subjects with a prior episode of major depression (8). The odds of dying in the 18 months after a MI are three times greater in patients with concurrent depression than in those without depression (9).
In economic terms, the burden of depressive illnesses in the United States in 2000 was 83.1 billion dollars, of which 26.1 billion dollars (31%) were direct medical costs, 5.4 billion dollars (7%) were suicide-related mortality costs, and 51.5 billion dollars (62%) were workplace costs (10). This was despite a dramatic increase in the proportion of depression sufferers who received treatment. In comparison, the estimated burden of diabetes was estimated to be 57.6 billion dollars in 1996 (11).
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Prevalence of Mood Disorders
Mood disorders are among the most prevalent forms of mental illness. Serious depression is especially common, with the past-year prevalence rate of clinically significant major depressive disorder estimated to be between 4% and 16.6% in epidemiologic studies, affecting more than 9 million Americans in 1999 (12). A national community survey of mental disorders, the Epidemiological Catchment Area Study, estimated that 6% to 12% of women and 2% to 5% of men experience at least one major depressive episode during their adult life, and such an episode may occur at any age (13). Perhaps just as many patients suffer from depressive symptoms that are clinically significant but do not reach a level of severity sufficient to be diagnosed as major depression, so-called minor depression (14). The 12-month prevalence of dysthymic disorder, characterized by chronic, smoldering depressive symptoms that last for years, has recently been estimated to be 2.5% (15).
Only 0.6% to 1.2% of adults develop bipolar disorder; which is equally common in men and in women (16). Over the past decade the concept of bipolar spectrum disorders has developed to describe illnesses, usually with predominantly depressive symptomatology, that also include briefer periods of elation or extreme irritability. The inclusion of these less severe disorders may increase the prevalence of bipolar disorders as much as fivefold, to about 5% of the general population (17).
As this discussion may suggest, the classification of mood disorders continues to be unsatisfactory. Many patients with mood disturbances do not fit neatly into the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Text Revision (DSM-IV TR) categories of major depression, dysthymia, or bipolar disorder, and are classified as depressive disorder, not otherwise specified, a subcategory of which isminor depression. Sometimes patients meet criteria for different DSM-IV TR disorders at different times.
Bereavement and Adjustment Disorders
Some disturbances of mood are the normal and expected, perhaps even the inevitable sequelae of personal, medical, or financial setbacks. It is important and appropriate to evaluate and help patients in these situations not only because these symptoms affect the patient's sense of well-being but also because patients with nonpathologic mood disturbances are at risk for development of significant medical conditions. Bereavement, for example, is associated with increased rates of medical visits, heart attacks, and death in the first year after the loss of a spouse (18). Various medical conditions have been noted to have poor medical outcomes in patients with even mild depression (19).
Normal Bereavement
Although grief reactions are individual in their content, they share characteristic features as to course. The intensity of distress reflects the bereaved person's closeness to the deceased. The grief reaction tends to proceed in phases, beginning at the time at which the death is made known. The first phase is called the numbness or shock phase. Although painful, this first period of about 1 week is remarkable for the organized or calm way in which many bereaved people appear to go through the societal rituals of mourning, funeral, burial, and the visits with close family and friends. In retrospect, patients often describe themselves as confused and not fully appreciating their loss during this first week. A second phase has been called confrontation and emerges after completion of the structured rituals of mourning with increasingly intense feelings of sadness, loneliness, and pining for the lost loved one. During this periods of weeks to months, the bereaved becomes more fully aware of his loss and begins to face the changes the loss has brought about in his life. Wellings of grief, intense feelings of loss that come in waves, are initially as relentless as ocean surges but usually begin to come less frequently over a period of several weeks. The waves then progressively and substantially diminish in frequency and intensity over a period of 6 to 12 months, although they may recur from time to time for years, perhaps for a lifetime, especially when reminders of the loved one are encountered. Apathy, a diminished sense of organization, disinterest in doing a job that was previously engaging, and an inability to enjoy things are the characteristic signs of this period. The feelings of apathy and disengagement usually remit slowly and incrementally over many months as they are replaced by a sense of re-engagement in old and new activities. As the wellings of grief diminish in frequency, a third phase, that of acceptance, emerges as the bereaved person returns to his or her normal daily activities such as work, school, and social activities and is able to reclaim the emotional energy that was invested in the relationship with the deceased and re-invest it in other relationships and activities.
Patients may seek out or be brought to primary care clinicians during any of the three phases of bereavement. In the early stages, it is usually because of sleeplessness or agitation. Validating the reasons for distress, normalizing and explaining the grieving process, and instructing family members on how to help are useful responses. Prescribing hypnotic or anxiolytic medications may sometimes be necessary. Patients may come on their own during the later phases of grief because they are concerned about their physical health or about persistent problems in functioning at work or at home. These patients benefit from reassurance and from explanations of the phenomenology
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of the normal bereavement process, emphasizing that 12 months is usually necessary for the substantial completion of “grief work.”
The bereavement process may be more lengthy, complex, and difficult if the loss has been very unexpected, and especially if the death has been violent or the result of a crime. Referral to a grief counselor is often appropriate in such cases. The death of a child is especially difficult. Local chapters of a national organization, The Compassionate Friends, provide grief counseling for families who have experienced the death of a child. Local hospices often have grief counselors on staff or can be a source of referrals.
It is important to remember that major depression is often precipitated by the loss of a loved one in susceptible patients. This becomes apparent in the later phases of bereavement when persistent mood symptoms can give way to the full-blown depressive syndrome. Chapter 13 contains additional information about the experience of the family members of dying and deceased patients.
Adjustment Disorder with Depressed Mood
Adjustment disorder with depressed mood is a normal or an exaggerated emotional reaction to a recent or imminent loss or stressful life event that is characterized by predominantly depressive symptomatology. Table 24.1 shows the criteria for the diagnosis of adjustment disorder from the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), published by the American Psychiatric Association. The diagnosis of adjustment disorder is usually straightforward and depends on identifying the link between emotional or behavioral symptoms and the precipitating stressors.
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TABLE 24.1 Diagnostic Criteria for Adjustment Disorder |
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A critical and sometimes difficult diagnostic task is the assessment of individuals who present with what seem like unexpected, exaggerated, or prolonged emotional reactions to stressful events. Patients with any form of depression and those with personality disorders are more likely to overreact or to become functionally impaired in the face of a significant stressor. The identification of axis I disorders (e.g., major depression) or of personality disorders becomes a priority in these cases.
Major depressive disorders regularly manifest in the context of an apparent adjustment disorder. At the time of presentation the patient's distress is often focused on the stressor, and the doctor needs to help the patient adapt to the stressor, but this empathic task is distinct from the diagnostic task of identifying a major depression.
If the history does not suggest a coexisting axis I or II disorder, the appropriate intervention for an adjustment disorder is very similar to the approaches described earlier for bereaved patients and to those described in Chapter 20.
Identifying Patients with Depressive Disorders
Symptoms of Depression
Depressed patients who seek medical attention often do not complain of depressed mood as a primary symptom. Even if they acknowledge depressed feelings, they may do so in relation to other complaints that they see as primary.
Depressed patients usually present to generalists with three types of general complaints: (a) vegetative symptoms of depression (loss of energy, inability to concentrate, poor sleep, poor appetite, weight loss, decreased motivation or interests) and autonomic anxiety symptoms (tachycardia, chest discomfort, light-headedness); (b) aches and pains that may have anatomic bases but are out of proportion to what the patient usually experiences (e.g., worsening of migraine headaches, irritable bowel, or back pains) or what is expected (e.g., postsurgical pain that continues to require narcotic analgesics a month after surgery); and (c) nervous complaints such as increased tension and feelings of anxiety, often expressed in relation to stressful life circumstances such as marital distress or job difficulty. The presence of a mood disturbance should not, however be taken to explain or invalidate physical complaints: coexistence of psychiatric and medical disorders is the rule rather than the exception.
Even when specifically asked about mood, almost half of depressed patients deny depression or sadness as their
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predominant mood. They may describe their predominant mood as apathetic (e.g., “blah”), anxious, or even “numb” (i.e., unable to experience normal emotions including sadness, love, and grief). If appropriate inquiries are made however, it is likely that typical symptoms of depression can be elicited. Changes in mood (e.g., sadness, anger, irritability), mental sluggishness, decreased physical energy, pessimistic feelings about the future, and negative self-attitude are features central to depressive disorders. Despite the difficulty describing these pathologic states, patients should be asked specifically about them as well as about their sleep, appetite, and libido.
The term atypical depression appears in the DSM-IV and refers to depressive states in which hypersomnia, overeating, and lethargy are seen rather than insomnia, anorexia, and psychomotor agitation. Patients with atypical depression seem particularly prone to panic and anxiety symptoms and although they have the characteristic depressive changes in self-attitude and vital sense, they often describe their mood as fatigued rather than as sad. The term atypical may not be strictly justified, because all three of the “atypical” symptoms are common among depressed patients. However, the concept of atypical depression serves to remind clinicians of the importance of surveying both sides of eating and sleeping behaviors. When asked, “How is your appetite?” a depressed patient may respond, “Good,” or “Too good,” or “No problem.” It easy to misinterpret these answers as negative screening responses rather than as clues to the overeating that can be associated with depression.
Family members, if available, should be asked to corroborate and augment the information obtained from the patient. With the patient's agreement, the physician also should share with the family the diagnostic assessment, the plans for treatment, and the prognosis as the depressed patient is often hard pressed to remember what was said by the doctor during the appointment.
Routine Depression Screening in Primary Care
Studies in primary care settings over many years have shown that depressive disorders are under-diagnosed in primary care settings, with between 30% and 50% of depressed patients going unrecognized during usual care by primary care physicians (20). Since 2002, the U.S. Preventive Services Task Force (USPSTF), which conducts rigorous, impartial assessments of the scientific evidence for the effectiveness of a broad range of clinical preventive services, has recommended screening adults for depression as a part of routine clinical practice in primary care settings (21).
A whole variety of screening methods have been suggested, including formal screening instruments such as the Beck Depression Inventory and the PRIME-MD (Primary Care Evaluation of Mental Disorders) (19). All appear to be effective and correlate well with each other (22); clinicians may choose any method that fits their patient population and clinical setting.
A positive response to either of two questions: (a) “Have you had a down, low, or depressed mood in the past month?” or (b) “Have you been bothered by a loss of interest and pleasure in your usual activities?,” has been reported to have a 96% sensitivity in the diagnosis of major depression (23).
Positive screening should trigger a more complete diagnostic interview to elicit symptoms of depression as above.
Major Depressive Disorder
Diagnosis
The most common form of clinical depression is major depressive disorder (Table 24.2). The differential diagnosis of symptoms that suggest major depression varies depending on the patient's age, the presenting manifestations, and other associated factors. In younger patients, the differential is between adjustment disorder and major depression in those with recent onset of symptoms, and between adjustment disorder and dysthymia in those with more chronic presentation. In adolescents, irritability, oppositional behaviors, or substance abuse can predominate, although low mood, anhedonia, and vegetative symptoms can usually be easily elicited upon careful questioning. In elderly patients with memory complaints, the differential diagnosis is more complex because memory complaints without substantial memory performance problems are common in the depressed elderly and also because a modest but reversible dementia can result from the depression alone (so-called pseudodementia; see Chapter 26). Additionally, depression and dementia syndromes can both be related to underlying neuropathologic disorders, particularly Parkinson disease and stroke (see Chapters 90 and 91).
Stressful life events are common precipitating factors for major depression, so their presence is not useful for either making or excluding the diagnosis. In patients with panic attacks or obsessive-compulsive symptoms, it is important to remember that both panic disorder and obsessive-compulsive disorder (see Chapter 22) can occur in the context of a major depressive syndrome.
Alcohol abuse and the abuse of other substances commonly cause mood syndromes that may be indistinguishable from those of the major affective disorders. Substance abuse is a comorbidity common in patients with major affective disorders as well. Therefore, screening for substance abuse should be a routine part of the assessment of the depressed patient.
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TABLE 24.2 American Psychiatric Association Diagnostic Criteria for Major Depressive Episodea |
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A variety of prescribed medications have been reported to cause mood syndromes (Table 24.3). Unfortunately, the lengthy lists of pharmaceutical agents reported to be depressogenic that appear in most textbooks are often based on case reports or uncontrolled case series and are of questionable utility for the physician who is trying to decide whether to discontinue an effective medication in a patient who becomes depressed while taking it. A survey of more than 2000 community subjects found that most commonly prescribed medications are not associated with depressive syndromes. In this study, β-blockers, angiotensin-converting enzyme (ACE) inhibitors, lipid-lowering agents, and digoxin—all drugs often reported to cause depression—showed no association with the depressive syndrome (24). An association between β-blockers and depression, touted as a clinical pearl since this class of drugs first became available, remains unproven and controversial despite many years of investigation (25). A more impressive association between depression and treatment with digitalis has been demonstrated, and digitalis intoxication can present as a depressive syndrome (26). Steroid medications have clearly been shown to precipitate both the major depressive syndrome and manic syndrome in some patients (27). Drug-induced depression caused by interferon during treatment for hepatitis C or malignancy, by acute estrogen deficiency during the treatment of breast cancer with tamoxifen, and by naltrexone in the treatment of alcoholism has also been well established. Medication-induced mood syndromes often respond to reduction in dose of the causative agent or to treatment with antidepressant or mood-stabilizing medication (28). The differentiation of affective disorders from drug-induced syndromes and the management of mood symptoms in the medically ill patient who is taking multiple needed medications can be complex and challenging. Close coordination with a psychiatric consultant and thoughtful risk–benefit analysis of various medication approaches is the best course for the generalist in these situations.
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TABLE 24.3 Drugs and Substances That May Cause or Precipitate Mood Syndromes |
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Finally, it is important to differentiate unipolar from bipolar depressive states, because antidepressants can precipitate manic or mixed manic mood swings in patients with bipolar disorder.
The specific criteria of the American Psychiatric Association for major depressive episode (Table 24.2) require
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the presence of at least five of nine depressive symptoms and related functional impairment for 2 weeks, not caused by the direct effect of a medication or a drug of abuse or of a general medical condition. Either depressed mood or loss of interest or pleasure in usual activities (anhedonia) are always present; these symptoms can be considered core symptoms of major depression and should always be sought. A patient with a history of episodic depressive disorder and the fully developed symptom cluster is not difficult to diagnose. However, patients with major depression who present with a dominant somatic complaint or with a clear “reason” to be depressed, guilty, or hopeless may easily be missed if they are not specifically asked about depressive symptoms. When major depression is strongly suspected, probing inquiry about symptoms from both the patient and those close to the patient usually clarifies the diagnosis.
A fully developed major depression is characterized by a sustained alteration in mood, self-attitude, and vital sense. The sustained lowering of mood is impervious to environmental influence once the depression becomes severe. Events that are not usually stressful are perceived as overwhelming by a depressed patient as the syndrome develops. The change in self-attitude is usually manifested in expressions of guilt, inferiority, uselessness, and hopelessness. The changes in vital sense (the subjective assessment of one's physical and mental functioning) result in complaints of confusion or poor memory, inability to concentrate, lack of energy, and easy fatigability. Sometimes patients complain only of a vague sense of ill health. This preoccupation with physical symptoms can occasionally reach delusional intensity, and seriously depressed patients can become convinced that they are dying of cancer or another fatal illness when there is no evidence of these diseases.
Marked psychomotor retardation (i.e., slowed speech and movements), delusions with depressive content, and diurnal mood variation (worst mood in the morning) occur in a minority of patients but are diagnostically useful when present because they are fairly specific to this disorder.
Treatment
Once the diagnosis of major depression is made, treatment consists of explaining the diagnosis to the patient (and family), prescription and monitoring of antidepressant medication, and supportive counseling for the patient and family.
For the patient with major depression who is in good physical condition and who is neither overwhelmed with depressive delusions nor suicidal, antidepressant medication is the appropriate initial treatment. Any antidepressant drug is effective in approximately 70% of patients with major depression, and no antidepressant approved for use has been shown to be more effective than the others. Depressed patients tolerate side effects (and what they perceive to be side effects) poorly and often stop taking antidepressants without completing a full 8-week trial of the medication. Therefore, the selection of the first antidepressant has more to do with convenience of administration and side effect profile than with the probability of a therapeutic response. The exception to this rule is the patient who has had a prior good (or poor) response to a particular antidepressant.
Depressed patients with delusions, hallucinations, or profound psychomotor retardation tend to be less responsive to drugs. Referral for psychiatric consultation and consideration of electroconvulsive therapy (ECT) are appropriate for such patients. Among patients with suicidal intent (see Suicide Prevention), antidepressants, especially tricyclics, should be dispensed in small amounts to avoid providing enough drug for a lethal overdose.
Characteristics of Available Antidepressants
Table 24.4 lists characteristics of available antidepressant drugs. There are six selective serotonin reuptake inhibitors (SSRIs) available in the United States: citalopram, (Celexa) and its S-enantiomer, escitalopram (Lexapro), fluoxetine (Prozac and Sarafem), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft). They are similar in efficacy and side effect profiles. Fluvoxamine, citalopram, and paroxetine are more sedating than fluoxetine and sertraline. Because of its extremely long half-life (up to 4 days), fluoxetine has been formulated for once-a-week dosing during the maintenance phase of treatment (Prozac Weekly). Although preliminary studies support the efficacy of once-weekly compared with daily dosing of fluoxetine (29), whether it actually improves patient compliance is not known.
Bupropion (Wellbutrin) is an antidepressant of the aminoketone class, unrelated to the tricyclic and SSRI antidepressants that inhibits serotonin, norepinephrine, and dopamine reuptake. At the higher dosages (up to 700 mg) originally approved by the U.S. Food and Drug Administration (FDA), bupropion was associated with a higher rate of seizures; a finding that led to the recommended 450-mg limit on total daily dosage. Several controlled release preparations (Wellbutrin SR, Wellbutrin XL) have become available that now allow for twice daily or even once daily dosing. Bupropion has also been found to be useful in smoking cessation and is marketed under the brand Zyban for this indication.
Venlafaxine (Effexor) and duloxetine (Cymbalta) are phenylethylamine antidepressants that have been dubbed selective serotonin and norepinephrine reuptake inhibitors. Both venlafaxine and, to a lesser extent, duloxetine cause diastolic hypertension in a small fraction of patients, particularly at higher dosages, therefore, blood
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pressure monitoring for 2 weeks after starting the drug and after any dosage elevation is recommended. Duloxetine has also been approved for the treatment of diabetic neuropathy.
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TABLE 24.4 Characteristics of Antidepressant Drugs |
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Trazodone (Desyrel) and nefazodone (Serzone) are closely related agents that have been called atypical antidepressants. Trazodone is usually too sedating at the doses required to treat depression for it to be recommended as such. However, in smaller small doses (50 to 100 mg), it is a reasonably effective alternative to benzodiazepine hypnotics for depressed patients. Cases of life-threatening hepatic failure reported in patients taking nefazodone led the manufacturer of Serzone to discontinue its manufacture, although it is still available as a generic preparation. Both trazodone and nefazodone have been associated with priapism that has required surgical intervention (30). Male patients should be instructed to discontinue these drugs immediately if they experience prolonged or painful erections and seek emergency treatment as necessary.
Mirtazapine (Remeron) is associated with significant sedation but has a sufficiently long half-life to allow bedtime dosing. It is available as an instantly dissolving wafer that can be taken without water (Remeron SolTab), a useful option for patients unable to swallow. An uncommon but serious side effect is granulocytopenia.
Tricyclic antidepressants (TCAs), the oldest class, include two subgroups: secondary and tertiary amines. The side effect burden of these agents is significant and they are usually reserved for use in patients who have failed to respond to newer drugs. Nortriptyline has fewer side effects than the other TCAs and has the most clearly established therapeutically effective serum concentration range. Imipramine, desipramine, amitriptyline, and doxepin blood levels are also available. Starting dosages of TCAs should be reduced by approximately 50% in older patients (especially those with medical illnesses). Giving the total daily dosage at bedtime is desirable for most patients to minimize side effects.
The monoamine oxidase inhibitors (MAOIs) were the main alternatives to tricyclics before 1990, but are uncommonly used today except by psychiatrists specializing in the treatment of mood disorders because of their
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substantial side effects and the need for patients to follow a low-tyramine diet while taking them. Nevertheless, some patients are uniquely responsive to these agents. Patients who are taking MAOIs have usually failed all other treatments for depression. For this reason, primary care physicians should become comfortable treating patients for medical problems who are also taking MAOIs for depression, and avoid advising patients to discontinue MAOIs without psychiatric consultation.
Complementary and Alternative Treatments
A number of nutritional supplements and herbs have been claimed by enthusiasts to be safe and effective for depression (see Chapter 5). Patients may ask about alternative treatment because trials with standard antidepressants have failed or because of the misconception that herbal and nutritional preparations must be safer than the FDA-approved medications for which numerous possible adverse reactions are listed. St. John's wort gained considerable attention in the late 1990s after several studies seemed to indicate its effectiveness in depressed patients. One meta-analysis of 22 controlled clinical trials found St. John's wort to be as effective as standard antidepressants for the treatment of depression but a Cochrane collaboration report concluded that evidence for superior efficacy was weak in patients who meet diagnostic criteria for major depression or who suffer from “prolonged” depression (31). Several randomized, placebo-controlled studies have found no difference between St. John's wort extract and placebo in the treatment of patients with DSM-IV major depression (32,33).
Selection and Dosage Adjustment of Antidepressants
Because of their favorable side effect profile and ease of use, the SSRIs have become the drugs of first choice for most depressed patients. Because almost every patient is more prone to or more intolerant of some side effects than others, selection of an antidepressant for a particular patient depends on the fit between the patient's medical history and the antidepressant's side effect profile. The SSRIs have a significant advantage over the TCAs because of their relative safety in overdose. Both fluoxetine and the tricyclic nortriptyline have been shown to be safe for use during the first trimester of pregnancy. Although both were associated with a small increase in spontaneous abortions, neither was associated with any increase in fetal abnormalities (34).
In the otherwise healthy depressed patient, it is reasonable to initiate antidepressant treatment with 20 mg/day of fluoxetine or paroxetine. These two SSRIs are administered once a day and require no titration of the daily dosage as studies show that most responders do as well on the usual starting dosage of 20 mg/day as on higher dosages (35). For patients who are very sensitive to medication side effects, initiating treatment at 10 mg/day and advancing to 20 mg/day after 1 week is a reasonable option.
The benefits of pharmaceutical interventions for depression may take several weeks to become apparent and it is important to warn patients that they may notice little or no improvement during the first weeks of treatment. Patients should take a new medication at the starting dosage for 2 to 4 weeks before a dose increase is considered. Dosage increases likewise should occur at intervals of not less than 2 to 4 weeks. Symptoms should not be considered refractory to a particular agent unless the patient has taken it at the top of the recommended dosage range or, if serum determinations are available, at the top of the therapeutic range, for 4 to 8 weeks. Patients may continue to improve for months after starting on a new medication.
Recovery from depression can be slow and characterized by starts and stops in the recuperation process. Even as they are trending toward steady improvement, patients will frequently have good days and bad along the way. Frequent assessment (weekly during the initial stages of treatment, and at least every 2 weeks as long as there are significant symptoms) is necessary to ensure accurate assessment of recovery over time. Cross-sectional assessments at longer intervals may mislead as to the extent of progress. Family members should be encouraged to attend followup appointments in order to report their impressions. Patients can also be encouraged to keep a journal or mood chart and bring the results to appointments.
Antidepressant Side Effects
Mild side effects often occur before the therapeutic effects of antidepressant drugs begin and depressed may patients tolerate even mild side effects poorly and need frequent reassurance that the treatment is safe and likely to be effective (in 3 to 8 weeks). Emphasizing that side effects are not unusual, that they are benign and usually temporary is very helpful in getting patients through this period.
The common side effects of all SSRIs are transient mild nausea, transient insomnia, and transient nervousness and muscular irritability. All SSRIs have good antianxiety properties when taken for 2 weeks or longer at a steady dosage.
The SSRIs and selective serotonin and norepinephrine reuptake inhibitors can cause sexual dysfunction in up to one third of patients, usually decreased interest in sex (decreased libido), delayed orgasm or anorgasmia, and, less commonly, diminished sensation in the genital areas. Erectile function usually is not affected by these agents, but impotence can be caused by TCAs. Strategies for managing SSRI-related sexual dysfunction fall into several categories (36). Monitoring and waiting is appropriate for patients with delayed orgasm, because many patients notice improvement in this side effect after several months.
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Decreased libido and anorgasmia do not often resolve spontaneously, and other measures are usually necessary to relieve these problems. The section on antidepressant side effects in Chapter 6 provides details about the approaches that can be tried in these patients.
The most common side effects of the TCAs are anticholinergic: dry mouth, constipation, and, less often, delayed micturition, blurred vision, and an anticholinergic delirium. Orthostatic hypotension is particularly problematic in elderly patients and in any patient with unsteady gait or balance problems. TCAs may also produce increased appetite with weight gain, granulocytopenia (rarely), hypomania or mania, slowed cardiac conduction, and cardiac arrhythmias.
Because of the cardiac side effects, TCAs should be given cautiously to patients with pre-existing conduction abnormalities or any unstable cardiac conditions (e.g., recent MI). Nortriptyline has been studied in cardiac patients and can be safely administered to those with pre-existing stable heart disease (37). SSRIs, venlafaxine, and bupropion have few cardiac effects and therefore offer greater safety for the cardiac patient.
Bupropion is contraindicated in patients with a seizure disorder. The FDA recommends that the dosage not exceed 150 mg/dose or 450 mg/day (400 mg/day of Wellbutrin SR) to minimize the risk of seizures.
Drug Kinetics and Interactions
Among the TCAs and SSRIs, fluoxetine has an unusually long half-life (7 days for its active metabolite, norfluoxetine). This property can be advantageous because this antidepressant is less often associated with a withdrawal syndrome when discontinued, compared with other SSRIs and the selective serotonin and norepinephrine reuptake inhibitors. However, the long half-life increases the time required to achieve washout before changing to another antidepressant.
All SSRIs inhibit one or more of the cytochrome P-450 enzymes, but the clinical impact of this property, first reported in 1991, has proven to be modest. In patients taking paroxetine, fluoxetine, citalopram, or sertraline, blood levels of coadministered benzodiazepines, antipsychotics, TCAs, and flecainide-type antiarrhythmic agents may increase (Table 24.5).
Switching Antidepressants
Almost one third of depressed patients fail to respond to an adequate trial of an antidepressant medication. Switching antidepressants is one reasonable approach to the patient with treatment-resistant depression. Naturalistic studies indicate that switching antidepressants results in a treatment response approximately 50% of the time. Most authorities recommend switching to an antidepressant with a mechanism of action different from that of the failed agent, such as switching from an SSRI to a selective serotonin and norepinephrine reuptake inhibitor, bupropion or mirtazapine, agents that have actions on both serotonin and norepinephrine transport. Open label studies indicate, however, that switching from one SSRI to another can also be effective (38). A medication wash-out period is clearly indicated only with a switch from a MAOI to another antidepressant. Immediate substitution is usually well tolerated when switching within the same medication class (e.g., one SSRI or TCA to another) and has the advantage of avoiding discontinuation symptoms. Immediate substitution of mirtazapine for a SSRI has also been shown to be well tolerated. Gradual introduction of the new agent while gradually tapering the failed one is another well-tolerated strategy (39). The time to treatment response after switching to another agent cannot be estimated with any reliability. Numerous studies indicate that some patients require up to 12 weeks or even longer to have a response to changes in treatment approaches (40).
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TABLE 24.5 Drugs That May Interact with Antidepressants |
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Treatment-Resistant Depression
The management of treatment-resistant depression is challenging and requires not only experience in managing complex mood disorders, but also a substantial investment of time and considerable patience on the part of both the patient and the clinician. Biweekly or weekly monitoring visits are fairly standard practice in psychiatric settings for such patients during the many weeks, sometime many months, required for adequate new trials of antidepressant agents and for treatment augmentation strategies such as the addition of lithium, anticonvulsant mood stabilizers, atypical antipsychotics, thyroid hormones and
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dopaminergic and glutamatergic agents. Clinicians should consider psychiatric referral of the patient who has not benefited from even an initial antidepressant trial if these time-intensive interventions are not possible in their own practice and for patients who have failed several adequate trials of antidepressants.
Duration of Drug Treatment
In a patient with persistent and significant depressive symptoms, an adequate therapeutic trial usually requires 2 months at a therapeutically effective dosage. After recovery from a first or from an infrequently recurrent depressive syndrome, the medication that induced the remission should be continued for at least 12 months, the time of highest risk for relapse (41). Most patients with a history of episodes and relapses should be advised to continue their antidepressant for a number of years. The terms “indefinite” and “for the rest of your life” may convey a sense of pessimism to patients. The commitment to long-term treatment should rather be an incremental decision, made after comparing 1 and then 2 years of treatment experience with the period before treatment. The use of a lower dosage of the patient's antidepressant for “maintenance” treatment is not recommended. Patients who took half of the acute antidepressant dosage had no better outcome than the placebo group in one controlled study (42). After electroconvulsive therapy (ECT) (see later section), maintenance treatment with antidepressants is essential for most patients to reduce the risk of relapse.
Drug Discontinuation
Patients who discontinue antidepressant medications can experience a variety of uncomfortable physical symptoms, especially if they stop a medication abruptly. Symptoms including dizziness, light-headedness, headache, insomnia, fatigue, nausea, sensory disturbances, and flu-like malaise have been reported after discontinuation of TCAs, SSRIs, and selective serotonin and norepinephrine reuptake inhibitors (43). Discontinuation symptoms are more common with agents that have a shorter half-life (e.g., paroxetine) and less likely with agents that have a longer half-life (e.g., fluoxetine) (44). The overall incidence of antidepressant withdrawal symptoms is difficult to estimate because of the wide variation among antidepressants and probable variations in patient sensitivity, but discontinuation symptoms have been reported in up to one third of patients within the context of controlled trials of drug efficacy (43). Symptoms can occur within hours or days and may persist for up to several weeks.
When medications must be discontinued, tapering the dosage usually, but not always, prevents discontinuation symptoms from developing. Antidepressants should be tapered over a period of at least 10 days and over a longer period if the drug has been taken at higher dosages. A reasonable approach is to taper by 25% of the patient's dose every 3 to 4 days until the patient has been taking half of the usual startingdose for 3 to 4 days, and then discontinuing altogether. Patients taking low doses of antidepressants can be tapered more rapidly. Other than reassurance, treatment of discontinuation symptoms is rarely necessary. However, if necessary, they can usually be aborted by restarting or increasing the dose of the medication being discontinued, followed by a more gradual taper.
Counseling and Psychotherapy
Counseling Visits
For the first 6 to 8 weeks, the patient with major depression should be seen at least every other week for adjustment of medication and for brief supportive psychotherapy as described in Chapter 20. For patients with major depression, the first priority in supportive counseling is consistent repetition of the answers to the three questions most troublesome to depressed patients: “What is wrong with me?”; “Is this treatment going to work?” (this question may be presented as a concern: “I think this pill is making me worse; I want to stop it.”); and “What is going to happen to me (if this doesn't work for me)?” Answers to these questions should be prefaced by a reassuring statement, like, “You have clinical depression. We don't understand how it is caused, but it is not your fault. It is a medical disease. You will get better. We are going to continue to care for you and fight the depression with you until you are better.” Supportive counseling is important for members of the patient's family as well.
A second focus of counseling is more directive. It is remarkable how many patients resign jobs and separate from spouses based on distorted depressive perceptions about not being able to do their usual work, or not being able to feel love for a spouse. It is important therefore that the physician counsel patients not to attempt any major life decisions while they are depressed. Job-related and personal relationship changes should likewise be deferred until the patient's ability to maintain a more objective and positive perspective recovers.
Frank discussion of suicidal feelings, plans, and intentions should be a routine part of each visit (see Suicide Prevention). Candid discussion of the level of risk and protective measures available is equally important and may require the participation of a family member or loved one.
The patient should be routinely assessed for the side effects that are most typical of the antidepressant being used. The more depressed the patient, the less tolerant he or she will be of minor adverse drug effects and the more likely to give up on the treatment before it has been given an adequate trial. The support of the doctor in encouraging persistence with drug therapy is crucial.
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Office Psychotherapy
Traditional or “insight-oriented” psychotherapy has been a two-edged sword for depressed patients. On one hand, it engages depressed patients in an empathic consideration of their feelings and concerns. On the other hand, the theories behind the practice propose that depression results from maladaptive responses to life experiences and can therefore be alleviated through the insights and personal growth that psychotherapy facilitates. Psychodynamic therapy may thus convey the message that, when depressive symptoms persist, the patient rather than the treatment has failed—a distinctly inaccurate and even harmful implication for patients with major depression.
Several specialized types of psychotherapy have been found to be effective in treating depressive disorders. Cognitive therapy (also called cognitive behavior therapy or CBT) challenges the ingrained self-deprecating thoughts and attitudes (called schemas) that are common in depressed persons that are thought to lead to self-defeating behaviors that intensify and sustain depressive symptoms. Table 24.6 lists some of the more common cognitive distortions that depressed patients experience and express. Even someone who is not trained in cognitive therapy can help patients by gently challenging negative thoughts such as those listed. A supportively offered challenge can help patients access what they already know and what they have experienced, both of which usually argue against the most negative and distorted conclusions of the depressed state. Interpersonal therapy (IPT) emphasizes the social contexts and consequences of the patient's depression. It includes skills such as identifying and addressing stressors, pointing out assets, and providing alternative choices. Chapter 20describes these and other skills useful in interpersonal therapy. A meta-analysis of six trials comparing treatment with CBT or IPT to antidepressant medication and placebo in 883 outpatients found these psychotherapies to be as effective as medication in treating mild to moderate nonpsychotic major depression (45).
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TABLE 24.6 Cognitive Distortions in Depression |
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A combination of psychotherapy and medication has been shown to be more effective than either intervention alone for some patients. Thase et al. found in a meta-analysis of six clinical trials that CBT or IPT were as effective as medication in milder depression, but that there was a highly significant advantage of combining psychotherapy with medication in patients with more severe, recurrent depressions (46). When 707 patients being treated for dysthymic disorder were randomized to treatment with sertraline, with IPT, or with combination treatment, patients in either medication group had superior and equivalent symptomatic remission compared to patients receiving IPT, but patients on combination therapy had significantly lower health care and social services costs over the 2 years of treatment (47).
Psychotherapy is not indicated during the most acute depressive states however, as it requires that the patient be able to concentrate, recall, and maintain a level of objectivity and hopefulness that is not possible for the severely depressed patient.
Referral for Psychiatric Treatment
General physicians should be able to treat many of the patients in whom they diagnose major depression. However, some depressed patients should be referred to a psychiatrist: those in whom the diagnosis is not clear enough to allow confident treatment; those who show no improvement after 8 weeks of treatment with therapeutic dosages of antidepressant medications (about one in three patients); those who cannot or will not take antidepressant medications; those who are overtly suicidal; and those with delusions, hallucinations, or depressive stupor (i.e., mute and unresponsive). Hospitalization, more aggressive drug therapy, or ECT are often appropriate for these patients.
Although many patients initially resist the idea of seeing a psychiatrist, a primary care physician with whom a patient has good rapport can be most persuasive in helping the patient understand the need for and reasons necessitating psychiatric consultation or referral. Because patients may interpret psychiatric referral as an indication that their situation is hopeless, or that they are being shunned by their physician (as many depressed patients fear), it is
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important to explain the reasons for referral, specifically, that additional treatments, with which the psychiatrist has more experience, are available.
Electroconvulsive Therapy
ECT is an effective and rapid treatment for major depressive disorder. The decision to use ECT should be made in consultation with a psychiatrist, with the informed consent of the patient and, when available, with the informed consent of the patient's family. This treatment was previously given only to hospitalized patients, but outpatient ECT is increasingly available and suitable for medically and behaviorally stable patients. The indications for ECT involve emergency situations mandating a rapid response (such as the malnourished, dehydrated, or suicidal patient); the presence of medical illness that makes drug therapy excessively risky; the presence of delusions or overwhelming severity of the depression; and failure of drug therapy. The likelihood of marked benefit from ECT is higher than with antidepressants: It is approximately 80% in patients with major depression. The benefit is short-term however, lasting anywhere from several weeks to 6 months. Therefore, ECT is an excellent first choice for patients with clearly episodic depressions that are severe but infrequent. The benefit usually requires 6 to 12 treatments given two to three times per week. The procedure involves anesthetization administered with a muscle-relaxing agent.
Aside from the small risk of brief anesthesia, the adverse effects that follow ECT primarily involve memory. Retention of new and occasionally old memories is mildly defective for weeks to months after a series of ECT treatments. These memory gaps are usually spotty and involve primarily declarative memories (events, things that were heard or read) as opposed to procedural memories (how to perform a task). Typically, the patient in whom this effect becomes clinically apparent (perhaps 40% of treated patients) has trouble recalling names of recent acquaintances or forgets events that occurred during or just before beginning ECT. Clinically apparent memory defects typically resolve within 2 months. Formal testing has revealed mild defects lasting up to 3 months, but none at 6 months after treatment.
Prognosis
The clinical course of depressive illness varies greatly in individuals. A significant number of patients completely recover from a single major depressive episode and suffer no further recurrences (48). Some patients have recurrent illness, but enjoy sustained periods of virtually complete symptom remission between their illness episodes. But approximately 25% of patients with major depression have a chronic course of illness with long periods of residual symptoms and only incomplete remission over many years (49). These patients have been shown to have worse long-term outcomes than patients without chronic symptoms, having a greater number of relapses into periods of incapacitating depression, and worse occupational and social functioning over the long term (50). A naturalistic, prospective study of 431 patients with unipolar major depressive disorder found that they met diagnostic criteria for major depression or for dysthymic disorder or had subthreshold depressive symptoms during 59% of the weeks of the 12-year study. Twenty-seven percent of these patients had no weeks during which they were completely free of symptoms (49). The term double depression has been coined to describe patients with major depressive episodes superimposed on the chronic symptoms of dysthymic disorder.
Dysthymic Disorder
Dysthymia is a chronic depressive state (lasting 2 years or longer) in which the number of depressive symptoms experienced is fewer than what is required for the diagnosis of major depressive disorder (Table 24.7 versus Table 24.2). Although many dysthymic patients are fairly functional in their occupational life, this chronic illness is often associated with marked impairment in social functioning, especially in close personal relationships. Long-term avoidant behavioral patterns and lonely solitary lifestyles are not unusual in dysthymic patients. Superimposed substance abuse problems are not uncommon and can mask the underlying low grade, but debilitating depressive symptoms. Dysthymia not infrequently begins in childhood and, because the low mood is so persistent, patients, their family and friends, and also their physician often judge the problem to be an innate part of a chronically unhappy person's disposition (i.e., a personality disorder) rather than a mood disorder. For this reason, many dysthymic patients do not present for treatment of depression because they do not identify their mood problems as symptoms of illness. In reality, the disposition of dysthymic patients derives to a large degree from their chronic depression. Heightened public awareness of depression brought about by public service campaigns, advertisements for antidepressant medications in the lay media, and celebrity accounts on television may be leading more patients with chronic depression to seek treatment. Pharmacotherapy can be dramatically beneficial for these patients.
Diagnosis
In addition to self-recognition of depressive symptoms, complicating problems associated with depressed mood such as suicide attempts, self-injurious behavior, excessive medical care-seeking behavior, or abnormal illness behavior may prompt dysthymic patients to seek treatment.
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Serious diagnosable medical disorders, alcohol and drug abuse, and worries about family and marital discord or job difficulties may also bring the dysthymic to the attention of primary care physicians.
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TABLE 24.7 American Psychiatric Association Diagnostic Criteria for Dysthymic Disordera |
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Patients with dysthymic disorder have the characteristic sustained changes in self-attitude and vital sense seen with major depression. Hypersomnia, increased appetite and weight gain, and loss of energy and libido are common, as are anxiety symptoms.
Table 24.7 shows the criteria of the American Psychiatric Association for making the diagnosis of dysthymic disorder.
Treatment
Studies have revealed strong similarities in treatment response between patients with dysthymia and those with major depression. Also, dysthymic patients have a high likelihood of developing a superimposed major depression (so-called double depression). Thus the treatment of dysthymia has increasingly resembled the treatment of major depressive episodes.
SSRIs and TCAs have been shown to be effective in reducing dysthymic symptoms (51). In addition, brief psychotherapies are also known to be helpful (see Chapter 20). The major differences in treatment for the two types of depression relate to the increased rate of comorbid behavioral and social problems associated with this more chronic form of depression (dysthymia), problems usually requiring intensive psychotherapeutic interventions.
Recognizing that depression plays an important part in their life problems can be helpful for dysthymic patients. However, appreciating the difference between accepting medical regimens to treat mood disorders and making the effort required to overcome maladaptive behavior patterns is equally important.
Prognosis
In contrast to the major affective syndromes, discussions of prognosis in dysthymic disorder is problematic. The disorder typically continues beyond a 2-year period, and the time to remission cannot be estimated with much confidence. Superimposed major depressive episodes in dysthymic patients tend to respond well to antidepressants but subsyndromal symptoms are not uncommon. Poor outcomes are most common among patients with severe social maladjustments and personality disorders (see Chapter 23).
Bipolar disorders
Diagnosis
The manic syndrome, like major depression, is defined by a sustained change in mood, self-attitude, and vital sense. The manic patient's mood may be euphoric or irritable, or may alternate between or even seem to be a combination of the two. The self-attitude is usually one of overconfidence; in more severe cases, it is reflected in an inflated sense of power, position, and importance. Heightened vital sense is manifested in the patient's sense of quickened and totally accurate thinking. The patient has an overconfident ease in decision-making and a sense of heightened perception of sounds, colors, and tastes. The patient sees only continued well-being in his or her future. The patient manifests dramatically increased energy and a decreased need for sleep. In the speeded-up and overconfident state, the patient is observed by his or her family to be very distractible in speech (jumping from topic to topic) and behavior (jumping from one new project to another, completing none). Finally, judgment ranges from poor to catastrophic as patients spend impulsively, including giving away money and
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personal belongings on the street, and are uncharacteristically disinhibited and provocative in word and deed.
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TABLE 24.8 American Psychiatric Association Diagnostic Criteria for a Manic Episode |
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Delusions and hallucinations, when present, are usually either persecutory or grandiose. Occasionally symptoms characteristic of schizophrenia occur (see Chapter 25), but follow the course of the other manic symptoms, remitting as the mood and behavior normalize. The diagnosis of schizoaffective disorder–manic type is reserved for patients in whom the psychotic symptoms persist well beyond the manic syndrome so that the patient is psychotic in the absence of the manic symptoms throughout most of the course of the illness. Whether these patients have an unusually severe form of bipolar disorder or a condition more related to schizophrenia is currently unknown. Table 24.8shows the specific criteria of the American Psychiatric Association for mania.
Initial Treatment
General Principles
The disruptive and disinhibited symptoms of mania are more difficult to manage in medical terms, and the manic patient's behavior can be quite agitated and out of control. Therefore, manic patients are almost always best referred to psychiatrists, and many will require inpatient psychiatric treatment.
The referral may be difficult, because acceptance by a manic patient of the need for help is the exception rather than the rule. The patient's personal physician can be a crucial—at times the only—clinician involved with the manic patient in the initial presentation, and by virtue of an already established relationship with the patient or the family, this physician may be able to persuade the patient to take some medication and to accept a referral to a psychiatrist, emergency room, or hospital inpatient unit. Basic knowledge about the use of antipsychotic drugs and mood-stabilizing medications is therefore important for primary care physicians.
Hypomania, a milder form of the manic syndrome, can sometimes by treated on an outpatient basis but usually indicates the presence of a complex mood disorder that will require specialized care. Close symptom monitoring, discontinuation of any antidepressant medication that the patient may be taking, and prompt psychiatric evaluation usually are indicated. Hypomania can escalate rapidly and dangerously into full-blown mania, and initiation of antipsychotic medication is often appropriate.
Winning the cooperation of the acutely manic patient can be very difficult. The euphoric or irritable manic patient often will not accept the notion that his or her behavior is disturbed, much less that it requires hospitalization. Explaining the need for medical treatment in a manner that does not inflame the patient and provoke even more disordered behavior is a valuable skill. If possible, consultation with the family about the diagnosis and plan of treatment should be arranged before, not after, confronting the patient with the diagnosis and treatment plan. Despite the uncontrollable behavior of the manic patient, family members may be afraid to support the doctor's resolve to have the patient treated out of fear of being seen by the patient as betraying his or her trust. The clinician's task is to calm the patient and the family, to persuade the manic patient to accept hospitalization voluntarily if needed, and to resort to civil commitment if necessary.
Although laws on commitment vary among states, all states currently have legal provisions to allow the involuntary hospitalization of patients with mental disorders who are clearly dangerous to themselves or others and for whom no less restrictive alternative is appropriate. Physicians should make themselves familiar with commitment laws in the community where they practice and know the steps necessary to initiate commitment procedures before they are faced with this psychiatric emergency. These procedures often require the teamwork of the clinician, the family, the staff of an emergency room, and sometimes law enforcement officials to be successful.
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Medication for Severe Mania
Severe acute mania requires initial treatment with antipsychotic medications and later with mood stabilizers, such as lithium, anticonvulsant mood stabilizers, and/or atypical antipsychotics. For the first week or two, this treatment is usually carried out in the hospital. The generalist's role with such patients many include initial diagnosis, treatment with sufficient medication to get the manic patient to the hospital, and then continued participation in followup care.
For acute manic agitation, the use of parenteral fluphenazine (Prolixin) or another high-potency neuroleptic is usually effective. Modest doses (5 to 10 mg intramuscularly) calm most patients with little or no depression of blood pressure and little sedation. Parenteral preparations of the newer atypical antipsychotic medications are becoming available (olanzapine and ziprasidone as of this writing) and have been shown to be effective in the treatment of acute agitated states including mania (52). Older, more sedating phenothiazines such as chlorpromazine (Thorazine) are more difficult to work with because repeated doses are often necessary to break the agitated manic state and these preparations often produce significant orthostatic hypotension. Within 15 to 20 minutes, intramuscular high-potency neuroleptics usually bring about a calming effect that may last for several hours. This period can be used to get the patient admitted to hospital. Even in this short period, however, patients may develop extrapyramidal side effects from the high-potency neuroleptics, most often acute dystonic reactions. This condition is alleviated by 50 mg of intramuscular diphenhydramine (Benadryl) or 1 to 2 mg of trihexyphenidate (Cogentin).
Maintenance Therapy for Bipolar Disorder
Although the management of patients with bipolar disorder on a long-term basis is best thought of as requiring specialty care, primary care physicians will encounter patients on maintenance medications for bipolar disorder in their routine practice and should be knowledgeable about the agents used. Additionally, patients in remission from bipolar symptoms may request that their primary care physician manage their maintenance medications, either on an ongoing basis or during transitions in psychiatric care as might be necessitated by relocation to a new community. This necessarily brief overview summarizes the use of several of the most commonly used agents for maintenance treatment.
Patients recovering from an episode of mania will usually be taking a lithium preparation, an anticonvulsant mood stabilizer and/or an atypical antipsychotic medication. Patients recovering from an episode of depression may be taking an antidepressant in addition to lithium and/or an anticonvulsant. Since many patients can be protected against recurrences of their illness with lithium or an anticonvulsant alone, adjunctive medications are often gradually tapered and discontinued. Substantial numbers of patients with bipolar disorder will, however, need to take a combination of medications to remain well.
Lithium
Lithium continues to be the standard criterion for the maintenance treatment of bipolar disorder despite a fairly substantial side-effect burden and the need for ongoing monitoring of serum lithium levels and other laboratory tests.
Regular serum lithium levels are necessary during lithium maintenance not only because of a narrow therapeutic index but also because of an extensive literature indicating that the prophylactic efficacy of lithium requires that it be taken at a dose sufficient to achieve a threshold level. The American Psychiatric Association's guidelines note that 0.6 to 0.8 meq/L is the range “commonly chosen by patients and their psychiatrists” for lithium monotherapy (53). Serum lithium levels, which should be measured 12 hours after a dose (trough levels), should be obtained whenever there has been a change in dosage and at least every 6 months in stable patients. Elderly and medically frail patients should be tested more often.
Most of lithium's side effects correlate with peak serum levels and can often be ameliorated by changing the dosage schedule or using sustained-release preparations. Gastrointestinal symptoms are not uncommon; polydipsia and polyuria as well as edema that occur early on often resolve with time and can be managed with low doses of loop diuretics (patients who develop polyuria only after months or years should be evaluated for nephrogenic diabetes insipidus, discussed in this section). Diuretics, especially thiazide diuretics, alter lithium excretion, and serum lithium levels must be closely monitored in these patients to avoid toxicity. Nonsteroidal anti-inflammatory drugs (NSAIDs) also alter lithium excretion and should be avoided by patients taking lithium. Table 24.9 lists drugs that interact with lithium.
Side effects associated with long-term lithium treatment include weight gain, cognitive dulling, and fine hand tremor (all dose-related). Dermatologic problems associated with lithium use include acne and hair loss. Lithium can exacerbate pre-existing psoriasis so severely as to preclude lithium therapy in some individuals, although some patients with psoriasis will respond to the agents usually effective for this problem (54). Lithium has been associated with a variety of benign electrocardiogram (EKG) changes but significant cardiac conduction changes or arrhythmias are very uncommon.
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TABLE 24.9 Important Drug Interactions with Lithium |
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As the long-term effects of lithium on the kidney have become clearer, earlier concerns about it as a nephrotoxic substance have eased significantly. Although the risk of reduced glomerular function appears very low, a very small group of patients appear to develop glomerular and tubulointerstitial nephropathy that can progress to renal insufficiency and be irreversible if not detected early enough. In a review of such cases, the reversibility of renal insufficiency after discontinuation of lithium appeared correlated with serum creatinine levels under 2.5 mg/dL, further emphasizing the need for monitoring of renal function in patients taking lithium (55). Creatinine clearance (CrCl) determinations are no longer recommended for routine monitoring and obtaining serum creatinine determinations every 3 to 12 months depending on factors such as age and general medical conditions is reasonable. Patients with serum creatinine levels consistently above 1.6 mg/mL (or when the level has increased by 25% or more) should be referred for specialty evaluation.
The more common lithium associated renal problem is a nephrogenic diabetes insipidus caused by loss of renal concentrating ability. A mild but significant decrease in urine concentrating ability has been demonstrated in most (though not all) longitudinal studies of lithium's effect on the kidney. Patients should be asked about polyuria and a 24-hour urine volume measurement obtained if polyuria is suspected.
Lithium decreases thyroid hormone release and may interfere with other steps in the synthesis of thyroid hormones. Patients may respond to these thyroid suppressing effects with a rise in thyroid-stimulating hormone (TSH) that is usually temporary, but some progress to clinical or subclinical hypothyroidism. Kleiner et al. recommends that both antithyroperoxidase autoantibodies and antithyroid globulin determinations be done on patient at the beginning of lithium therapy to identify patients at greater risk for developing hypothyroidism. They recommend that TSH, the most sensitive and therefore only needed test, be measured every 3 months during the first year of therapy and semi-annually to annually thereafter to detect lithium-induced thyroid dysfunction (56).
Although lithium remains a Class D drug for teratogenic risk, there is some evidence that the risk is much lower than initially thought and that healthy outcomes in patients who become pregnant while taking lithium can be expected (57). However, lithium levels change dramatically during pregnancy and the postpartum period is one of extremely high risk for the development of mania. The management of the pregnant and postpartum patient with bipolar disorder is a complex challenge best left to a psychiatrist skilled in the management of mood disorders.
Lamotrigine
Lamotrigine (Lamictal) is a phenyltriazine anticonvulsant that has been found to be effective for the maintenance treatment of bipolar disorder in a number of open and controlled trials, and its use for this purpose will only continue to grow. It has a very low side-effect burden compared to lithium and does not require any ongoing laboratory monitoring.
Headache and dizziness are the most common side effect complaints. At higher doses, some patients complain of cognitive dulling similar to that seen with lithium and other anticonvulsants.
Early trials with lamotrigine for the treatment of epilepsy were marked with relatively high rates of erythema multiforme, including Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN). It was noted however, that pediatric age range, rapid upward titration of dose, and the combined use with valproate were associated with the highest risk of serious rash. Since the introduction of new dosing guidelines, the incidence of serious rash has dropped to levels similar to that of other anticonvulsant agents.
A few case reports of agranulocytosis have been reported but a causal relationship has not been established.
Valproate
Valproate is another anticonvulsant medication of proven efficacy in the treatment of acute mania (58). Although its efficacy for maintenance treatment is more controversial, it is often used for that purpose, especially in combination with other agents (59).
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Serum valproate levels are routinely used to monitor its use in epilepsy but there is substantially less data on the serum levels that are effective in bipolar disorder and essentially no data on effective levels for maintenance treatment. Studies suggest that levels above 45 µg/mL are necessary for antimanic efficacy and side effects become increasingly problematic at levels above 125 µg/mL.
Dose-related side effects of valproate include nausea, vomiting, and other gastrointestinal complaints such as abdominal pain and heartburn. A fine tremor is frequently seen at higher levels. Other reversible adverse effects include weight gain, increased appetite, and hair loss.
Transient minor elevations in hepatic transaminases are common when starting treatment with valproate and usually subside over time and the risk of severe hepatotoxicity in adults appears to be very low. Careful monitoring of liver functions is recommended when starting the drug as the hepatotoxicity is often reversible if the drug is withdrawn. Rare cases of hemorrhagic pancreatitis have been reported that seem related to initiation of the drug or dosage increase in susceptible individuals. Delay of diagnosis has been implicated as a contributing factor to these rare cases, and patients should be warned about the symptoms and potential severity of pancreatitis. Thrombocytopenia is a rare idiosyncratic response to valproate.
There have been reports linking valproate with gynecologic problems including menstrual irregularities, polycystic ovary syndrome, and androgenization in women taking it for the treatment of epilepsy. Other studies have not replicated this work and the topic is intensely controversial (60). Regular monitoring of reproductive function in female patients taking valproate is recommended with questioning during visits regarding menstrual disorders, fertility, weight gain, hirsutism, and galactorrhea.
Epidemiologic studies of valproate suggest an increased incidence of spina bifida in the offspring of women who took the drug during pregnancy. Additionally, an increased incidence of cardiovascular, orofacial, and digital abnormalities has been reported. Women in the childbearing years should practice birth control while taking valproate.
Atypical Antipsychotic Medications
Antipsychotic medications have been used mainly as adjunctive agents in the acute phases of bipolar disorder, especially manic states, for many years but a role for the atypical antipsychotics in maintenance treatment is developing. Although their use as monotherapy agents for prophylaxis is still being evaluated in controlled trials, impressive results have been obtained in studies of olanzapine (Zyprexa), especially for the prevention of mania, leading to FDA approval of olanzapine as maintenance treatment for bipolar disorder (61).
Sedation is the main dose-related side effect of these agents, which usually cause little in the way of extrapyramidal symptoms making adjunctive treatment with anticholinergic agents rarely necessary.
Soon after the introduction of this class of drugs in the mid-1970s, excessive weight gain was reported in some patients taking atypical antipsychotics, especially clozapine and olanzapine. Although weight gain in the short term is usually small, several studies have shown that it can continue for many months after starting on antipsychotic medications making the potential for significant weight gain in patients on long-term treatment substantial (62). The weight gain from these drugs more often results in central or abdominal obesity, a pattern thought to impose more health risks than generalized obesity. Such health risks include type 2 diabetes mellitus, coronary artery disease secondary to hyperlipidemia, osteoarthritis, and other conditions. Body weight, blood glucose, and serum lipid levels should be monitored at the beginning of treatment and regularly thereafter in patients taking antipsychotics for maintenance treatment. Nutritional counseling for patients taking these agents is important, emphasizing portion size, low-fat foods, and regular exercise.
Prognosis
The course of the bipolar disorders is so widely variable as to defy simple description or easy categorization. Some patients enjoy many years of symptom remission with maintenance treatment, and others endure almost unrelenting mood cycling and substantial psychosocial morbidity (63).
Cyclothymic Disorder
An episodic bipolar affective disorder that is sufficiently mild or so brief that the episodes fail to meet the American Psychiatric Association criteria for major depression or mania is categorized as a cyclothymic disorder. Patients with cyclothymic disorder must be distinguished from patients with the personality traits of emotional lability and self-dramatization who often report rapid but unsustained mood changes. The family histories of cyclothymic patients are similar to those of patients with bipolar affective disorders. The long-term course is also similar to that of bipolar disorder, and 35% of such patients have been found to experience full-blown manic, hypomanic, or depressive episodes in a 2- to 3-year period of followup (64).
Counseling the Family
Family members of patients with serious affective disorders often experience feelings of confusion, hopelessness, guilt, and recrimination toward the patient. Not only are these feelings painful, but they impede the family's attempts to support their ill relative. Physicians need to address the family's needs directly through meetings with
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them. Above all, the family must recognize major affective disorders as diseases and realize that these disorders are not caused by the family, the patient, or even the social predicaments affecting the patient. The family also should know that although the pathophysiology of affective disorders is unknown, empiric treatments are effective and the prognosis for complete recovery from an episode is generally good, although relapses occur frequently. These points usually require some repetition and are best repeated in response to questions that the family should be encouraged to raise in such a meeting or consultation. It is equally important to reassure families and patients with dysthymic and transiently demoralized mood states that the patients are not suffering from a major mental illness.
Educational materials on affective disorders are available from the American Psychiatric Association and the National Institutes of Mental Health (NIMH), and a number of accessible and well-written books about the disorders for patients and their families are available (seehttp://www.hopkinsbayview.org/PAMreferences). Additionally, patients and families will gain considerable help from patient and family-member support groups (see Sources of Information at http://www.hopkinsbayview.org/PAMreferences).
Heredity of Depression
Evidence from many studies of concordance comparing identical and nonidentical twins has established a substantial genetic contribution to major affective disorders, although the relevant genes have not yet been isolated. The modest findings to date support the supposition that genetic heterogeneity underlies these disorders and that the disease genotype comprises an ensemble of genes that act in concert to predispose people to these illnesses. It appears that a sibling or offspring of a patient with a major affective disorder has a 10% chance of developing the disorder. However, in some families this risk may be as high as 50%. The risk is also greater for monozygotic twins. Counseling of patients and their families about the genetic risk should be tailored to the needs and relevant history in each family. The major themes of counseling should be that most cases are genetically influenced, that effective treatment is available, and that treatment is greatly enhanced by early detection of the disorder.
Suicide Prevention
The rate of suicide in most countries is so low (11 per 100,000 in the United States) that successful prediction of an individual suicide at a given point in time is very unlikely.
Practical strategies in this area are to protect those with high risk in the short term and to reduce the risk in these patients over a longer term. Risk factors for successful suicide include depressive disorder (greater severity is associated with greater risk), older age, male gender, alcoholism, living alone, previous suicide attempt, and refusal to accept referral for psychiatric treatment. Retrospective studies of patient groups with major affective disorders in the era before affective drugs were available suggest that approximately 15% of the deaths were caused by suicide. Additionally, clinical observations suggest that the risk of suicide increases when improvement begins (or just after a depressed patient is discharged from the hospital) or when the depressive ruminations become frankly delusional convictions. Retrospective studies also suggest that there are fewer suicides among patients treated with ECT or long-term lithium therapy (65).
When evaluating any patient with depressed mood, direct and open inquiry should be made regarding suicidal ideas (e.g., “Have you at times felt so low that you feel life is not worth living,” followed by “Have you had any thoughts of hurting yourself or taking your own life?”), and the patient should be asked about specific plans that he or she may have formulated (“Have you thought about how you might try to harm yourself?”). An assessment of the lethality of the patient's plans and the availability of the means to carry them out should be made. Seriously depressed patients should always be asked about the presence of firearms in the home, and any weapons should be removed, even in the face of a patient's disavowal of plans to use them. A study of adolescent suicide showed that the presence of a firearm in the home increased the risk of completed suicide regardless of whether the weapon was a handgun or a long gun, kept loaded or unloaded, locked up or not (66). Information about the capability and availability of constant family supervision is also helpful in determining whether treatment may be attempted safely on an outpatient basis. Asking patients to “contract for safety”—that is, to promise verbally or even in writing to contact a family member or the physician, to call police or to go to an emergency room, if their suicidal impulses should intensify or become difficult to resist—has frequently been recommended in the management of suicidal patients. Obtaining a “no-harm contract” helps the physician engage the patient in a discussion of his or her suicidal thinking, emphasizes the physician's concern for the safety of the patient, communicates the physician's assessment of the gravity of the situation, and also requires the development and discussion of an action plan should suicidal thinking worsen. This “contract” does not, however, substitute for a complete assessment of the patient's risk for suicidal behavior, and it is only as effective as the soundness of the underlying therapeutic alliance (67). The suicide risk evaluation should also be guided by the knowledge that delusionally depressed patients have a significantly increased risk of suicide and that patients with prior suicide attempts are more likely than others to attempt it again when depressed.
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Short-term protection of patients with suicidal intent by means of hospitalization, including involuntary commitment, is sometimes required. The most crucial activities of physicians in preventing suicides, however, are the diagnosis, treatment, and prophylaxis of major depressive episodes.
Most patients who present to emergency facilities after an overdose of pills do not have major depression but rather an adjustment disorder or personality disorder, and they usually do not die by suicide. However, they should be methodically evaluated in the same manner as noted previously because many such patients are prone to take overdoses again when stressed. These patients may benefit from brief hospital admissions when social support for them is lacking and suicidal feelings are intense. All should have outpatient counseling.
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
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