Bipolar disease is a disorder of mood consisting of prolonged episodes of depression, interrupted by, or coexistent with episodes of mania. It was given the name manic-depressive disease by Kraepelin in 1896, and it was with him that our current clinical concept of this disorder originated. He viewed the manic and depressive attacks as opposite poles of the same underlying process and pointed out that, unlike dementia praecox (his name for schizophrenia), bipolar psychosis entails no intellectual deterioration with recurrent episodes. A traditional view of this disease was that of a periodic or cyclic condition in which one major mood swing was followed by an equal but opposite excursion. This is seldom the case, however. Episodes of depression are more than twice as frequent as manic ones, and according to current experts, the most common form of the illness is characterized by episodic depression alone and many patients have several episodes of depression before their first period of mania.
Recurrence of episodes of pure mania without interspersed episodes of depression is known but relatively uncommon. As a consequence, bipolar psychosis has been divided into two subtypes: the unipolar group, in which only an endogenous depressive illness occurs, and a bipolar group, in which one or more bouts of mania occur with or without depression. The bipolar variety occurs in approximately 10 percent of patients with affective disorder. The biologic accuracy of this classification has not been critically determined. There has been an arbitrary further subdivision of bipolar I to denote at least one episode of full mania, and bipolar II when the process entails an episode of hypomania.
In addition, there are mixed affective states, in which symptoms of both depression and mania occur within a single episode of the illness. A so-called "rapid-cycling" form of bipolar disease has also been recognized in which four or more circumscribed episodes occur in a year. Like other variants of the disease, it tends to have an aberrant or unpredictable response to medication. Still other patients with affective elements of depression present with atypical features; for example, instead of anorexia, weight loss, and insomnia, they sleep and eat excessively.
The prevalence of bipolar disease cannot be stated with precision, mainly because of varying criteria used for diagnosis. Certainly depression and depressive episodes are ubiquitous and mania is less common. The apparent increase of the disease in the past 50 years probably reflects a growing awareness of the condition among both physicians and the laity. Studies of large groups of patients from isolated areas of Iceland and the Danish islands of Bornholm and Samsø indicate that 5 percent of men and 9 percent of women will develop symptoms of major depression, mania, or both at some time during their lives (Goodwin and Guze). Some recent studies, such as the one conducted by the National Comorbidity Survey, report lifetime prevalence for bipolar disorder in the United States as 4.5% (Merikangas et al).
Bipolar disease occurs most frequently in middle and later adult years, with a peak age of onset between 55 and 65 for both sexes. However, a significant proportion of patients experience the first attack in childhood, adolescence, or early adult life. Depression is also a major problem in the elderly. Blazer and Williams, who studied 997 persons older than age 65 years in North Carolina, found symptoms of a major depressive illness in 3.7 percent. The disease was two or three times more frequent among women. There is no known explanation for this gender difference, but some have speculated that just as many men are depressed, only they deny it or turn to alcohol. Patients in the bipolar group have an earlier age of onset, more frequent and shorter cycles of illness, and a greater prevalence of affective disorder among their relatives than do patients with unipolar depression (Winokur).
The manic state is, in most ways, the opposite of the depressed state, being characterized by a flight of ideas, motor and speech hyperactivity, and an increased appetite and sex urge. When such a state is fully developed, it qualifies as a psychosis. After a minimum of sleep, the patient awakes with enthusiasm and expectation. The manic individual appears to possess great drive and confidence yet lacks the ability to carry out plans. Often headstrong, impulsive, socially intrusive behavior is characteristic. Judgment may be so impaired that reckless investments are made; fortunes are spent in gambling or on extravagant shopping sprees. Setbacks do not perturb the patient, but rather act as goads to new activities. Euphoria and expansiveness sometimes bubble over into delusions of power and grandeur, which, in turn, may make the patient offensively aggressive. Up to a point, the patient's mirth and good spirits may be contagious, and others may join in; however, if the patient is thwarted, the warmth and good humor can suddenly change to anger. Irritability rather than elation may become the prevailing mood. The threshold for paranoid thinking is low, which makes the patient sensitive and suspicious. Personal neglect may reach the point of dishevelment and poor hygiene. In its most advanced form, a condition described as "delirious mania," the patient becomes totally incoherent and altogether disorganized in behavior. At this stage visual and auditory hallucinations and paranoid delusions may be rampant.
Hypomania describes a milder degree of the disorder but this term is also used loosely to depict behavior in a normally functioning individual who is unusually energetic and active. In this latter sense, hypomania is a personality trait found in many talented and productive persons and need not arouse concern unless it is excessive and out of character for the individual. As Belmaker noted, a number of highly creative individuals have had bipolar disorders, but full-blown mania is uniformly destructive of careers and personal relationships. Such individuals are actually more creative when treated with appropriate medications.
First attacks of either depression or mania last an average of 6 months if untreated, although the duration varies greatly. With treatment, this can be reduced by more than half in most patients. Although most attacks of bipolar disease subside in a matter of months, a significant number, unipolar patients more than bipolar ones, remain chronically ill for long periods. According to Winokur and colleagues, 14 percent of their bipolar patients had not recovered after 2 years and 5 percent had not recovered after 5 years. Comparative figures for primary unipolar patients were 19 and 12 percent, respectively. The majority of depressed patients have one or more recurrences. Variables that are predictive of an unfavorable outcome are high degrees of anxiety, strongly positive family history of a similar psychiatric illness, and presence of depression-provoking circumstances (Hirschfeld et al). Perhaps most important is the duration of illness before treatment, i.e., earlier treatment is generally associated with a more favorable prognosis.
Mania Presenting as an Encephalopathy
The manic patient may be disoriented and slightly agitated, with a clouded sensorium. This extreme is not frequently encountered but we have several times admitted patients to the neurology service with mania that presented in a manner suggesting an encephalopathy and global confusional state. The patient conducted himself pleasantly, without psychosis, pressured speech or overactive motor behavior but with an inattentive, confusion as the dominant feature. Conditions such as herpes encephalitis, alcohol or drug withdrawal, stroke, and paraneoplastic encephalitis were considered until the patient began filling notebooks with writing, manifesting insomnia, and making connections between ideas and events that were individually valid but just outside the realm of likelihood. One insisted that one of us was also his wife's cardiologist and another, that one of the authors had scored a winning touchdown at a college football game at which he was present. Stories about public figures were factually correct but attached to the wrong person. The patient sat near the door to his hospital room and incessantly but pleasantly attracted our attention to speak to him every time one of us was in sight. At the same time, performance on orientation, arithmetic, and language tasks were normal.
Special Problems in Patient with Depressive Illness
In our experience, the following are some of the common and troublesome clinical situations in which it may prove difficult to recognize an underlying depression:
Patients with chronic pain. The association of chronic pain and depression has long been appreciated. This is far from a homogeneous group. The special case of chronic headache, confronted often by neurologists, is discussed below and in Chap. 10. In some patients with chronic pain, the symptoms and signs of depression are quite apparent. If the pain has been present for less than a year and had its onset at the same time as other depressive symptoms, response to antidepressant treatment is likely to be favorable. Far more difficult to understand, and to manage, are patients with persistent pain as the only complaint; the head, face, and lower back are the most common loci. Weeks or months of unremitting daily tension-type headaches in the context of a normal examination are highly suggestive of depression at any age. If an exhaustive search for the source of the pain proves unsuccessful, the conclusion is finally reached that the pain is "psychogenic." This attribution of pain to some obscure psychologic mechanism is hardly helpful. Nevertheless, in a fair proportion of such patients, that pain will be alleviated by antidepressant drugs is suggestive of a linkage of the pain and depression. The problem may have been made even more difficult by repeated surgical operations as well as dependency on analgesic drugs, which in themselves deplete energy and have other adverse effects. Such patients are to be found among those disabled after multiple operations for ruptured intervertebral disc or arthritic hips or those with atypical facial pain.
Depression and alcoholism. These are commonly associated, and it is important to determine which is primary and which is secondary. A depressive syndrome developing for the first time on a background of alcoholism is a common clinical occurrence. In a large series of alcoholic patients studied by Cadoret and Winokur, a secondary depression occurred in 30 of 61 females and in 41 of 112 males; moreover, once the alcoholism was established, depression became evident much earlier in the women than in the men. The opposite occurrence (i.e., the development of alcoholism on the background of a primary depression) is less common. Again, women are disproportionately affected. As mentioned earlier, these differences may be spurious; Winokur's family studies (1991) suggest that the same genetic predisposition leads to depression in females and alcoholism and sociopathy in men.
Depression in childhood and adolescence. We have observed depressive states in children and they have often been misdiagnosed by both pediatricians and psychiatrists. The common manifestations have been chronic headache, refusal to go to school, withdrawal from social activities, anorexia, vomiting and weight loss, and scholastic failure. Puberty is a time of onset in many cases, but we have seen depressive disease in late childhood and it is frequent in high school and college students. It is a tragic mistake not to appreciate this fact and to treat the patient for some presumed nonaffective nervous symptoms, only to have the patient commit suicide.
Anxiety, hypochondriasis, and pseudodementia. These are clinical circumstances in which an underlying depressive illness may not be immediately apparent but must be suspected, as discussed in detail in Chap. 51. The complaint of severe chronic fatigue without medical explanation should raise the same suspicion (see Chap. 24). An elderly person with seemingly early signs of dementia may, on closer examination, turn out to have a severe depressive illness.
The following are the main theories, not mutually exclusive, that have been proposed to explain the origin of depression; for a detailed review of the subject, the reader is referred to the review by Belmaker and Agam.
The capacity to experience sadness and depression is common to all people but there is no question that some individuals are more liable to depression than others who are subjected to similar psychosocial forces. It has been estimated, using various genetic techniques, that as much as 40 percent of the risk of depression is heritable (lower than for schizophrenia and bipolar disease). Adopted children whose biologic parents had affective disorder are at greater risk of developing this disease than are adoptees whose biologic parents were not affected (Mendlewicz and Rainer; Cadoret). The frequency of these illnesses is greatly increased in the relatives of affected patients (prevalence rate of 14 to 25 percent in first-degree relatives). Similarly, the risk of depression among first-degree relatives is increased (15 percent, in comparison to 1 to 2 percent risk in the general population). If several twin studies are taken together, 72 percent of monozygotic twins are concordant for bipolar disease, compared with 14 percent of same-sex dizygotic twins; comparative figures for unipolar disease are 40 percent and 11 percent, respectively (see Goodwin and Guze). All of these findings indicate a strong genetic factor. The genes for bipolar disease remain to be discovered, and current thinking holds that several are likely to be involved. One indication that specific genes may alter the susceptibility to depression has been presented by Ogilvie and colleagues; they and others have found allelic variations in the serotonin transporter gene (the main target of the selective serotonin antidepressants) that were associated with a sevenfold increased risk of major depression. Not all studies agree on these points. This result has been reinforced by Caspi and colleagues who reported that a variant in the serotonin transporter correlates with an increase in depression in response to stress. Other hypotheses have postulated susceptibility loci on chromosomes 18, 21, and X. Again, a single gene locus seems unlikely (see Sanders et al).
Several lines of study, including those employing functional imaging, indicate that a few select regions of the brain are implicated in the pathogenesis of the complex symptomatology of depression (Drevets). Hypometabolism in the left frontal cortex is among the most consistent findings. Also prominent in many studies are metabolic changes in the cingulate and orbitofrontal cortices, related parts of the medial limbic system, and the hippocampus.
An intriguing observation, and one that does not entirely accord with the above, has been made by Bejjani and colleagues in the course of deep brain stimulation for the treatment of Parkinson disease. One of their patients displayed transient but dramatic manifestations of depression only when high-frequency stimulation was delivered to the left substantia nigra. Positron emission tomography imaging during stimulation showed activation in the left orbitofrontal cortex and, less consistently, in the left amygdala, globus pallidus, thalamus, and right parietal lobe. In two other cases with no prior psychiatric symptoms, deep brain stimulation of the subthalamic nucleus induced a reversible manic state (Herzog et al; Kulisevsky et al). Fisher noted a hypomanic episode in the early stages of herpes encephalitis, and numerous cases of temporary secondary mania have been reported after stroke and after brain trauma, the latter affecting most often the right temporal lobe.
On histologic level, several studies have shown a depletion of and changes in the pyramidal neurons of the CA3 region of the hippocampus in both depression and stress, but the meaning of these findings is unclear (Sapolsky). They are referred to later in relation to neurogenesis (the appearance in adults of new neurons) in the temporal lobe and recovery from depression. These ideas regarding neurogenesis, which are still speculative, are discussed in Chap. 29. Interestingly, in a rodent model of depression, neurogenesis was required for the beneficial effects of antidepressants to take place (Santarelli). Based in part on this observation, a relationship has been suggested between depressive illness and the later development of dementia. The reviews of Starkstein (1987, 1991) and Robinson and their colleagues, and that of Belmaker and Agam mentioned earlier, may be consulted for further information on anatomic lesions that cause changes in affect.
It has been evident for several years that the biogenic monoamines (norepinephrine, serotonin, and dopamine) are in some way involved in the biology of depression. However, most of the neurochemical theories of depression suffer from the weakness that they have been the result of backward reasoning from the effects of antidepressants on various neurotransmitters to the putative mechanisms of the disease. Following the observations that the tricyclic antidepressants and the monoamine oxidase (MAO) inhibitors exerted their effect by increasing norepinephrine and serotonin at central adrenergic receptor sites in the limbic system and hypothalamus and that depression-provoking drugs (such as reserpine) deplete biogenic amines at these sites, it was proposed that naturally occurring depressions might be associated with a deficiency of these substances. Furthermore, depressed patients and their first-degree relatives, as well as healthy individuals, develop a depressed mood after dietary depletion of the monoamine precursor tryptophan and concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), a metabolite of norepinephrine, are reduced in the cerebrospinal fluid during endogenous depression and the levels are elevated in manic states. Some neurochemical imaging studies corroborate these findings and others do not. Along similar lines, 5-hydroxyindoleacetic acid (5-HIAA), a deaminated metabolite of serotonin, is reduced in the cerebrospinal fluid of depressed patients (Carroll et al).
Certain of the newer antidepressants act as selective serotonin reuptake inhibitors (SSRIs) and apparently produce their salutary effects by increasing the amount of serotonin that is functionally active in the synapse (they also raise the concentrations of norepinephrine). For these reasons, serotonin and its neuronal pathways are also currently implicated in the genesis of depression. However, the reader should be reminded that only two decades ago it was widely held that depletion of norepinephrine fulfilled this role. It is also not yet clear which neurochemical alterations are primary and which modulate other systems. For example, reports suggest that substance P plays an important role in the causation of depression (Kramer et al) and that blockade of substance P receptors has antidepressant effects. Why there is a delay of several weeks in the improvement of depression related to the taking of the various antidepressants is unexplained by any of the neurochemical models.
Another set of observations that has continued to capture interest for more than a decade implicates a disorder of hypothalamic–pituitary–adrenal axis function (summarized by Schlesser et al). It had been found several decades ago that the parenteral administration of 1 to 2 mg of dexamethasone failed to suppress serum cortisol secretion while the patient was ill with endogenous depression, but did so after recovery. In a comparable series of reactive depressions, there was a normal suppression of cortisol secretion. Originally, the dexamethasone suppression test was believed to separate the two large groups of depressed patients and to predict the response to drug therapy. However, subsequent studies have shown that the specificity of this test was far less than earlier reports had indicated (Amsterdam et al; Insel et al). Accumulated evidence indicates that 50 percent of severely depressed patients do not show suppression of cortisol secretion, and a positive test can be obtained in a significant number of patients with other psychiatric disorders.
The failure of dexamethasone suppression has been attributed to hyperactivity in the hypothalamic pituitary axis and a corresponding increase in secretion of corticotropin-releasing hormone, adrenocorticotropic hormone (ACTH), and glucocorticoids. Elevated levels of glucocorticoids have been theorized to impede neurogenesis in the medial temporal lobe, and perhaps to explain or exaggerate the loss of hippocampal neurons demonstrated in some studies of the brains of deceased depressed patients. A proposal that ECT acts by elevating levels of neurotrophic factors is at least consistent with this view and with the hypothesis that one component of recovery from depression is in some way associated with restoration of normal neuronal architecture in regions of the hippocampus and the hypothalamus (Chen). Although highly speculative, perhaps some of these changes explain the delay in improvement after the administration of antidepression drugs.
At the present time, it must also be conceded that there is no reliable biologic test for depression. One must resort to clinical analysis not only for diagnosis but also for the differentiation of special types of depressive reactions.
Many experienced psychiatrists have emphasized the importance of psychosocial factors in the genesis of depressive illness. Among patients with primary depressive disorders, life events of a stressful nature were found to have occurred more frequently in the months preceding the onset of depression than in matched control groups. In the study by Thomson and Hendrie, this was equally true of patients with a positive family history of depression and of those without such a history. Nor did patients with endogenous depression differ in this respect from those with reactive depression. Left unanswered is the question of why some individuals are subject to a reactive depression. Are they predisposed by psychologic, personality, or genetically transmitted factors of heightened vulnerability to the effects of psychosocial stress? One is tempted to conclude that many depressions attributed to psychosocial stress are contaminating a group of endogenous depressions. Psychiatrists have also failed to find a consistent correlation between depressive illness and personality type or a particular psychodynamic mechanism.
The use of medications for depression is now so widespread that all physicians should be familiar with them. Those untrained in psychiatry would, however, be unwise to undertake the management of bipolar disease or a serious endogenous depression without the advice or assistance of a psychiatrist. On the other hand, if the symptoms are primarily neurologic (e.g., chronic headache, generalized weakness, and fatigability) and if there is a low risk of suicide, it is appropriate for the neurologist or generalist to institute treatment with antidepressant medication.
In the management of bipolar and depressive disease, six main categories of drugs are in general use—the tricyclic antidepressants, the "atypical" or nontricyclic group of compounds, the MAO inhibitors, serotonin agonists (reuptake inhibitors), antiepileptic drugs, and lithium. The pharmacologic properties and modes of action of these drugs were considered in Chap. 43. Additional points of therapeutic interest are mentioned here. It should also be stated that meta-analyses of several large studies on the therapeutic effects of antidepressants suggest that clinical improvement attributable to the drugs themselves occurs in approximately 50 percent of patients; remarkably, an additional improvement in up to 25 percent is attributable to a placebo effect or, more likely, to the natural course of the disease. The remainder fails to improve in a timely manner or relapse while on medication. The incremental value of certain forms of psychotherapies is discussed further on.
Most psychiatrists currently prefer to begin treatment with one of the functional serotonin agonists (SSRIs)—fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), escitalopram (Lexapro), and others, or one of a related group, exemplified by venlafaxine (Effexor) and nefazodone (Serzone). New drugs of similar type are appearing yearly. These drugs have less sedating and anticholinergic effects than the tricyclic antidepressants discussed below, and may have a slightly faster onset of effect against depression. Fluoxetine has a tendency to produce insomnia and weight loss, making it particularly useful in the treatment of depressions that are characterized by overeating and hypersomnia. Some female patients have experienced an opposite effect, i.e., weight gain. Patients with anorexia, insomnia, and high levels of anxiety may do better with a more sedating medication, such as amitriptyline. Fluoxetine would be a reasonable choice for patients in whom lethargy is a prominent complaint. Certain side effects such as loss of libido and erectile dysfunction occur in a proportion of patients and are difficult to differentiate from the signs of depression. Other side effects occur in a proportion of patients, including gastrointestinal upset, increased anxiety as discussed in Chap. 51, blurred vision, dizziness, among many (see Chap. 43).
The contentious issues of (1) inducing mania, (2) precipitating suicide soon after the institution of these medications, and (3) the use of these drugs in children are important issues that can only be addressed here cursorily. Ryan summarizes these problems and points out that the overall rates of suicide among adolescents are decreasing at the time of increasing use of SSRI agents. The precipitation of a manic episode by serotonergic antidepressants in some patients with bipolar disorder seems a regular enough occurrence that it is no longer a point of contention. Also to be emphasized is an increased risk of pulmonary hypertension in the babies of mothers exposed to SSRI during the pregnancy.
The tricyclic antidepressants comprise amitriptyline, imipramine, desipramine, doxepin, clomipramine, and trimipramine, and the closely related drugs nortriptyline and protriptyline. Among this group, most psychiatrists start with imipramine or amitriptyline because of their relative safety. In general, all of these drugs are equally effective, although an individual patient may have a better response or tolerance to one than to another. The starting dose for amitriptyline or imipramine is 25 mg/d, which is then raised by 25 mg q3–4d as needed up to 150 mg/d. These drugs, taken at bedtime, are also very helpful in alleviating the insomnia that accompanies depression. The therapeutic effect of tricyclic medication is generally not evident for 2 to 4 weeks after treatment has been initiated, and it is important that this be explained to the patient and family. Common side effects are orthostatic hypotension, dry mouth, constipation, tachycardia, urinary hesitancy or retention (especially in patients with prostatic hypertrophy), tremor, and drowsiness. Closed-angle glaucoma may decompensate. Caution should be exercised in elderly patients with cardiac disorders of all types because of the possibility of causing heart block or arrhythmia. For such patients, the serotonin drugs or one of a newer group of nontricyclic antidepressant drugs—bupropion and trazodone—may be preferable, but the latter causes orthostatic hypotension and sedation in doses required for consistent antidepression effects. The latter drugs appear to be as effective as the tricyclic agents in the treatment of depression without the adverse anticholinergic and cardiotoxic effects.
If one of the SSRI or tricyclic and related drugs, given in full doses for 4 to 6 weeks, does not produce the desired effect, or, as often happens, if the patient is intolerant of the given drug, another one from an alternative group, e.g., an MAO inhibitor, may be tried. In one of the many new "effectiveness" trials sponsored by the National Institutes of Mental Health, as distinguished from "efficacy" in controlled and randomized trials, failure of citalopram to accomplish remission of depression (about half of patients, as expected), changing to bupropion, sertraline, or venlafaxine had equivalent effects and were successful in 25 percent of cases (Rush et al). In the case of SSRIs, there must be a drug-free interval of 1 to 2 weeks before instituting an MAO inhibitor. Some studies suggest that MAO inhibitors are superior in depression with atypical features such as increased appetite. Phenelzine, isocarboxazid, and tranylcypromine are in this category, of which the first is said to be the least likely to produce serious side effects. The usual starting dose is 15 mg tid, which is gradually increased as needed to a maximum of 45 mg tid. The most serious risk of MAO inhibitors is the occurrence of a hypertensive crisis; consequently, these drugs should be dispensed with caution in patients with hypertension and with cardiovascular or cerebrovascular disease. Patients taking these drugs should avoid foods with a high tyramine content (aged cheese, many pickled foods, chicken liver, beer, wines, yeast extract) as well as medications containing sympathomimetic agents or L-dopa (decongestants, amphetamines, caffeine) and the aforementioned serotonin agonists. The use of the MAOI (monoamine oxidase inhibitor)-B drugs for Parkinson disease (see Chap. 39) is also interdicted.
Supplementation of antidepressants with the administration of an antiepileptic medication is a popular approach with many psychiatrists. Valproate or gabapentin are used, but also used are carbamazepine or phenytoin. There are few credible studies by which to judge the value of this strategy, but these drugs may provide some additional benefit as "mood stabilizers," if only as antianxiety agents. More persuasive are the data suggesting that antiepileptic drugs are useful in treatment of the manic state.
Because many depressed patients are responsive to one of the tricyclic drugs, MAO inhibitors, or serotonin agonists but not to all of them, the clinician is greatly aided by information regarding which of these drugs has been helpful in past episodes. As mentioned, response to antidepressant drugs is not expected for several weeks. Treatment, if successful, should be continued for 6 to 9 months and generally combined with some type of psychotherapy. The premature discontinuation of medications is a major source of relapse. The dosage of medication may then be reduced slowly over a period of weeks. Rapid reduction may result in withdrawal symptoms (nausea, vomiting, malaise, and muscular pains). If depressive symptoms recur upon withdrawal, the effective dose should be gradually reinstituted. Mann (2005) provides a thorough review of the medical treatment of depression; the side effects of each are given in tabular form and adapted for Table 52-3.
Table 52-3 Classification and Side Effects of Antidepressants ||Download (.pdf)
Treatment of Bipolar Disease
This has for decades, until very recently, been the drug of choice in treating the manic phase of bipolar disease and it is useful in preventing relapses of depression in some patients. Certain of the newer antipsychotic drugs, discussed in the next chapter, have overtaken lithium for the treatment of bipolar disease, with little evidence that they are superior. During an acute manic attack, hospitalization may be required to protect the manic patient from impulsive and aggressive behavior that might cause personal and interpersonal difficulty or jeopardize a career. Haloperidol (Haldol), or one of the newer antipsychosis agents discussed in Chap. 53—or ECT if these drugs are ineffective—can be used to control the mania until lithium carbonate becomes effective, usually a matter of 4 or 5 days. The usual dosage of lithium is 1,200 to 2,400 mg daily in divided oral doses, which produces a desired serum level of 0.9 to 1.4 mEq/L. The serum level of lithium must be checked frequently, both to ensure that a therapeutic dose is being taken and to guard against toxicity (see later).
The side effects of lithium are nausea and vomiting, diarrhea (especially if the dose is increased too rapidly), a feeling of mental dullness, action tremor, weakness, ataxia, slurred speech, blurred vision, dizziness, nystagmus (especially vertical or down beating), stupor, and coma. A confusional psychosis with polymyoclonus and ataxia-simulating Creutzfeldt-Jakob disease (including periodic sharp waves in the electroencephalogram) may occur at toxic levels. In patients who do not tolerate lithium, carbamazepine, valproate, or another antiepileptic may be substituted. A combination of lithium and a tricyclic or SSRI medication at the lowest effective level has been one of the best long-term preventive therapies for bipolar disease, and the same combination is useful for patients with mixed bipolar disorder in which depressive and manic manifestations occur within a single episode of illness.
Antipsychotic Drugs and Mood Stabilizers
Perhaps the most marked change in the treatment of bipolar disease is to initiate one of the approved antipsychotic medications (quetiapine, fluoxetine) rather than lithium to bring both the depression and episodic cycling into mania under control. Failing this, a "mood stabilizing" drug such as lamotrigine or divalproex has been used. As mentioned earlier, there is scant evidence that these approaches are superior to lithium but the point to be made is that the use of conventional antidepressants is currently less popular because of the risk of worsening depression to the point of a suicidal state or of inducing mania or hypomania. Other combinations have been used such as olanzapine with a serotonergic antidepressant (e.g., fluoxetine). These are ably summarized in the review by Frye but taken together the effectiveness of these new approaches serve to emphasize the importance of proper diagnosis of bipolar disease in contrast to unipolar depression. Haloperidol may be necessary to control a dangerous manic episode while one of these newer medications becomes effective.
Electroconvulsive Therapy and Transcranial Magnetic Stimulation
What used to be called infelicitously "electroshock" therapy continues to be a highly effective treatment for severe endogenous depression and can also be used to interrupt manic episodes. The technique is relatively simple and, in properly supervised clinics, quite safe. The patient is anesthetized by an intravenous injection of a short-acting barbiturate, benzodiazepine, or propofol, and is also medicated with a muscle relaxant (succinylcholine). In the conventional method, an electrode is placed over each temple and a current of about 400 mA and 70 to 120 V is passed between them for 0.1 to 0.5 s. The machine itself has as the essential element a large capacitor that is discharged to produce an electrographic seizure. The succinylcholine prevents strong and injurious muscle spasms. The patient is awake within 5 to 10 min and is up and about in 30 min. The mechanism by which ECT produces its effects is unknown. Treatments are usually given every other day for 6 to 14 sessions. The only absolute contraindication is the presence of increased intracranial pressure, as may occur with a neoplasm or intracranial hematoma. Whether epilepsy is precipitated or worsened by ECT is still debated. This treatment should also be used cautiously in the presence of uncontrolled systemic hypertension or with a known sensitivity to the anesthetic agents that are used as premedication, particularly malignant hyperthermia.
The major drawback of ECT is the production of a transient impairment of recent memory for the period of treatment and for the days that follow, the degree of impairment related to the number of treatments given. Placing both electrodes on the nondominant side (unilateral ECT) or using lower amounts of current and a briefer pulse rather than a sine wave produces less memory disturbance and has been adopted because it is almost as effective against the depression.
With the recognition that transcranial magnetic motor stimulation sometimes produced an elevation of mood, its use as a substitute for ECT is being introduced. The magnetic technique has the advantage of being free of any but minor physical effects, and because it produces no loss of consciousness, anesthesia and neuromuscular paralysis are not needed. Brief pulses of high-frequency stimuli are used. Few controlled studies have as yet been performed and this technique could conceivably replace ECT, but the initial sense is that it is not as effective against severe or prolonged depressions and probably not at all for catatonia.
Until the advent of the antidepressant drugs, ECT was the treatment of choice for the agitated depression of middle and late life and for catatonia. Following a course of 6 to 14 treatments, close to 90 percent of patients recovered within 2 months or less. Prior to the use of ECT, this type of depression might last for 2 years or longer before remission or suicide occurred. In cases of catatonia or severe psychotic depression most psychiatrists favor the initial use of one of the newer antipsychosis agents, followed by a trial of an antidepressant before resorting to ECT. Following ECT therapy, maintenance therapy with an antidepressant, or lithium is necessary to prevent relapse. Deep brain stimulation is under study for refractory depression.
In all patients with depression or bipolar disease, careful explanations of the patient's illness, reassurance that the illness is self-limited, and encouragement and instruction of the family are of value in helping both the patient and family to understand the illness and cope with it. At the same time, there should be vigilance for suicidality, admittedly a difficult task given its unpredictability. As a general rule, bipolar illness is best managed by a physician who is willing to follow the patient over a long period of time and who is known to the family. He should be available to reevaluate the patient on suspicion of a relapse. Although the prognosis for any individual attack is relatively good, it is wise to arrange for a plan of action that will be set in operation at the first hint of a recurrence.
Tomes have been written about various psychodynamic approaches to psychotherapy and the authors are unable to comment authoritatively on them. A structured and problem-oriented approach to psychotherapy using "cognitive-behavioral" and "interpersonal" strategies has gained considerable popularity since its introduction in the 1970s by Beck. It draws to a limited extent on psychoanalytic and other psychodynamic theories and has been used in patients with depression and in those with anxiety chronic pain, and other disorders. According to Blenkiron, cognitive-behavioral therapy is most effective in patients with mild to moderate (not chronic) depression, generalized anxiety and panic disorder, and obsessive-compulsive and phobic disorders. Essentially, in the short term, the therapist provides the patient with information on the nature of the illness, its common symptoms, and the active interventions that are to be undertaken by the patient with the aid of the therapist to alter the specific misperceptions and the dysfunctional behaviors that spring from them. In difficult chronic forms of depression, Keller and colleagues compared an antidepression drug (nefazodone), cognitive-behavioral therapy, or the combination, and found remissions in approximately 50 percent of each of the first two groups and in 85 percent of the combined treatment cohort by 12 weeks. This stands as one of the better demonstrations of the value of modern, result-oriented psychotherapy. The interested reader can find discussion of this subject in the current edition of Kaplan and Sadock's Comprehensive Textbook of Psychiatry (Sadock and Sadock). Noteworthy is the opinion of Gabbard that behavioral-cognitive psychotherapy has been shown to be no better or worse than other forms of psychotherapy, but it has the virtues of relative brevity, uniformity of application, and straightforwardness that avoids blaming the patient, family, environment, or other external forces.
Some 30,000 suicides are recorded annually in the United States, and attempted suicides exceed this number by approximately 10 times. All psychiatrists agree that these are conservative figures. Suicide is the eighth leading cause of death among adults in the United States and the second leading cause among persons between the ages of 15 and 24 years, figures that emphasize the importance of recognizing depression that has a high potential for self-destruction. Every physician should be familiar with the few clues we possess to identify those patients who intend to end their lives. Some of the questions that may be broached in the interview regarding depression were listed earlier, but particularly, "Do you think of hurting yourself or taking your own life?" and the follow-through query, "Do you have a plan?" Physicians should also be aware that the majority of suicides are accomplished by taking an overdose of prescribed medications, for which reason caution needs to be exercised in their distribution and administration in depressed patients.
Some views, summarized by Mann (1998), are that suicidal intent represents a special form of depression, or an important variant of it, and that certain individuals are by nature susceptible as a result of biologic factors. In other words, suicide is not simply a cognitive response to extreme stress or despondency. There is no way for the authors to judge this view, but it seems correct and proponents have pointed to particular indices of serotonin function that differ between depressed individuals who attempt suicide and those who do not. It has also been observed that the inception of modern antidepressant medications has not greatly altered the rate of suicide among depressed patients. Bipolar illness, endogenous depression, depression resulting from a debilitating disease (particularly Huntington disease, cancer, and AIDS), pathologic grief, and depression in an alcoholic or schizophrenic, all carry the risk of suicide. In bipolar disease and endogenous depression, the risk of suicide over the lifetime of the patient is approximately 15 percent (Guze and Robins). In Robins' series of 134 patients who committed suicide, 47 percent had a known depressive illness and 25 percent were alcoholic. Other series have recorded even higher rates of depression, alcoholism, and drug abuse (see Andreasen and Black).
Most suicides are planned, not impulsive. Furthermore, the intention of committing suicide is more often than not communicated to someone significant in the patient's life. The message may be in the form of a direct verbal statement of intent, or it may be indirect, such as giving away a treasured possession or revising a will. It is known that successful suicide is three times more common in men than in women and particularly common among men older than 40 years of age. Patients with a history of suicide in either mother or father carry a higher risk than those without such a history. A previous suicide attempt adds to the risk. As alluded to earlier, important deterrents to suicide are devout Catholicism or comparable religious belief (suicide is a sin), concern about the suffering it would cause the family, and fear of death sincerely expressed by the patient. However, no single one of these attributes stands out as entirely predictive of suicide. As a consequence, one is left with clinical judgment and an index of suspicion as the main guides. The only rule of thumb is that all suicidal threats are to be taken seriously and all patients who threaten to kill themselves should be evaluated quickly by a psychiatrist.
For the depressed patient with terminal disease, the authors have taken the personal position of providing comfort by all possible means, but not in assisting the patient to commit suicide.