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Bipolar Disorder (DSM-IV-TR #296.0–296.89)
Bipolar disorder is characterized by the occurrence of at least occurrence of gradual transitions between all the various one manic or mixed-manic episode during the patient’s states.” In a similar vein, Carlson and Goodwin, in their lifetime. Most patients also, at other times, have one or more elegant paper of 1973, divided a manic episode into “three depressive episodes. In the intervals between these episodes, stages”: hypomania, or stage I; acute mania, or stage II; and most patients return to their normal state of well-being. Thus delirious mania, or stage III. As this “staging” of a manic bipolar disorder is a “cyclic” or “periodic” illness, with episode is very useful from a descriptive and differential patients cycling “up” into a manic or mixed-manic episode, diagnostic point of view, it is used in this chapter. Thus, then returning to normal, and cycling “down” into a when the term “manic episode” is used it may refer to any depressive episode from which they likewise eventually more one of the three stages of mania: hypomania, acute mania, or Bipolar disorder is probably equally common among men Manic episodes are often preceded by a prodrome, lasting and women and has a lifetime prevalence of from 1.3 to from a few days to a few months, of mild and often transitory and indistinct manic symptoms. At times, however, no prodromal warning signs may occur, and the episode starts quite abruptly. When this occurs, patients often Bipolar disorder in the past has been referred to as “manic unaccountably wake up during the night full of energy and depressive illness, circular type.” As noted in the introduction vigor—the so-called “manic alert.” to the chapter on major depression, the term “manic depressive illness,” at least in the United States, has more and more come to be used as equivalent to bipolar disorder. As The cardinal symptoms of mania are the following: this convention, however, is not worldwide, the term heightened mood (either euphoric or irritable); flight of ideas “bipolar” may be better, as it clearly indicates that the patient and pressure of speech; and increased energy, decreased need has an illness characterized by “swings” to the manic “pole” for sleep, and hyperactivity. These cardinal symptoms are and generally also to the depressive “pole.” most plainly evident in hypomania. In acute mania they exacerbate and may be joined by delusions and some fragmentation of behavior, and in delirious mania only tattered scraps of the cardinal symptoms may be present, otherwise being obscured by florid and often bizarre Bipolar disorder may present with either a depressive or a psychotic symptoms. Although all patients experience a manic episode, and the peak age of onset for the first episode, hypomanic stage, and almost all progress to at least a touch whether depressive or manic, lies in the teens and early of acute mania, only a minority finally are propelled into twenties. Earlier onsets may occur; indeed some patients may delirious mania. The rapidity with which patients pass from have their first episode at 10 years of age or younger. After hypomania through acute mania and on to delirious mania the twenties the incidence of first episodes gradually varies from a week to a few days to as little as a few hours. decreases, with well over 90% of patients having had their Indeed, in such hyperacute onsets, the patient may have first episode before the age of 50. Onsets as late as the already passed through the hypomanic stage and the acute seventies or eighties have, though very rare, been seen. manic stage before he is brought to medical attention. The duration of an entire manic episode varies from the extremes of as little as a few days or less to many years, and rarely Premorbidly, these patients may either be normal or display even to a decade or more. On the average, however, most mild symptoms for a variable period of time before the first first episodes of mania last from several weeks up to 3 months. In the natural course of events, symptoms tend to gradually subside; after they fade many patients feel guilty CLINICAL FEATURES
over what they did and perhaps are full of self-reproach. Most patients are able to recall what happened during hypomania and acute mania; however, memory is often The discussion of signs and symptoms proceeds in three spotty for the events of delirious mania. With this brief parts: first, a discussion of a manic episode; second, a general description of a manic episode in mind, what follows discussion of a depressive episode; and, third, a discussion of now is a more thorough discussion of each of the three stages Manic Episode
Hypomania.
The nosology of the various stages of a manic episode has In hypomania the mood is heightened and elevated. Most changed over the decades. In current DSM-IV nomenclature, often these patients are euphoric, full of jollity and hypomanic episodes are separated from the more severe full cheerfulness. Though at times selfish and pompous, their manic episodes, which in turn are characterized as either mood nevertheless is often quite “infectious.” They joke, mild, moderate, severe, or severe with psychotic features. make wisecracks and delightful insinuations, and those Kraepelin, however, divided the “manic states” into four around them often get quite caught up in the spirit, always forms—hypomania, acute mania, delusional mania, and laughing with the patient, and not at him. Indeed, when delirious mania—and noted that his observation revealed “the physicians find themselves unable to suppress their own laughter when interviewing a patient, the diagnosis of yet another prospect. Spending sprees are also typical. hypomania is very likely. Self-esteem and self-confidence are Clothes, furniture, and cars may be bought; the credit card is greatly increased. Inflated with their own grandiosity, pushed to the limit and checks, without any foundation in the patients may boast of fabulous achievements and lay out bank, may be written with the utmost alacrity. Excessive plans for even grander conquests in the future. In a minority jewelry and flamboyant clothing are especially popular. The of patients, however, irritability may be the dominant mood. overinvolvement of patients with other people typically leads Patients become demanding, inconsiderate, and intemperate. to the most injudicious and at times unwelcome They are constantly dissatisfied and intolerant of others, and entanglements. Passionate encounters are the rule, and brook no opposition. Trifling slights may enrage the patient, hypersexuality is not uncommon. Many a female hypomanic and violent outbursts are not uncommon. At times, has become pregnant during such escapades. If confronted pronounced lability of mood may be evident; otherwise with the consequences of their behavior, hypomanic patients supremely contented patients may suddenly turn dark, typically take offense, turn perhaps indignantly self- righteous, or are quick with numerous, more or less plausible excuses. When hypomanic patients are primarily irritable rather then euphoric, their demanding, intrusive, and In flight of ideas the patient’s train of thought is injudicious behavior often brings them into conflict with characterized by rapid leaps from one topic to another. When flight of ideas is mild, the connections between the patient’s successive ideas, though perhaps tenuous, may nonetheless be “understandable” to the listener. In somewhat higher Acute Mania.
grades of flight of ideas, however, the connections may seem to be illogical and come to depend more on puns and word The transition from hypomania to acute mania is marked by a plays. This flight of ideas is often accompanied by pressure of thought. Patients may report that their thoughts race, that severe exacerbation of the symptoms seen in hypomania, and they have too many thoughts, that they run on pell-mell. the appearance of delusions. Typically, the delusions are grandiose: millions of dollars are held in trust for them; Typically, patients also display pressure of speech. Here the listener is deluged with a torrent of words. Speech may passersby stop and wait in deferential awe as they pass by; become imperious, incredibly rapid, and almost unstoppable. the President will announce their elevation to cabinet rank. Religious delusions are very common. The patients are Occasionally, after great urging and with great effort, patients may be able to keep silent and withhold their speech, but not prophets, elected by God for a magnificent, yet hidden, for long, and soon the dam bursts once again. purpose. They are enthroned; indeed God has made way for them. Sometimes these grandiose delusions are held constantly; however, in other cases patients may suddenly Energy is greatly, even immensely, increased, and patients boldly announce their belief, then toss it aside with laughter, feel less and less the need for sleep. They are on the go, busy only to announce yet another one. Persecutory delusions may and involved throughout the day. They wish to be a part of also appear and are quite common in those who are of a life and to be involved more and more in the lives of those predominantly irritable mood. The patients’ failures are not around them. They are strangers to fatigue and are still their own but the results of the treachery of colleagues or hyperactive and ready to go when others must go to bed. family. They are persecuted by those jealous of their Eventually, the patients themselves may finally go to sleep, grandeur; they are pilloried, crucified by the enemy. but within a very brief period of time they then awaken, Terrorists have set a watch on their houses and seek to wide-eyed, and, finding no one else up, they may seek destroy them before they can ascend to their thrones. someone to wake up, or perhaps take a whistling stroll of the Occasionally, along with delusions, patients may have darkened neighborhood, or, if alone, they may spend the isolated hallucinations. Grandiose patients hear a chorus of hours before daybreak cleaning out closets or drawers, angels singing their praises; the persecuted patients hear the catching up on old correspondence, or even paying bills. resentful muttering of the envious crowd. In addition to these cardinal symptoms, hypomanic patients The mood in acute mania is further heightened and often are often extremely distractible. Other conversations and quite labile. Domineeringly good-natured one moment, the events, though peripheral to the patients’ present purposes, patient, if thwarted at all, may erupt into a furious rage of are as if glittering jewels that they must attend to, to take as screaming, swearing, and assaultiveness. Furniture may be their own, or simply to admire. In listening to patients, one smashed and clothes torn apart. The already irritable patient may find that a fragment of another conversation has may become consistently, and very dangerously, hostile. suddenly been interpolated into their flight of ideas, or they may stop suddenly and declare their unbounded admiration for the physician’s clothing, only then again to become one Flight of ideas and pressured speech become very intense. Patients seem unable to cease talking; they may scream, shout, bellow, sing in a loud voice or preach in a declamatory fashion to anyone whose ear they can catch. Hypomanic patients rarely recognize that anything is wrong with them, and though their judgment is obviously impaired Hyperactivity becomes more pronounced, and the patient’s they have no insight into that condition. Indeed, as far as hypomanic patients are concerned, the rest of the world is behavior may begin to fragment. Impulses come at cross sick and impaired; if only the rest of the world could feel as purposes, and patients, though increasingly active, may be unable to complete anything. Fragments of activity abound: they do and see as clearly as they do, then the rest of the world would be sure to join them. These patients often enter patients may run, hop in place, roll about the floor, leap from into business arrangements with unbounded and completely bed to bed, race this way and then that, or repeatedly change their clothes at a furious pace. uncritical enthusiasm. Ventures are begun, stocks are bought on a hunch, money is loaned out without collateral, and when the family fortune is spent, the patient, undaunted, after Occasionally, patients in acute mania may evidence a passing perhaps a brief pause, may seek to borrow more money for fragment of insight: they may suddenly leap to the tops of tables and proclaim that they are “mad,” then laugh, lose the Self-control is absolutely lost, and the patient has no insight thought, and jump back into their pursuits of a moment ago. and no capacity for it. Attempting to reason with the patient Some may devote themselves to writing, flooding reams of in delirious mania is fruitless, even assuming that the patient paper with an extravagant handwriting, leaving behind an stays still enough for one to try. The frenzy of these patients almost unintelligible, tangential flight of written ideas. is remarkable to behold and rarely forgotten. Yet in the Patients may dress themselves in the most fantastic ways. height of delirious mania, one may be surprised by the Women may decorate themselves with garlands of flowers appearance of a sudden calm. Instantly, the patient may and wear the most seductive of dresses. Men may be become mute and immobile, and such a catatonic stupor may festooned with ribbons and jewelry. Unrestrainable sexuality persist from minutes to hours only to give way again to a may come to the fore. Patients may openly and shamelessly storm of activity. Other catatonic signs, such as echolalia and proposition complete strangers; some may openly and echopraxia and even waxy flexibility, may also be seen. exultantly masturbate. Strength may be greatly increased, and sensitivity to pain may be lost. As noted earlier not all manic patients pass through all three stages; indeed some may not progress past a hypomanic state. Delirious Mania.
Regardless, however, of whether the peak of severity of the individual patient’s episode is found in hypomania, in acute mania, or in delirious mania, once that peak has been The transition to delirious mania is marked by the appearance reached, a more or less gradual and orderly subsidence of of confusion, more hallucinations, and a marked symptoms occurs, which to a greater or lesser degree retraces intensification of the symptoms seen in acute mania. A the same symptoms seen in the earlier escalation. Finally, dreamlike clouding of consciousness may occur. Patients once the last vestiges of hypomanic symptoms have faded, may mistake where they are and with whom. They cry out the patient is often found full of self-reproach and shame that they are in heaven or in hell, in a palace or in a prison; over what he has done. Some may be reluctant to leave the those around them have all changed—the physician is an hospital for fear of reproach by those they harmed and executioner; fellow patients are secret slaves. Hallucinations, offended while they were in the manic episode. more commonly auditory than visual, appear momentarily and then are gone, perhaps only to be replaced by another. The thunderous voice of God sounds; angels whisper secret In current nomenclature, those patients whose manic encouragements; the devil boasts at having the patient now; episodes never pass beyond the stage of hypomania are said the patient’s children cry out in despair. Creatures and faces to have “Bipolar II” disorder, in contrast with “Bipolar I” may appear; lights flash and lightning cracks through the disorder wherein the mania does escalate beyond the room. Grandiose and persecutory delusions intensify, hypomanic stage. Recent data indicate that bipolar II disorder especially the persecutory ones. Bizarre delusions may occur, may be more common than bipolar I disorder; however, including Schneiderian delusions. Electrical currents from the should a patient with bipolar II disorder ever have a manic nurses’ station control the patient; the patient remains in a episode wherein stage II or III symptoms occurred, then the telepathic communication with the physician or with the diagnosis would have to be revised to bipolar I. Occasionally the age of the patient may influence the Mood is extremely dysphoric and labile. Though some presentation of mania. Adolescents and children, for patients still are occasionally enthusiastic and jolly, example, seem particularly prone to the very rapid irritability is generally quite pronounced. There may be development of delirious mania. On the other extreme, in the cursing, and swearing; violent threats are made, and if elderly, one may see little or no hyperactivity. Some elderly patients are restrained they may spit on those around them. manic patients may sit in the same chair all day long, Sudden despair and wretched crying may grip the patient, chattering away in an explosive flight of ideas. Mental only to give way in moments to unrestrained laughter. retardation may also influence the presentation of mania. Here in the absence of speech one may see only increased, seemingly purposeless, activity. Flight of ideas becomes extremely intense and fragmented. Sentences are rarely completed, and speech often consists of words or short phrases having only the most tenuous Depressive Episodes
connection with the other. Pressure of speech likewise increases, and in extreme cases the patient’s speech may become an incoherent and rapidly changing jumble. Yet even The depressive episodes seen in bipolar disorder, in contrast in the highest grades of incoherence, where associations to those typically seen in a major depression, tend to come on fairly acutely, over perhaps a few weeks, and often occur become markedly loosened, these patients remain in lively contact with the world about them. Fragments of nearby without any significant precipitating factors. They tend to be conversations are interpolated into their speech, or they may characterized by psychomotor retardation, hyperphagia, and hypersomnolence and are not uncommonly accompanied by make a sudden reference to the physician’s clothing or to a disturbance somewhere else on the ward. delusions or hallucinations. On the average, untreated, these bipolar depressions tend to last about a half year. Hyperactivity is extreme, and behavior disintegrates into numerous and disparate fragments of purposeful activity. Mood is depressed and often irritable. The patients are Patients may agitatedly pace from one wall to the other, jump discontented and fault-finding and may even come to loathe not only themselves but also everyone around them. to a table top, beat their chest and scream, assault anyone nearby, pound on the windows, tear the bed sheets, prance, twitter, or throw off their clothes. Impulsivity may be Energy is lacking; patients may feel apathetic or at times extreme, and the patient may unexpectedly commit suicide Thought becomes sluggish and slow. Patients cannot then go on to execute a lively dance, all the while with tears concentrate to read and cannot remember what they do read. still streaming down their faces. Or a depressed and Comprehending alternatives and bringing themselves to psychomotorically retarded patient may consistently dress in the brightest of clothes, showing a fixed smile on an otherwise expressionless face. These mixed-manic episodes must be distinguished from the transitional periods that may Patients may lose interest in life; things appear dull and appear in patients who “cycle” directly from a manic into a depressive episode, or vice versa, without any intervening euthymic interval. These transitional periods are often Many patients feel a greatly increased need for sleep. Some marked by an admixture of both manic and depressive may succumb and sleep 10, 14, or 18 hours a day. Yet no symptoms; however, they do not “stand alone” as episodes of matter how much sleep they get, they awake exhausted, as if illness unto themselves, but are always both immediately they had not slept at all. Appetite may also be increased and preceded and followed by a more typical episode of weight gain may occur, occasionally to an amazing degree. homogenous manic or homogenous depressive symptoms. In Conversely, some patients may experience insomnia or loss contrast the mixed-manic episode “stands alone.” It starts with mixed symptoms, endures with them, and finishes with them, and is neither immediately preceded nor immediately followed by an episode of mania or by an episode of Psychomotor retardation is the rule, although some patients may show agitation. In psychomotor retardation the patient may lie in bed or sit in the chair for hours, perhaps all day, profoundly apathetic and scarcely moving at all. Speech is At this point, before proceeding to a consideration of course, rare; if a sentence is begun, it may die in the speaking of it, as two other disorders that are strongly associated with bipolar if the patient had not the energy to bring it to conclusion. At disorder should be mentioned, namely alcoholism and times the facial expression may become tense and pained, as cocaine addiction. During manic episodes, patients with these if the patient were under some great inner constraint. addictions are especially likely to take cocaine or drink even more heavily, and the effects of these substances may cloud the clinical picture. Pessimism and bleak despair permeate these patients’ outlooks. Guilt abounds, and on surveying their lives patients find themselves the worst of failures, the greatest of sinners. Effort appears futile, and enterprises begun in the past may be abandoned. They may have recurrent thoughts of suicide, Bipolar disorder is an episodic or, as noted earlier, “cyclical” and impulsive suicide attempts may occur. illness, being characterized in most patients by the intermittent lifelong appearance of episodes of illness, in Delusions of guilt and of well-deserved punishment and between which most patients experience a “euthymic” persecution are common. Patients may believe that they have interval during which they more or less return to their normal let children starve, murdered their spouses, poisoned the wells. Unspeakable punishments are carried out: their eyes are gouged out; they are slowly hung from the gallows; they The pattern and sequencing of successive episodes is quite have contracted syphilis or AIDS, and these are a just variable among patients. The duration of the euthymic interval varies from as little as a few weeks or days to as long as years, or even decades. In contrast, however, to the Hallucinations may also appear and may be quite fantastic. extreme variability of the euthymic intervals among patients, Heads float through the air; the soup boils black with blood. finding a certain regular pattern in the history of any given Auditory hallucinations are more common, and patients may patient is not unusual. Indeed in some patients the euthymic hear the heavenly court pronounce judgment. Foul odors may interval is so regular that patients can predict sometimes to be smelled, and poison may be tasted in the food. the month when the next episode will occur. The postpartum period is a time of increased risk. Occasionally, one may also see a “seasonal” pattern, with manic episodes more likely in In general a depressive episode in bipolar disorder subsides the spring or early summer and depressive ones in the fall or gradually. Occasionally, however, it may come to an abrupt termination. A patient may arise one morning, after months of suffering, and announce a complete return to fitness and vitality. In such cases, a manic episode is likely to soon Early on in the overall course of the illness the cycle length, or time from the onset of one episode to the onset of the next, tends to shorten. Specifically, whereas the duration of the episodes themselves tends to be stable, the euthymic interval Mixed-Manic Episode
shortens, so episodes come progressively closer together. With time, however, the duration of the euthymic interval Mixed-manic episodes are not as common as manic episodes or depressive episodes, but tend to last longer. Here one sees various admixtures of manic and depressive symptoms, Patients who have four or more episodes of illness in any one sometimes in sequence, sometimes simultaneously. Euphoric year are customarily referred to as “rapid cyclers.” Although patients, hyperactive and pressured in speech, may suddenly only about 10% of all patients with bipolar disorder display plunge into despair and collapse weeping into chairs, only to such a pattern of rapid cycling, these patients are nevertheless rise again within hours to their former elated state. Even clinically quite important as they tend to be relatively more extraordinary, patients may be weeping uncontrollably, “resistant” to many currently available treatments. On the with a look of unutterable despair on their faces, yet say that other extreme, the euthymic interval may be so long, lasting they are elated, that they never felt so well in their lives, and many decades, that the patient dies before the second episode is “due,” thereby having only one episode of illness during an COMPLICATIONS
In mania, spending sprees and ill-advised business ventures The sequence of episodes is also quite variable among may land patients in serious debt, or even bankruptcy. patients. Rarely would one find a patient whose course is Hypersexuality may lead to unplanned and unwanted characterized by regularly alternating manic and depressive pregnancies or ill-considered marriages. A reckless episodes; most patients show a preponderance of either exuberance may carry the patient past all speed limits and depressive episodes or of manic ones. For example, in an into conflict with the law; accidents are common. Irritable extreme case a patient may have throughout life perhaps six manics are likewise often in conflict with the law and may depressive episodes and only one manic one. On the other pick fights and create disputes with whomever they come in extreme, another patient might have up to a dozen episodes contact. Friendships may be broken, and divorce may occur. of mania and only one depressive one. Indeed one may encounter a patient who has only manic episodes and never any depressive ones. Such “unipolar manic” patients are very Suicide occurs in from 10 to 20% of patients with bipolar rare. In general, a depressive preponderance is more common disorder and appears to be more common in those who have only hypomanic episodes (i.e., those with bipolar II disorder) than in those whose manic episodes progress beyond the first stage (i.e., those with bipolar I disorder). Although most As noted earlier, for most patients the interval between suicides appear to occur during episodes of depression, episodes is euthymic and free of symptoms. In at least a patients in a mixed-manic episode may be at an even higher quarter of all cases, however, the interval may be “colored” by very mild symptoms, and the direction of this “coloring,” or its “polarity,” correlates with the preponderance of episodes. For example, a patient with very mild The complications of a depressive episode are as outlined in subhypomanic symptoms during the interval is likely to have more manic episodes than depressive ones, and the converse holds true for the patients whose interval is clouded with ETIOLOGY
mild depression or fatigue. In general, among women the preponderance of episodes are depressive; among men, manic. Genetic factors almost certainly play a role in bipolar disorder. A higher prevalence of bipolar disorder exists among the first-degree relatives of patients with bipolar In perhaps a quarter of all cases, the course exhibits disorder than among the relatives of controls or the relatives “coupling.” Here a manic episode may invariably and of patients with major depression, and the concordance rate immediately be followed by a depressive one, or vice versa. among monozygotic twins is significantly higher than that In such cases the transition from one episode to the next may among dizygotic twins. Similarly and most tellingly, be marked by a mixture of symptoms, as if the various adoption studies have demonstrated that the prevalence of symptoms of the preceding episode trailed off at different bipolar disorder is several-fold higher among the biologic rates, while the various symptoms of the following episode parents of bipolar patients than among the biologic parents of appeared also at varying rates, such that the two coupled episodes in a sense overlapped and interdigitated with each other, with this interdigitation presenting as the mixture of symptoms. Such “overlap” or transitional experiences must, Genetic studies in bipolar disorder have been plagued by as noted earlier, be distinguished from mixed-manic episodes failures of replication. In all likelihood, multiple genes on multiple different chromosomes are involved, each conferring a susceptibility to the disease. Occasionally, one may find bipolar patients in whom certain conditions, pharmacologic and otherwise, can more or less Autopsy studies, likewise, have often yielded inconsistent reliably precipitate a manic episode. These include results. Perhaps the most promising finding is of a reduced serotoninergic agents such as tryptophan or 5- neuronal number in the locus ceruleus and median raphe hydroxytryptophan; noradrenergic agents, such as cocaine, stimulants, or sympathomimetics, or situations in which noradrenergic tone is increased as in alcohol or sedative- Endocrinologic studies have yielded robust findings, similar hypnotic withdrawal or in the abrupt discontinuation of long- to those found in major depression, including non- term treatment with clonidine; dopaminergic agents such as suppression on the dexamethasone suppression test and a L-dopa or bromocriptine; and treatment with exogenous steroids, such as prednisone. Older antidepressants, such as the MAOIs and tricyclics, are particularly notorious for precipitating manic episodes in bipolar patients, and some Other robust findings include a shortened latency to REM evidence suggests that these antidepressants, in addition to sleep upon infusion of arecoline and the remarkable ability of being capable of precipitating a manic episode, may also alter intravenous physostigmine to not only bring patients out of the fundamental course of bipolar disorder and increase the mania but also to cast them down past their baseline and into frequency with which future episodes occur: newer antidepressants, such as SSRIs, bupropion and venlafaxine, do not appear as likely to precipitate mania. Phototherapy Taken together, these findings are consistent with the notion may also induce manic episodes in those patients whose that bipolar disorder is, in large part, an inherited disorder course exhibits a “seasonal pattern.” characterized by episodic perturbations in endocrinologic, noradrenergic, serotoninergic and cholinergic function, with these in turn possibly being related to subtle microanatomic changes in relevant brainstem structures. DIFFERENTIAL DIAGNOSIS
very long prodrome to bipolar disorder. Thus continued observation over many years may necessitate a diagnostic revision if a manic episode should ever occur. In distinguishing bipolar disorder from other disorders, the single most useful differential feature is the course of the illness. Essentially no other disorder left untreated presents The differential between a postpartum psychosis and a with recurrent episodes of mood disturbance at least one of bipolar disorder that has become “entrained” to the which is a manic episode, with more or less full restitution to postpartum period is discussed in that chapter. normal functioning between episodes. Thus if the patient in question has had previous episodes and if the available history is complete, then one can generally state with The persistence of very mild affective symptoms between certainty whether the patient has bipolar disorder. However, episodes might suggest, depending on the polarity of the symptoms, a diagnosis of dysthymia or of hyperthymia. Here, these are two big “ifs,” and in clinical practice history may either be absent or unobtainable, and herein arises diagnostic however, temporal continuity of these symptoms with a full episode of illness betrays their true nature, that of either a prodrome or of a condition of only partial remission of a prior episode. Occasionally a patient in a manic episode is brought to the emergency room by police with no other history except that he was arrested for disturbing the peace. If the patient is in The distinction between a depressive episode occurring as part of a major depression and one occurring as part of the stage of acute mania with perhaps irritability and delusions of persecution, one might wonder if the patient is bipolar disorder is considered in the chapter on major currently in the midst of the onset of paranoid schizophrenia or of its exacerbation. Here the behavior of the patient when left undisturbed is helpful: left to themselves, patients with TREATMENT
paranoid schizophrenia often sit quietly, patiently waiting for the next assault, whereas patients with acute mania continue to display their hyperactivity and pressured speech. If the The overall treatment of bipolar disorder is conveniently patient is in the stage of delirious mania, the differential approached by considering, in turn, the treatment of the would include an acute exacerbation of catatonic manic or mixed-manic episode first, then the treatment of the schizophrenia and also a delirium from some other cause. depressive episode, in each instance considering three phases The quality of the hyperactivity seen in the excited subtype of treatment: acute, continuation, and preventive. As will be of catatonic schizophrenia is different from that seen in seen, of all the medications useful in bipolar disorder, lithium mania. The catatonic schizophrenic, no matter how frenzied, is probably the best choice as it is the only one which has remains self-involved and has little contact with those around been shown to be effective for all three phases of treatment him. By contrast, manic patients, no matter how fragmented their behavior, show a desire and a compelling interest to be involved with others. In the highest grade of delirious mania, Manic or Mixed-Manic Episodes
the patient, as noted earlier, may lapse into a confusional stupor. At this point, the differential becomes very wide, as discussed in the chapter on delirium. At times, a “cross- Acute Treatment.
sectional” view of the patient, say in the emergency room, may allow an accurate diagnosis; however, a “longitudinal” The acute treatment of a manic or mixed-manic episode view is always more helpful. As noted earlier, all patients in almost always involves the administration of either a mood delirious mania or acute mania have already passed from stabilizer (i.e., lithium, valproate or carbamazepine) or an relatively normal functioning through the distinctive stage of antipsychotic (i.e., olanzapine, risperidone, aripiprazole, mania. Obtaining a history of this progression from normal quetiapine or ziprasidone), or most commonly, a combination through and past stage I hypomania allows for a more certain of a mood stabilizer and an antipsychotic. Although there are no hard and fast rules for choosing among these agents, some general guidelines may be offered. Certainly, if the patient The distinction between secondary mania and a manic has a history of an excellent response to a particular agent, episode of bipolar disorder is discussed in that chapter. then it should be seriously considered. Lacking such a history, and assuming there are no significant contraindications, the first choice among the mood stabilizers At times patients with schizoaffective disorder, bipolar type, is probably lithium, as it has the longest track record. may be very difficult to distinguish from those with bipolar Divalproex is a close second, and, in the case of episodes disorder. Here a precise interval history is absolutely with a significant depressive component, and certainly in the necessary. In schizoaffective disorder psychotic symptoms, case of a mixed-manic episode, is actually superior to such as delusions, hallucinations, or incoherence, persist lithium. Another advantage of divalproex is the rapidity with between the episodes, in contrast to the “free” intervals seen which it becomes effective when a “loading” strategy is used, in bipolar disorder. The interval psychotic symptoms seen in with patients often responding in a matter of days, in contrast schizoaffective disorder may be very mild indeed, and thus with the week or two required with lithium. Carbamazepine close and repeated observation over extended periods of time is probably a little less effective than lithium, and, in general, may be required to ascertain their presence. is not as well-tolerated. Among the antipsychotics, the first choice is probably olanzapine in that it has the longest track Cyclothymia may at times present diagnostic difficulty, for it record among these second generation agents in this regard also presents a history of discrete individual episodes. The and has also, in contrast with the other second generation difference is that in cyclothymia the manic symptoms are agents, been shown to be effective in preventive treatment. very mild. The possibility also exists, however, that the apparently cyclothymic patient is presenting, in fact, with a When symptoms are relatively mild, that is to say of need for tapering has not been demonstrated for the other hypomanic intensity, utilization of a mood stabilizer alone agents, prudence dictates the use of a gradual taper here also. may be sufficient. However, when the mania has escalated into stage II or III, a mood stabilizer alone is generally not capable of controlling the clinical storm quickly enough, and Preventive Treatment.
in such cases it is common practice to initiate treatment with a combination of a mood stabilizer and one of the second- The decision to embark on preventive treatment is based on generation antipsychotics. In emergent situations, one may several factors including the following: frequency of also employ one of the protocols outlined in the chapter on episodes, severity of episodes, rapidity with which episodes rapid pharmacologic treatment of agitation. Consideration develop, and side effects of the agent used. Frequent should also be given to ECT: bilateral ECT is effective for episodes, perhaps occurring more than once every 2 years, mania and is indicated when the foregoing treatments are not usually constitute an indication for preventive treatment; a successful or in life-threatening situations where urgent frequency of one every 5 or 10 years, however, may be such improvement is absolutely required. Should ECT be utilized, that the risk to the patient of another episode is outweighed lithium should not be administered concurrently, as it may by the trouble of taking medicine and any attendant side effects. Severe episodes, however, no matter how infrequent, may warrant prevention. Whereas the patient’s employer and Many manic patients require admission to a locked unit. family may be able to tolerate a manic episode limited to a hypomanic stage, a mania that enters a delirious stage is Stimulation, including visitors, mail, and phone calls, should be kept to an absolute minimum, as it routinely exacerbates usually so destructive that it should be guarded against. manic symptoms. Indeed, occasional patients in acute mania, Patients whose episodes tend to develop very slowly, over perhaps weeks or a month, may be able to “catch” themselves still possessed of a few tattered shreds of insight, may demand to be put in seclusion. Isolated from all stimuli, they before their insight and judgment are lost. By making timely gradually improve, although their symptoms only partially application for treatment, they may be able to bring the episode under control on an outpatient basis. Those whose abate. A calm, patient, and nonconfrontive manner is generally best; sometimes sharing the patient’s jokes may be episodes come on acutely over a few days or even hours, calming and helpful in enlisting cooperation. At times, however, are defenseless and thus more appropriate for preventive treatment. however, a “show of force” may be necessary; indeed violent, irritable, and very agitated patients, though completely unfazed by routine measures, may calm down If preventive treatment is elected, then the patient should be immediately upon the appearance of several formidable male treated with a mood stabilizer (lithium, divalproex or orderlies, who, though calm, clearly “mean business.” carbamazepine) or olanzapine. Among the mood stabilizers, lithium has the longest track record and is therefore a reasonable first choice. Divalproex and carbamazepine may also be considered; however, the data supporting the use of Continuation Treatment.
divalproex as a preventive agent are not that good and carbamazepine is generally not very well tolerated. If lithium Once acute treatment has been successful in bringing the is used, it is important to keep the serum level between 0.6 manic symptoms under control, continuation treatment is and 1.0 mEq/L. The optimum dose for valproate and for begun. As noted earlier the average duration of the first carbamazepine for prophylaxis has not as yet been manic episode is about 3 months, and that of a mixed-manic determined; prudence suggests using a dose similar to that episode a little longer. The purpose of continuation treatment which was effective for continuation treatment. When is to prevent a breakthrough of symptoms until such time as “breakthrough” symptoms of mania occur it is imperative to the episode itself has run its course. Generally this is determine the patient’s thyroid status: hypothyroidism, even accomplished by continuing the regimen that was effective if manifest by only a slight rise in TSH, will blunt the during the acute phase. If lithium is used it may be necessary response to any mood stabilizer, and must be corrected. during the continuation phase to reduce the dose. In many When breakthrough mania occurs despite normal thyroid patients even though the dose of lithium is held constant, the status and good compliance, consideration may be given to blood level rises when the manic symptoms eventually come switching to monotherapy with another mood stabilizer or to under complete control. The unexpected appearance of side using a combination of mood stabilizers such as lithium plus effects to lithium may indicate this and should prompt a divalproex or lithium plus carbamazepine. Given the blood level determination. If ECT were used, a mood possibility of such “breakthrough” manias, it is generally stabilizer should be started after treatment is terminated. prudent, in the case of reliable patients being maintained on a mood stabilizer, to prescribe a supply of adjunctive medication (e.g., olanzapine) to take at home in order to abort If the patient decides not to enter into a preventive phase of an episode and obviate the need for admission. In this regard, treatment, one must estimate when the patient’s current outpatients should be clearly instructed to call the physician episode, in all likelihood, will go into a spontaneous should they even experience a “hint” of manic symptoms. remission. A prior history of manic episodes may provide Olanzapine has recently been shown to be effective in some guidance here; if that is lacking, one is guided by the preventive treatment, and thus may be considered as an duration of an average episode, mentioned earlier. Clearly, if alternative to a mood stabilizer. It must be borne in mind, the patient is having breakthrough manic symptoms, no however, that, as compared with the mood stabilizers, matter how mild, treatment should continue. Furthermore, especially lithium, the experience with olanzapine is limited; even when the estimated date of remission has passed, one furthermore, emerging data regarding the risks of diabetes should continue treatment if the patient’s life is unstable, and and hyperlipidemia with olanzapine may also temper wait until a period of relative stability has occurred before enthusiasm for the long-term use of this agent. exposing the patient to the risk, however small, of relapse. If lithium was utilized, it is important to taper the dose over a few weeks time, as it appears that abrupt discontinuation of As noted in the section on course, various pharmacologic lithium predisposes to a recurrence of mania. Although the conditions, such as the use of sympathomimetics, the abrupt discontinuation of long-term treatment with clonidine, and Other Treatment Considerations
the like, may precipitate manic episodes, and these conditions should be avoided whenever possible. Furthermore, as noted earlier, insomnia, or simply voluntarily going without sleep, Pregnancy.
may also precipitate a manic episode, and consequently, good sleep hygiene should be promoted. Pregnancy constitutes a special challenge in the treatment of bipolar disorder. None of the mood stabilizers are safe during Recently it has been shown that cognitive behavioral therapy pregnancy (especially the first trimester). First generation antipsychotics, such as haloperidol, are probably less may, when used in conjunction with preventive pharmacologic treatment, reduce the frequency of teratogenic; the teratogenic potential of olanzapine is not as breakthrough episodes. The mechanism here is not clear, and yet clear. If mania does occur during pregnancy, then the risks to the fetus must be carefully weighed against the risks it also must be kept in mind that no form of psychotherapy is effective for either acute or continuation treatment of mania. inherent in a manic episode. ECT should be carefully considered given that, with proper anesthetic technique, it is of low risk to the fetus. Depressive Episodes
Bipolar women currently in the preventive phase of treatment Acute Treatment.
may often be safely managed into and through a planned pregnancy. Preventive treatment may be continued up to a few days before conception is attempted. If conception does When a depressive episode occurs in a patient with bipolar not occur, preventive treatment is restarted and continued disorder the first step in the acute phase of treatment is to until the couple again wishes to conceive. Once conception ensure that the patient is taking an antimanic drug, such as does occur, preventive treatment is withheld, to be restarted lithium, valproate, or carbamazepine, in a dose that would be immediately upon delivery; indeed, barring obstetric effective in the acute treatment phase of mania. If the complications, it should be restarted within hours. In depression is not severe, one may want to wait 2 or 3 weeks collaboration with the obstetrician, adjunctive treatment is to see if the depressive symptoms begin to clear, as this may then made available should manic symptoms appear. In cases often happen when one of these three agents is used. When where the risk of a relapse of mania is high and outweighs depressive symptoms persist or when they are so severe to the risk to the fetus, one may consider restarting a mood begin with that one cannot wait, one may add an stabilizer after the first trimester. With regard to breast antidepressant or consider adding lamotrigine or perhaps feeding, no firm advice can be given: although maternal use topiramate. Traditionally an antidepressant has been used; of lithium, valproate and carbamazepine have all been rarely however, though effective, all the antidepressants entail the associated with adverse effects in breast-fed infants, large, risk of precipitating a manic episode; a strategy for choosing controlled studies are lacking. Consequently the decision to and utilizing an antidepressant is discussed in the chapter on breast feed or not should be made in light of the entire major depression. Neither lamotrigine nor topiramate carry a clinical picture, including the mother’s illness and response risk of inducing a manic episode, and between the two, the evidence for the effectiveness of lamotrigine is much stronger. In mild cases of depression, one may also consider the use of cognitive-behavioral therapy. Substance Use.
Continuation Treatment.
As noted earlier, alcohol abuse or alcoholism and cocaine addiction are not infrequently associated with bipolar disorder, and these must also be treated. Once the depressive symptoms are relieved, treatment should be continued until the patient has been asymptomatic for a significant period of time. If an antidepressant were added to a mood stabilizer, one should probably consider discontinuing the antidepressant after the patient has been BIBLIOGRAPHY
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The Depakote Mania Study Group. The Journal of the American Medical Association 1994;271: 918–924. Lithium, carbamazepine and lamotrigine are all effective in preventing future depressive episodes. Preventive treatment Bowden CL, Calabrese JR, McElroy SL, et al. A randomized, with antidepressants in bipolar disorder is generally not placebocontrolled 12-month trial of divalproex and lithium in justified, given the ongoing risk of precipitating a manic treatment of outpatients with Bipolar I disorder. Divalproex Maintenance Study Group. Archives of General Psychiatry 2000;57:481–489. Bunney WE, Murphy D, Goodwin FK, et al. The “switch process” in manic depressive illness. I. A systematic study of McElroy SL, Keck PE, Stanton SP, et al. A randomized sequential behavior change. Archives of General Psychiatry comparison of divalproex oral loading versus haloperidol in the initial treatment of acute psychotic mania. The Journal of Clinical Psychiatry 1996;57:142–146. Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind placebo-controlled study of lamotrigine in outpatients with McIntyre RS, Mancini DA, McCann S, et al. Topiramate bipolar I depression. Lamictal 602 Study Group. The Journal versus bupropion SR when added to mood stabilizer therapy of Clinical Psychiatry 1999;60:79–88. for the depressive phase of bipolar disorder: a preliminary single-blind study. Bipolar Disorders 2002;4:207–213. Carlson GA, Goodwin FK. The stages of mania: a longitudinal analysis of the manic episode. Archives of Meehan K, Zhang F, David S, et al. A double-blind, General Psychiatry 1973;28:221–228. randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo Chaudron LH, Jefferson JW. Mood stabilizers during in treating acutely agitated patients diagnosed with bipolar breastfeeding: a review. The Journal of Clinical Psychiatry mania. Journal of Clinical Psychopharmacology 2001; Craddock N, Jones I. Molecular genetics of bipolar disorder. Mukherjee S, Sackheim HA, Schnur DB. Electroconvulsive The British Journal of Psychiatry 2001;(Suppl 41):128–133. therapy of acute manic episodes: a review of 50 years’ experience. The American Journal of Psychiatry Gelenberg AJ, Kane JM, Keller MB, et al. Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. The New England Journal of Muller-Oerlinghausen B, Berghofer A, Bauer M. Bipolar disorder. Lancet 2002;359:241–247. Goodwin FK. Rationale for long-term treatment of bipolar Swann AC, Bowden CL, Morris D, et al. Depression during disorder and evidence for long-term lithium treatment. The mania. Treatment response to lithium or divalproex. Archives Journal of Clinical Psychiatry 2002;63(Suppl 10):5–12. of General Psychiatry 1997;54:37–42. Greil W, Ludwig-Mayerhofer W, Erazo N, et al. Lithium Tohen M, Baker RW, Altshuler LL, et al. Olanzapine versus versus carbamazepine in the maintenance treatment of divalproex in the treatment of acute mania. The American bipolar disorders—a randomized study. Journal of Affective Journal of Psychiatry 2002;159:1011–1017. Tohen M, Ketter TA, Zarate CA, et al. Olanzapine versus Himmelhoch JM, Mulla D, Neil JF, et al. Incidence and divalproex sodium for the treatment of acute mania and significance of mixed affective states in a bipolar population. maintenance of remission: a 47-week study. The American Archives of General Psychiatry 1976;33:1062–1066. Journal of Psychiatry 2003;160:1263–1271. Janowsky DS, El-Yousef K, David JM, et al. Zajecka JM, Weisler R, Sachs G, et al. A comparison of the Parasympathetic suppression of manic symptoms by efficacy, safety, and tolerability of divalproex sodium and physostigmine. Archives of General Psychiatry 1973;28:542– olanzapine in the treatment of bipolar disorder. The Journal of Clinical Psychiatry 2002;63:1148–1155. Joffe RT, MacQueen GM, Marriott M, et al. Induction of mania and cycle acceleration in bipolar disorder: effect of different classes of antidepressant. Acta Psychiatrica Scandinavica 2002;105:427–430. Keck PE, Versiani M, Potkin S, et al. Ziprasidone in the treatment of acute mania: a three-week, placebo-controlled, double-blind, randomized trial. The American Journal of Psychiatry 2003;160:741–748. Kramlinger KG, Post RM. Adding lithium carbonate to carbamazepine: antimanic efficacy in treatment-resistant mania. Acta Psychiatrica Scandinavica 1989;79:378–385. Lam DH, Watkins ER, Hayward P, et al. A randomized controlled study of cognitive therapy for relapse prevention for bipolar affective disorder: outcome of the first year. Archives of General Psychiatry 2003;60:145–152. Lipkin KM, Dyrud J, Meyer GG. The many faces of mania: therapeutic trial of lithium carbonate. Archives of General Psychiatry 1970;22:262–267. Lusznat RM, Murphy DP, Nunn CM. Carbamazepine vs lithium in the treatment and prophylaxis of mania. The British Journal of Psychiatry 1988;153:198–204.

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Research Article Effect of Whole Body Massage by Patient's Companion on the Level of Blood Cortisol in Coronary Patients: A Randomized Controlled TrialMohsen Adib-Hajbaghery 1, *, Rahman Rajabi-Beheshtabad 2, Ali Abasi 31 Trauma Nursing Research Center, Kashan University of Medical Sciences, Kashan, IR Iran2 Department of Nursing, Dehdasht Imam Khomeini Hospital, Yasouj University of Medical

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Animal Reproduction Science 78 (2003) 99–110Role of estradiol-17␤ on nuclear and cytoplasmica Animal Reproduction Laboratory, Embrapa Genetic Resources and Biotechnology, Parque Estação Biológica, Avenue W5 Final Norte, Bras´ılia CEP 70770-900, DF, Brazil b Department of Animal Science, University of Illinois, 1207 West Gregory Drive, Urbana, IL 61801, USA Received 3 September

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