Clinical and evolutional aspects in bipolar disorder, manic episode (1)

Acknowledgement:
“This paper is published under the frame of European Social Fund, Human Resources Development Operational P r o g r a m m e 2 0 0 7 – 2 0 1 3 , p r o j e c t n o . POSDRU/159/1.5/S/138776″/ “Acest articol este publicat prin Fondul Social European, Programul Operational Dezvoltarea Resurselor Umane 2007-2013, contract nr. POSDRU/159/1.5/S/138776”

To understand the maniac-depressive illness, to diagnose it precisely and to treat it in an efficient way, it is necessary to get familiarized to what Kraepelin called “common fundamental features” of the disease.
The models of maniacal and depressive symptoms clearly have a cyclic character, but the aspects of overlapping, transition as well as the fluctuating ones are extremely important in the description and understanding of the entire disease. Thus, Kraepelin (1) wrote: “The delimitation of the individual clinical forms of the malady is in many respects wholly artificial and arbitrary. Observation not only reveals the occurrence of gradual transitions between all the various states, but it also shows that within the shortest space of time the same morbid case may pass through most manifold transformations”.
Manic states are usually characterized by heightened mood, more and faster speech, quicker thought, brisker physical and mental activity levels, greater energy (with a corresponding decreased need for sleep), irritability, perceptual acuity, paranoia, heightened sexuality and impulsivity. The degree, type and chronicity of these cognitive, perceptual and behavioral changes determine the major sub-classification of mania, namely hypomania or mania. In hypomania, the above changes are generally moderate and may or may not result in serious problems for the individual experiencing them. In more intense episodes, however, they deeply disrupt the lives of patients, their families and society.
Mood in acute mania is not well described by the classic writers, perhaps because extreme changes in cognition and behaviour are more clearly observable than subjective mood states. However, two thousand years ago, Aretaeus of Cappadocia noted that those who are manic are gay, active and expensive. They are naturally joyous, they laugh and they joke: “they show off in public with crowned heads as if they were returning victorious from the games; sometimes they laugh and dance all day and all night” (2). Kraepelin (1), writing centuries later agreed, but stressed the instability of the manic mood: “Mood is unrestrained, merry, exultant, occasionally visionary or pompous, but always subject to frequent variation, easily changing to irritability and irascibility or even to lamentation and weeping”.
Bleuler (3) commented that thought remains relatively intact in the less severe forms of mania: “The thinking of the manic is flighty. He jumps by by-paths from one subject to another, and cannot adhere to anything. With this the ideas run along very easily and involuntarily, even so freely that it may be felt as unpleasant by the patient. . . . Because of the more rapid flow of ideas, and especially because of the falling off of inhibitions, artistic activities are facilitated even though something worth while is produced only in very mild cases and when the patient is otherwise talented in this direction”.
Thinking becomes fragmented and often psychotic in acute mania. Coherence gives way to incoherence; rapid thinking proceeds to racing and disjointed thinking; distractibility becomes all-pervasive. Paranoid and grandiose delusions are common, as are illusions and hallucinations. In Kraepelin’s description (1), patients show themselves sensible and approximately oriented but extraordinarily distractible in perception. Sometimes it is quite impossible to get into communication with them; they usually understand emphatic speech and even give isolated suitable replies, but they are influenced by every new impression; they digress and go into endless details. Activity and behavior are greatly increased and diversified in mania. Patients appear to be indefatigable; they are rash, virulently opinionated and interpersonally aggressive. For many patients, excessive energy translates directly into pressured writing in an inordinate production of written declarations, poetry and artwork.
The progression from hypomania to acute mania is usually accompanied not only by instability of mood and a sense of impending doom or premonitions of madness, but also by increasingly erratic behaviour. Rush (4) made this clear in his monograph Medical Inquiries and Observations upon the Diseases of the Mind: “Its premonitory signs are watchfulness, high or low spirits, great rapidity of thought, and eccentricity in conversation and conduct; sometimes pathetic expressions of horror, excited by the apprehension of approaching madness; terrifying or distressing dreams; great irritability of temper, jealousy, instability in all pursuits; unusual acts of extravagance manifested by the purchases of houses, and certain expensive and unnecessary articles of furniture and hostility to relations and friends”. Sexual or erotic excitement is common in mania. Aretaeus of Cappadocia (150 AD) (5), for example, wrote that “a period lewdness and shamelessness” exists in mania. Likewise, Kraepelin (1) noted that sexual excitability “is increased and leads to hasty engagements, marriages by the newspaper, improper love adventures, conspicuous behaviour, jealousy and matrimonial discord”.
Particularly dramatic and extreme among the clinical features of acute mania are the frenetic seemingly aimless and occasionally violent activities of manic patients. Bizarre, driven, paranoid, impulsive and grossly inappropriate behaviour patterns are typical.
Delirious mania, or Bell’s mania, is a relatively rare grave form of mania characterized by severe clouding of consciousness. When Bell (6) described the syndrome at the middle of the 19th century, he noted its sudden onset and the symptoms of severe insomnia, loss of appetite, disorientation, paranoia and extremely bizarre hallucinations and delusions. Kraepelin (1) also remarked the syndrome’s acute onset and noted that patients were “stupefied, confused, bewildered”, in addition to being completely disoriented in terms of time and place. At the basis of the illness he found a “dreamy and profound clouding of consciousness, and extraordinary and confused hallucinations and delusions”. Griesinger (7) also emphasized the acute onset of the syndrome and observed that the primary emotion experienced by patients is anxiety. Bond (8) noted that acute delirious mania can be distinguished by its sudden onset, with or without premonitory signs of irritability, insomnia or emotional withdrawal; the presence of the hypomanic or manic syndrome at some point during the illness; development of the signs and symptoms of delirium, a personal and/or family history of mania or depression, and responsiveness to standard treatments for mania.
Mood during delirious mania may shift quickly between extreme melancholia and mania suggesting a clinical link to mixed states. In Kraepelin’s (1) words, mood is “very changing, sometimes anxiously despairing (“thoughts of death”), timid and lachrymose, distracted, sometimes unrestrainedly merry, erotic and ecstatic, sometimes irritable or unsympathetic and indifferent”. The extreme cognitive and perceptual changes during delirious mania are primarily manifested through clouding of consciousnesses, hallucinations and delusions. The profoundly disturbed and psychotic behaviour of delirious mania underlines the origin of the phrase “raving maniac”. Chronic mania was observed and described by many early clinicians, including Pinel (9), Esquirol (10), Griesinger (7), Schott (11), Kraepelin (1), and Wertham (12). According to Schott (11), only the lack of recovery distinguished the chronic from the acute form of the illness. A first manic episode after the age of 40 was thought to put the patient at much higher risk for chronicity than one occurring earlier (13), an observation consistent with the result of subsequent research. Wertham (12) presents the central features of chronic mania: reduced intellectual productivity and general activity levels, increased behavioral stereotypy, and a general intellectual weakening. Hare (14), in an excellent historical review of the concept of mania, discussed the declining interest in the subject of chronic mania after the 19th century. He partially attributed it to the decreasing morbidity of manic illness and sustained that improvements in general health and hygiene has resulted in significant changes in the manifestation, severity and consequences of mania. (15)
T h e s e v e n B c r i t e r i a f o r t h e d i a g n o s t i c o f mania/hypomania may be reminded by DIGFAST mnemonic formula. Mania / hypomania are present when three (if mood is euphoric) or four DIGFAST criteria (if mood is irritable) are present. In mania, unlike hypomania, there is a significant dysfunction in the social and/or professional field. Thus, a patient having a corresponding number of DIGFAST criteria and who is not deteriorated or a psychopath or who does not need hospitalization may be considered in a hypomanic episode. (16)
DIGFAST mnemonic formula for Mania / Hypomania:
·Distractibility: the incapacity to stay focused on a task for a long time
·Sleep deficit: reduced need for sleep coupled with the increase of energy in manic/hypomanic patients (it must be differentiated from insomnia from the major depressive episode)
· G r a n d i o s i t y : h i g h , n o n – r e a l i s t i c s e l f – t r u s t o r hallucinations
·Flight of ideas: speedy thoughts
·Activity increase: excessive increase of activity for a goal in the social or sexual field, school or work
·Talkativeness: significantly more talkative than in the euthymia periods
·Indiscretion: dysfunctional activities focused on one’s self such as excessive expenses, unprotected sex with foreigners and other impulsive behaviours. (16)
Mania is a complex volatile and fluctuating mixture of symptoms. “The form and ways which mania manifests are manifold” said Aretaeus (5) nearly 2000 years ago. “Some are cheerful and like to play … others passionate and of destructive type who seek to kill others as well as themselves”. Although classically described as a state of extraordinary energy and activity, mania can also present clinically as manic stupor or “catatonia”.
Manic mood, frequently characterized as elated and grandiose, as often as not is riddled with depression, panic and extreme irritability; mania without significant mixed features is what is known as “classic mania”. For years, mania was differentiated mistakenly from schizophrenia because it reputedly lacked a thought disorder. Now it is recognized as an often floridly psychotic condition.
Manic episodes differ from person to person and in the same individual from time to time, although Falret (17, 18) and Kraepelin (1) noted a tendency for constancy in symptom patterns across episodes in the same individual. Wellner and Marstal (19) reporting on a study of 279 manic episodes in 221 patients, concluded that “atypical attacks are followed by atypical, and typical by typical significantly more often than not (P = 0.002), indicating the patients’ inclination to reproduce the type of their psychoses”. Beigel and Murphy (20) found that patients with multiple manic attacks tended to show similar behavior and mood patterns during subsequent episodes. Two more recent studies (21, 22) demonstrated that manic and mixed episodes show diagnostic stability over time; the interepisode stability of depressive mixed states, while significant, is much less pronounced than is the case for manic states (23).
Goodwin and Jameson (15) wrote that the symptomatic profile of catatonia is extremely consistent over episodes, whereas Casidy and colleagues (24), who evaluated 77 bipolar patients during two distinct manic episodes for 2 years, concluded that manic symptomatology generally remains consistent from one episode to the other. More precisely, they found out that the severity of mania, dysphoria, hedonic activation, psychosis and irritable aggression tend to correlate to each other over episodes, but not psychomotor symptoms. Regardless of the degree of constancy of the clinical picture across attacks, it is clear that symptoms vary widely during any given manic episode as it progresses through different stages. These stages, characterized by Carlson and Goodwin (25), begin with elation or irritability, evolve into a more severe form of arousal and hyperactivity escalate, and culminate in floridly psychotic disorganization.
Research (15) on mood symptoms in mania, shows that most patients, on average, are depressed (46 percent) or labile (49 percent) nearly as often as they are euphoric (63 percent) or expansive (60 percent); they are irritable (71 percent) even more often. The depression, irritability and mood lability are generally seen less often in early stages of an episode, although few studies have specified the stage, level or severity of mania at the time of observation. Winokur and colleagues (26) observed depressed mood in 68 percent of their manic patients. They found that “short depressive contaminations in the manic episode” were significantly more common in women (79 percent) than in men (49 percent). Like many investigators, they were especially impressed by the volatility of mood during manic episodes.
Nonpsychotic cognitive symptoms are common during mania. Grandiosity and flight of ideas – subjectively experienced as racing thoughts – were observed in approximately three quarters of the manic patients. Less clearly and more variably defined were distractibility, poor concentration and confusion. Definitions were very wide-ranging for confusion – from “somewhat confused an unable to follow the gist of conversation” to the more severe clinical use of the term to denote disorientation and serious memory disturbance. (15)
Here we use as a definition of thought disorder the one provided by Solovay and colleagues (27): thought disorder “is not intended to denote a unitary dimension or process; rather, it refers to any disruption, deficit or slippage in various aspects of thinking, such as concentration, attention, reasoning or abstraction”. Certain psychotic features of mania and bipolar depression – delusions and hallucinations – are relevant but not central to the concept of thought disorder. Andreasen (28) noticed that most manic patients, unlike schizophrenic patient, have a reversible thought disorder. Apart from a continuous pressure to speak, they showed an almost complete recovery over time. Hallucinations occur less frequently than delusions in both the manic and depressed phases of bipolar illness. Hallucinatory phenomena seem to represent the extreme end of the symptomatic picture, being nonexistent in milder forms of depression and mania and most pronounced in the gravest (most delirious) states. Hallucinations during mania are often ecstatic and religious in nature, brief and fleeting in duration and inconstant in their modality of expression. They appear qualitatively, at least in the few studies in which they have been approached, to be more similar to organic than to schizophrenic psychoses. Gender differences in the experience of hallucinatory phenomena are unclear, though there is some evidence that women are more likely to report having had hallucinations.
Like Bauer and colleagues (29), Akiskal and colleagues (30) concluded that rather than euphoria/irritability, the central defining focus of mania should be psychomotor activation. This conclusion is consistent with the emphasis of Heinroth (31) and Koukopoulos (32), which says that excitement is the fundamental state of the bipolar subgroup of manic-depressive illness. By incorporating new features of mania derived from EPIMAN study (30) (for example, pathological gregariousness and overfamiliarity) and using clinical expertise, different groups of investigators have developed a factorial structure of mania that incorporates psychomotor activation as the major criterion, along with mood disturbance, other signs and symptoms, and a lack of insight and judgment. Practically, all investigations of mania structure noticed the basic dimensions: a mood component characterized as preponderantly euphoric or dysphoric, psychomotor activation, psychotic features and irritability and/or aggression.
As noted earlier, Carlson and Goodwin (25) described progressive stages of mania, from mild hypomania to delirious psychotic mania. The stages were inferred from a study of 20 unmedicated bipolar patients who had experienced a manic episode at some time during their hospitalization. Patients’ longitudinal course was divided into three stages, with predominant mood as the primary criterion – from the euphoria of stage I to the anger and irritability of stage II, to the severe panic of stage III. In some of the patients, the onset of mania (the switch) was gradual, clearly unfolding in a sequence until the full syndrome had developed. In others, the onset was sudden and dramatic; even in these cases, the earlier stages were present and transient. According to Carlson’s and Goodwin’s affirmations (25), the initial phase of mania (stage I) typically is characterized by increased activity; by a labile mood that can be euphoric, irritable or both; and by expansive, grandiose and overconfident thoughts. Thinking remains coherent but is often tangential. Patients describe this change as “going high” and frequently report racing thoughts. In some cases, “high” does not go beyond stage I which corresponds to hypomania. But many episodes progress to the next stage. Psychomotor activity increases – evident in the more rapid speech – and the mood state becomes more labile, characterized by a mixture of euphoria and dysphoria. Irritability turns into open hostility and anger and the accompanying behavior often is explosive and assaultive. As racing thoughts progress to a definite flight of ideas, cognition becomes increasingly disorganized. Preoccupations intensify with grandiose and paranoid trends that are apparent as delusions. This level, which corresponds to acute mania, is referred to as stage II.
In some patients, the manic episode progresses further to an undifferentiated psychotic state (stage III) experienced by the patient as clearly dysphoric, usually terrifying and accompanied by frenzied movement. Thought processes that earlier had been difficult to follow become incoherent and definite loosening of associations is often seen. Delusions are commonly bizarre and idiosyncratic, and s o m e p a t i e n t s e x p e r i e n c e i d e a s o f r e f e r e n c e , disorientation and delirium-like state. This phase of the syndrome is difficult to distinguish from other acute psychoses, at least superficially. In general, as the manic episode unfolds, stage I is dominated by elation (or irritability) and grandiosity, stage II by increasing hyperactivity and arousal, and stage III by florid psychotic disorganization. In the Carlson and Goodwin study (25), many of the rated items showed continuous distributions, whereas others showed definite thresholds involving apparently qualitative shifts. The level of psychomotor activity escalated continuously through all three stages and ratings for manic mood increased in a similar way through stages I and II. Ratings of psychosis, by contrast, were not clearly distributed along a continuum. As can be seen, stage III mania was characterized by the relatively abrupt and initial appearance of hallucinations, formal thought disorder in Schneiderian sense and organic delirium. Bipolar affective disorder is a lifelong illness having a variety of forms, phases and subdivisions. (33) Bipolar disorder is frequently unrecognized, erroneously diagnosed and inadequately treated. A survey on the members of US bipolar association “Chapters” showed that more than 33% asked for professional help within one year since the appearance of symptoms. Out of these, 69% were erroneously diagnosed (especially suffering from unipolar depression), and there was an average of four physicians seen before obtaining a precise diagnostic and more than 33% waited for more than 10 years before getting a diagnostic (33), a finding astonishingly similar to the previous survey. (33)
As in many research domains, the studies of evolution of the manic-depressive illness involve methodological complexities that should be taken into account when we interpret the results of a study. Two aspects are extremely important.
The first refers to the patient selection. Index hospitalization required in many older studies may cause the overestimation or underestimation of relapses. Underestimation may appear when the patient, during a single hospitalization, experiences several episodes of rapid cycling that are considered as a single episode. On the other hand, overestimation may result from the information gathered from hospitalizations as these exclude patients who experienced a single episode, those who recovered without hospitalization as well as those who have never had a relapse. While some recent studies avoided these issues by recruiting patients from the general community, other samples were elaborated by clinical centers where sicker patients and the patients resilient to treatment are overrepresented. Indeed, the lots from clinical centers are not, by definition, representative since a substantial proportion of bipolar population does not receive treatment at a given moment. The second problem refers to diagnostic. Many of the classical studies regarding the natural evolution of the disease do not make the difference between recurrent bipolar and unipolar subgroups.
Apart from these problems, a traditional methodological issue is the lack of a generally accepted convention for the collection of data regarding the evolution of manic- depressive illness or the definition of recovery and relapse. Standardized methods to track the course of the disease proposed both for retrospective studies (34; 35) and prospective ones (36; 37) have improved this situation, but they are far from being enforced universally. These methods are useful both in the clinical enter and in research. Moreover, associations not recognized beforehand between the debut of the periods and the life events or other stress factors may be helpful in u n d e r s t a n d i n g p s y c h o t h e r a p y a n d b e h a v i o r a l management.
The age when manic-depressive disorder most often starts is important for the genetically vulnerable persons and their physicians and they may give clues about the future evolution. (Goodwin and Jamison, 2007) collected data from 15 studies published after 1990 which reported the average age of 22.2 years upon the diseases onset. As for the gender, the difference between men and women was not significant (38; 39; 40).
It is interesting that after 1990, the average is 6 years less than the weighted average obtained from the 22 pre-1990 studies examined in the first edition (41) while using the same inclusion criteria. Since data are not normally distributed, these figures may be misleading. Averages may be increased by a relatively small number of patients having, for example, a tardy onset. When reporting average age to onset, it usually belongs to the early twenties.
Some of the variations of individual studies are related to different criteria for onset. In general, the age when the first symptoms occur is younger than the age when patients meet the diagnostic criteria, and the age of the first clinical contact is usually higher (the first hospitalization is a measure that says very little about the onset age). Some studies used the age upon the first clinical contact based on the assumption that the information about initial symptoms might be too imprecise.
Indeed the literature is consistent in finding a significant time gap between onset of the illness and the first treatment. Meeks (42) found that mean age at first symptoms in a bipolar and unipolar population was almost 6 years younger than age at first treatment. A demographic study of the first 261 patients in the Stanley Bipolar Foundation (which may represent patients on the more severe end of the spectrum) revealed an 8-year difference between age at first diagnostic and age at first medical treatment (22.9 and 30.4 years, respectively), whereas age at first symptoms was only 2 years before age at diagnostic onset (40). In a Stanley Foundation recruitment survey administered by Kupfer and colleagues (43), more than 50 percent of a large bipolar sample indicated that they had received no treatment for their first affective episode. Thus it is to be expected that age at first treatment is a weak indicator of onset.
The lower age at onset is reported in more recent studies. Researchers have advanced several hypotheses to explain this reduction in age at onset. Changes in nosology and illness definition could be a partial explanation.
The increasing use of antidepressants and stimulants in teenagers and children may help induce the onset of bipolar disorder at an earlier age in those already susceptible (44, 45, 46). This phenomenon might be consistent with what we know about the effect of antidepressants on mania induction and cycle acceleration, but more research is necessary to draw a solid conclusion.
The switch into mania or hypomania may be the consequence of active treatment for bipolar depression, some drugs, such as tricyclic antidepressants and venlafaxine have bigger chances to cause the switch than others. Bu this increase of the switch rate might not be visible until after 10 weeks of treatment. To notice this switch, studies should include scales to define the event phenomenology (e.g. hypomania or mania) and its severity. These may be best used immediately after the clinical finding of switch occurrence. Long-term treatment is usually necessary in the bipolar disorder. (47) Similar to the association of antidepressants is the hypothesis that the increased use of recreational drugs and alcohol among the youth contributes to the decrease of age at onset. Here, again, consistent evidence is missing and it is difficult to establish a unidirectional association between the onset of affective symptoms and the onset of drug consumption. (48)
Very late onset of the bipolar affective disorder (e.g. after 60) has been generally considered rare (49, 50). Patients with very late onset are less likely to have a family history of the disorder and more likely to be organically impaired. Tohen and colleagues (51) compared two groups of elderly patients, one with late onset mania (first episode after age 65) and one with multiple manic episodes before age 65. The first group was significantly more likely to experience neurological abnormalities (15). These observations highlight the importance of differential diagnosis of primary mood disorders and mood disorders that occur secondary to specific neuropathology.
It is not clear yet to what extent grouping patients by age at onset really identifies distinct subgroups with differential phenomenology, pathophysiology, family history, outcomes and/or treatment response. Studies examining family history in early versus late onset groups have generally shown more genetic loading for recurrent mood disorder associated with early onset.11 But age at onset did not differ significantly in several studies comparing patients with mixed and pure mania (52, 53, 54), and it does not appear to be a distinguishing feature of bipolar I versus bipolar II disorder (55). On the other hand, early onset has shown rather consistent correlations with certain clinical features, including rapid cycling, presence of comorbid anxiety disorder, suicidal behavior, psychotic features, and treatment resistance. Carlson and colleagues (56) reported that patients with an early onset (before the age of 19) had significantly worse outcomes on a variety of measures than those with later onset (after the age of 19). (15)
An examination of a large group of Stanley Bipolar Foundation patients showed significant correlations between early onset (up to the age of 17) and greater incidence of learning disabilities, rapid cycling and family history of bipolar disorder (40), while Ernst and Goldberg (57) found that onset below the age of 19 was associated with more rapid cycling and comorbid substance abuse. Engstrom and colleagues (58) reported lower levels of treatment response and significantly greater number of suicide attempts in early versus late onset patients in a Swedish population.
Although the evidence for a connection between early onset and the complicating illness features is compelling, one must be cautious when using cross-sectional studies to distinguish damaging effects of the illness from the so- called “clinical subtype” features. Thus, bad outcomes in early onset patients could be a factor of longer duration of illness rather than a phenotypic characteristic.
Another author described the clinical features, evolution and results during a 1-year period after the first manic episode in the patients with bipolar disorder (BD). The analysis of recurrence of mood episodes showed that 46.7% of patients survived without a mood episode during 1 follow-up year, and the average time until the occurrence of another mood episode was 7.9 months. Early onset was the only variable that predicted significantly the recurrence of mood episodes. When examined separately, survival rates were 76% for a manic episode and 58.7% for a depressive episode.
These results suggest that recurrences are common after the first manic episode, more than half patients experiencing a mood episode within 12 months. Aggressive treatment strategies for the prevention of depressive episodes are necessary in the management of bipolar affective disorder with an early onset. (48)
The association between psychotic features and early onset among bipolar patients has considerable support in the literature. Angst (59) cited 10 studies reporting this relationship, a conclusion supported by Blumenthal and colleagues (60), in their study of the Amish and confirmed by subsequent research (61, 62, 63). Despite all these, adolescent-onset mania is not always associated with psychotic features, as shown by cross-sectional comparison studies (64, 65). A more recent cross-sectional study comparing early with non-early onset groups failed to find a significantly higher presence of psychotic features (66). However, cross-sectional studies cannot determine subsequent development of psychosis and may easily miss prior psychotic features, especially if investigators rely on patient recall. Taken as a whole, the evidence for a connection between psychotic features and younger age at onset is strong.
In another study, twenty-four patients at their first manic episode were followed-up for 4 years after their recovery from the manic episode. Patients did not have prior manic or depressive episodes documented. The presence of psychotic features during the index episode and the alcoholism history were significantly statistic predictors for a shorter period of remission. Occupational status decreased to baseline predicted the poor overall social adaptation after the 4 years (67). Coupled with the association between the deterioration of pre-morbid functioning and the psychosis level discussed above, this evidence supports the hypothesis that the pervasive psychotic features indicate a more severe form of illness which sometimes involves early syndrome manifestations and it is more frequently characterized by pre-morbid deterioration.
Considered together, findings of longitudinal studies of manic-depressive patients not taking prophylactic medication indicate that most patients – especially those studied in the past 35 years – had more than one episode. Most patients with major affective disorder (e.g. manic- depressive illness described by Krepelin) have a recurrent course. Many textbooks, apparently relying on older data, fail to emphasize this point sufficiently. The near-total probability of recurrence is supported by recent research. In a 4-yar naturalistic follow-up study of 75 bipolar patients, only 28 percent remained in remission (68). In the National Institute of Mental Health’s (NIMH) Collaborative Program on the Psychobiology of Depression-Clinical Studies (CDS), relapse into a new episode within 5 years was observed in 81 to 91 percent of patients, the variability in percentage being related to the polarity of the index episode (69).
Some differences among studies relate to varying definitions of what counts as an episode. Some studies underestimate recurrence because they rely only on hospitalization as a marker of episodes. 20 Other studies may be prone to overestimate recurrence because of treatment factors, such as the use of antidepressants and the selection of lithium clinic patients for study.
As for the question on the contribution of antidepressant drugs, it is important to note that the highest relapse rates are generally the most recent. Koukopoulos and colleagues (70) and Wehr and Goodwin (71) suggested that the increased use of antidepressants may have influenced the results. Indeed, in his analysis of the incidence of manic switches in one hospital (studied over six decades), Angst (72) noted a four times increase when the “pretreatment” decades were compared with the decades after ECT and when antidepressant drugs became widely used.
It is clear that wellbeing and functioning are inversely proportional to the number of bipolar episodes and thus the strategies for the reduction of relapses must be observed rigorously, mainly the reduction of bipolar depression difficult to treat (33).Unfortunately, the inadequate use of antidepressants in the undiagnosed bipolar disorder may result in more severe cycling(33). Good compliance is important, but we must be aware of the fact that the deterioration of memory and verbal learning in bipolar disorder might passively limit the adherence to treatment (33).
Optimal results in the bipolar disorder are obtained by an adequate consistent treatment, in concordance with mood stabilizers, personal training to cope with stress and risk factors, and the family support.

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