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(p. 379) Bipolar Disorder in Early Adulthood: Clinical Challenges and Emerging Evidence 

(p. 379) Bipolar Disorder in Early Adulthood: Clinical Challenges and Emerging Evidence
(p. 379) Bipolar Disorder in Early Adulthood: Clinical Challenges and Emerging Evidence

Alan C. Swann

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Subscriber: null; date: 13 December 2018

Ms. Y is a 24-year-old woman, recently evaluated in outpatient clinic after relocating. Her chief complaint was ‘‘I have severe attention problems and can’t hold down a job.’’ She was currently taking a norepinephrine reuptake blocker commonly used to treat attention-deficit disorder. In brief, she had done well in elementary school, with good grades, and a few regular friends. During high school, she developed periods of being restless, with poor concentration, and severely variable mood. In her initial psychiatric evaluation she received the diagnosis of depressive disorder and was treated with an SSRI. Restlessness and agitation increased, and she received a second evaluation, diagnosed as attention-deficit disorder. She was treated first with methylphenidate, then with the norepinephrine reuptake blocker. She stated that these treatments improved her attention problem. Meanwhile, she graduated from high school and was able to complete an Associate’s degree course at a local junior college. After graduating, she found work successfully, but she lost a succession of jobs due to sporadic attendance, inconsistent performance, and conflict with supervisors. She is currently unemployed and moved because her boyfriend was transferred. Further history revealed no problematic drug use or legal problems. Family history was positive for ‘‘hyperactivity’’ (her mother), depression, and substance use. On interview, she was casually dressed and cooperative. She was quite restless. She spoke rapidly and described racing thoughts. Her eyes were usually full of tears and she said she could cry at any moment. She was not currently suicidal but said she got no pleasure form her many activities, and that she must be an incompetent person and a misfit, because of her employment problems. Detailed history revealed that she had, in the past, met criteria for major depressive episodes and for hypomanic episodes, and she currently met criteria for both. She had never met criteria for attention-deficit/ hyperactivity disorder.


Bipolar disorder is a potentially devastating illness that afflicts from 1%–4% of the population (Judd & Akiskal, 2003; Swann, 2006b), depending on how the illness is defined (Judd et al., 2003). Defining bipolar disorder for epidemiological or genetic studies is not trivial, because there is no objective test to determine whether the illness is present. This leads to controversy over the existence and the incidence of the illness. The impact and clinical features of bipolar disorder vary across the life span. Early adulthood is a crucial time in the establishment of long-term occupational and social function. During early adulthood, individuals generally are completing their educations, entering the workforce, establishing their independent lives, and starting families. Bipolar disorder that is present at this stage of life can have a tremendous impact, usually had an earlier onset, and was likely to have been initially misdiagnosed. The onset of bipolar disorder is most commonly in adolescence, and there is, on average, a diagnostic delay of about 6 or 7 years (p. 380) with around one-third of patients requiring more than 10 years for accurate diagnosis (Hirschfeld, Lewis, & Vornik, 2003). Therefore, bipolar disorder with earlier onset is typically identified when it causes major problems during the crucial transitions of early adulthood.

Bipolar disorder appears to have cumulative effects on brain and health if it is not treated, and its clinical manifestations interfere with normal psychological, physical, and social development (Calabrese et al., 2003; Lish, Dime-Meenan, Whybrow, & Price, 1994). Untreated illness can end life, through suicide (Jamison, 2000) or increased all-cause mortality (Angst, Stassen, Clayton, & Angst, 2002), or can ruin it (Osby, Brandt, Correia, Ekbom, & Sparen, 2001). The potential for inappropriate labeling and treatment have hazards of their own (Healy, 2006), but prospective and retrospective studies converge to show that childhood-onset bipolar disorder continues into adulthood (Chang, 2007; Geller, Zimerman, Williams, Bolhofner, & Craney, 2001) and that early-onset illness is associated with severe impairment over the life span (Geller et al., 2000). In more severely ill patients, diagnostic delay can have severe consequences. For example, suicide is one of the three leading causes of death in young adults (Heuveline & Slap, 2002). Up to one-half of completed suicides in bipolar disorder occur during the first 6 years of illness, suggesting that for many patients suicide may occur before the illness has been accurately diagnosed or treated (Jamison, 2000).

In this chapter, we will attempt a practical focus on bipolar disorder in early adulthood. We will critically review and evaluate evidence for clinical pathways to early-onset bipolar disorder, mechanisms involved in the illness, and treatment strategies. In this way, we hope to be able to use science to foster a practical approach to this difficult illness.

Mechanisms of Recurrence and Chronicity in Bipolar Disorder

Recurrence and Sensitization

Bipolar disorder is an illness of recurrence and chronicity (Birmaher & Axelson, 2006). The course of illness varies widely, but it tends to fall into two patterns: (1) an episodic-stable course that emphasizes episodicity, with relative stability between episodes, and (2) an inherently unstable course that emphasizes progression toward chronicity, with more frequent episodes, susceptibility to depressive and manic features during the same episode, susceptibility to complications of bipolar disorder like substance-related and anxiety disorders, and persistent mood instability even between episodes (Masi, Perugi, Toni, et al., 2006). These courses of illness differ in treatment responsiveness, and they appear to run in families (Duffy et al., 2002; Duffy et al., 2007a). The inherently unstable course of illness appears to be associated with earlier onset of bipolar disorder and relative resistance to lithium treatment (Duffy et al., 2007a; Masi et al., 2000a, 2006b).

The course of illness in bipolar disorder resembles behavioral sensitization, a phenomenon described in animals (Cador et al., 1992) and in humans (Sax & Strakowski, 2001). Behavioral sensitization is characterized by a progressively increased response to repeated exposure to a stimulus, leading to a stable and persistently increased response. Classically the response is increased motor activity, and the stimulus is a central nervous stimulant drug (Robinson & Becker, 1986). Stimuli resembling stimulant drugs, whether endogenous or exogenous, can contribute to behavioral sensitization. Accordingly, cross-sensitization occurs among stimulants (Yang, Swann, & Dafny, 2003) and between stimulants and stressors (Barr, Hofmann, Weinberg, & Phillips, 2002; Covington & Miczek, 2001). In humans with bipolar disorder, frequency of episodes increases over time, exposure to so-called drugs of abuse accelerates the course of bipolar disorder (Post & Weiss, 1989), and exposure to severe stressors, especially early in life, is associated with more frequent episodes and a higher prevalence of substance abuse (Garno, Goldberg, Ramirez, & Ritzler, 2005).

There is substantial inter-individual variation in susceptibility to behavioral sensitization, in either humans or animals. In bipolar disorder, the course of illness runs in families. Relatives of patients with an episodic-stable course of illness tend to have that course pattern, while relatives of patients with an unstable course pattern have an (p. 381) unstable course pattern and are relatively resistant to lithium treatment (Duffy et al., 2007a).

Synthesis: Course of Illness

Bipolar disorder has general characteristics that must be kept in mind when interpreting psychiatric symptom presentations that may appear nonspecific. Table 23-1 summarizes characteristics of bipolar disorder in terms of its course of illness and clinical characteristics. In the evaluation of current problems or of histories of behavioral disturbance with early onset, these characteristics should be carefully considered in order to determine whether the disturbances are likely to be caused by bipolar disorder.

Table 23-1. Characteristics of Bipolar Disorder


Familial; multiple susceptibility genes; early onset associated with strong famili-ality (Chang, Steiner, & Ketter, 2000)


Usually adolescence (Leverich et al., 2007)


Recurrent, sensitization-like course (Post & Weiss, 1989); more severe with early onset and/or severe early stressors (Post et al., 2003)

Basic behavioral disturbances

Motivation, reward, arousal, impulsivity (Carroll, 1983; Swann, Anderson, Dougherty, & Moeller, 2001); susceptible to activation by pharmacological or environmental stimuli (Post, Weiss, & Pert, 1988)


Anxiety disorders (Masi et al., 2004), substance-use disorders (Borchardt & Bernstein, 1995), disruptive behavior disorders (Geller et al., 2006), ADHD (Geller et al., 2006; Masi et al., 2006a)

Characteristics associated with early onset

Chronicity/long symptomatic periods (Masi et al., 2006a); mixed states (Dilsaver, Benazzi, Rihmer, Akiskal, & Akiskal, 2005); high incidence of comorbidities (Masi et al., 2006)

The presence of these characteristics in an individual with prominent psychiatric symptoms should raise the possibility that the individual has bipolar disorder—but does not prove that bipolar disorder is present (Swann et al., 2005).

The nature and timing of the first affective episode may determine lifetime illness characteristics. As noted above, early first episodes are associated with a greater likelihood of an unstable and complicated course (Masi et al., 2006a, 2006b). In addition, while on average depression is more common than mania across all patients with bipolar disorder, individuals with bipolar disorder tend to have a predominately depressive or manic course (Perlis et al., 2005). The first episode tends to predict characteristics of future episodes: a first manic episode is associated with a predominately manic course; a first depressive episode with a predominately depressive course, and with a substantially greater likelihood of initial misdiagnosis (Daban, Colom, Sanchez-Moreno, Garcia-Amador, & Vieta, 2006; Perlis et al., 2005; Perugi et al., 2000).

Clinical Pathways to Bipolar Disorder

When Does Bipolar Disorder Begin?

Bipolar disorder is defined in our nosological system in terms of depressive and manic episodes. During early adolescence, childhood, and even early adulthood, development of the brain is not complete, so the manifestations of these episodes, and the way in which these manifestations are expressed, are likely to differ across age groups. These considerations must be taken into account when obtaining the psychiatric history from patients in early adulthood. Bipolar disorder is not mania or depression, but an illness that predisposes to these nonspecific mood syndromes (Zis & Goodwin, 1979). It was almost certainly already present before a patient met criteria for a characteristic mood episode (Correll et al., 2007). Further, though the diagnosis of bipolar disorder requires mania, depression usually occurs first (Lish et al., 1994; Perugi et al., 2000). Other psychiatric syndromes can also precede mania. Therefore, we will review clinical pathways that lead to bipolar disorder.

(p. 382) Depression

Most episodes of bipolar disorder are depressive episodes (Lish et al., 1994), most lifetime morbidity is associated with depression (MacQueen et al., 2000; Swann, Bowden, Calabrese, Dilsaver, & Morris, 2000), and the first episode is usually a depressive episode rather than mania (Lish et al., 1994; Perugi et al., 2000). This leads to a diagnostic paradox where a clinician who saw a patient early enough and applied diagnostic criteria strictly would initially misdiagnose most patients. When depression is the first episode of bipolar disorder, the course of illness tends to be characterized by more depressive than manic episodes, more chronicity, and more severe suicidal behavior (Daban et al., 2006; Perlis et al., 2005; Perugi et al., 2000).

Early depressive episodes in bipolar disorder must be distinguished from major depressive illness, prodromes of schizophrenia, depression secondary to another medical or psychiatric illness, or demoralization (Akiskal et al., 1994; Geller et al., 2001; Winokur & Wesner, 1987). We will focus on the most difficult distinction: bipolar versus major depressive illness. Core depressive symptoms, like anhedonia, suicidal ideation, hopelessness, or a negative affect that may be experienced as extreme sadness or as being distinct from the patient’s normal sadness, characterize childhood major depression of any cause. It should be remembered that the onset of bipolar disorder is, on average, earlier than major depressive illness (Strober et al., 1988), so as age decreases, the probability that a first depressive episode is bipolar disorder increases.

Clues that an early depressive episode may be bipolar are related to known characteristics of bipolar disorder summarized above and in Table 23-1. Geller studied a cohort of children whose average age was about 10 years old, who had major depressive episodes (average first episode at about 7 years). By 10 years later, during early adulthood, about half of the subjects had experienced manic or hypomanic episodes— even though patients with attention-deficit disorders or psychotic episodes had been excluded. The strongest predictor of bipolarity in this group was the presence of relatives with bipolar disorder (Geller et al., 2001).

The risk of bipolar disorder continues for patients with depressions in early adulthood. Goldberg and colleagues studied a group of 74 subjects who experienced major depressive episodes at a mean age of 23 years (Goldberg, Harrow, & Whiteside, 2001). At 15 years’ follow-up, 27% of subjects had experienced at least one hypomanic episode, and another 19% had experienced at least one full manic episode. Psychotic features during the index depressive episode predicted eventual manic or hypomanic episode (recall that this was an exclusion criterion in the Geller study). Combined with the report by Geller and colleagues, for childhood-onset depression, the data suggest that bipolar disorder emerges with a half-life of about 10–15 years after an initial depressive episode.

Early depression can also be a prodrome of schizophrenia (Meyer et al., 2005), preceding psychotic symptoms by years in a substantial minority of patients with schizophrenia. Family history and social function are potentially useful clues for diagnosis.


As with depression, a manic first episode tends to predict a predominately manic course of illness (Yap, Covington, Gale, Datta, & Miczek, 2005). Similar to the case with depression, early-onset mania is characterized by core manic symptoms like grandiosity, pressured speech, racing thoughts, elation, hypersexuality, and reward-seeking behavior without regard for consequences (Geller et al., 2002). Also like depression, early-onset mania is more likely that later-onset mania to be chronic and to have mixed features (Craney & Geller, 2003). Finally, in interpreting these symptoms, it is vital to take developmental context into account. Pathological grandiosity differs, for example, between children and adults. Geller and colleagues published a useful comparison of symptoms in adult mania compared to childhood mania and normal childhood (Geller et al., 2002). When taking the history, it is important to take these considerations into account and to obtain data from multiple sources if possible.

A potential history of early mania must be differentiated from attention-deficit disorder with hyperactivity. This is exacerbated by the (p. 383) fact that almost all children experiencing manic episodes also have attention-deficit disorder, though the relationship appears to weaken with later onset (Biederman, Faraone, Keenan, & Tsuang, 1991; Biederman, Faraone, Wozniak, & Monuteaux, 2000; Luby, & Belden, 2006). Therefore, one must often determine whether a patient had attention-deficit disorder alone, or combined with bipolar disorder. There are, however, important differences between attention-deficit/hyperactivity disorder and mania. Both are characterized by hyperactivity, apparent inattention, and irritability (Biederman, Russell, Soriano, Wozniak, & Faraone, 1998). However, they can be differentiated by an observant clinician on the basis of the presence of the core motivation and reward-related mania symptoms, the frequent presence of core depressive symptoms, and positive family history for bipolar disorder (Craney & Geller, 2003; Geller et al., 2002).


Psychosis is a nonspecific syndrome that can occur in any phase of bipolar disorder but that also can be associated with many other illnesses, some of which are considered to be primary psychiatric illnesses, such as schizophrenia or affective disorders, while others, such as toxic psychoses, neoplasms, or consequences of brain trauma or infections, are not (Krauthammer & Klerman, 1978). Early psychotic episodes in patients with affective disorders are more likely than later episodes to have mood-incongruent features (Fennig, Bromet, Karant, Ram, & Jandorf, 1996). Mood-incongruent features, while not diagnostically useful, predict a course of illness with more severe psychosocial impairment (Strakowski et al., 2000).

The first manic episode is more likely to be psychotic, if it occurs in adolescence, than subsequent episodes (Ballenger, Reus, & Post, 1982; Conus &McGorry, 2002; Corkery, 1987; Weller, Weller, Tucker, & Fristad, 1986). Psychotic features can also occur in depressive or mixed episodes, especially as part of the highly variable and unstable symptom pattern that characterizes early-onset bipolar disorder. A first depressive episode with psychotic features may be associated with bipolar disorder (Goldberg et al., 2001). Unless prominent mood symptoms are also present, the diagnosis must be made using characteristics not directly related to the psychotic episode itself. Some features that are potentially useful are summarized in Table 23-2 (Ballenger et al., 1982; Corkery, 1987).

Table 23-2. Diagnostic Clues in Psychotic Episodes



Other (Substance-Induced or Medical Disorder)





Premorbid social








Mood symptoms

Usually present

Can be depressive




Orientation usually preserved


Premorbid social function and family history may be at least as useful as characteristics of the episode itself. Bipolar disorder and schizophrenia confer increased susceptibility to ‘‘secondary’’ symptomatic episodes associated with medical problems or pharmacological treatments (Krauthammer & Klerman, 1978).

Anxiety-Related Disorders

Bipolar disorder is strongly related to anxiety disorders throughout the life span, with a high rate of generalized anxiety disorder, panic disorder, and phobic disorders (Birmaher et al., 2002; Goodwin & Hamilton, 2002); as many as two-thirds of patients were reported to have met diagnostic criteria for a preexisting anxiety disorder when bipolar disorder was diagnosed (Masi et al., 2001). In addition, patients with bipolar disorder are more likely than those with other major psychiatric illnesses to have diagnoses of posttraumatic stress disorder (Cannon & Clarke, 2005) (p. 384) and obsessive-compulsive disorder (Chen & Dilsaver, 1995). Onset of illness was reported to be younger in patients with both bipolar disorder and obsessive-compulsive disorder than for either illness alone (Masi et al., 2004).

Anxiety- or stress-related disorders are also more likely to occur in children or adolescents who eventually develop bipolar disorder than in those who do not (DelBello & Geller, 2001). A family history of bipolar disorder predicts eventual diagnosis of bipolar disorder in children with anxiety- or stress-related disorders (Henin et al., 2005), and it is associated with increased prevalence of anxiety disorders in offspring who have not yet experienced depressive or manic episodes (Chang et al., 2000).

Prodromal Symptoms and Problems

Before the first prominent affective symptoms, individuals at high risk for bipolar disorder may experience problems related to the patho-physiology of the illness (Shaw, Egeland, Endicott, Allen, & Hostetter, 2005). Characteristics summarized in Table 23-1 may be signs of underlying bipolar disorder. Family history is always a useful diagnostic clue in bipolar disorder, but it is especially important in patients with early onset of illness (Pavuluri, Henry, Nadimpalli, O’Connor, & Sweeney, 2006). Children of parents with bipolar disorder may be at risk for prodromal signs of bipolar disorder and were reported to have an 11-fold greater risk of eventual bipolar disorder than children of non-bipolar parents (Singh et al., 2007). Among characteristics that differentiated bipolar offspring from offspring of parents with bipolar disorder were greater emotionality (Duffy et al., 2007b), increased hostility and irritability (Farchione et al., 2007), increased laboratory-measured dis-inhibition (Hirshfeld-Becker et al., 2006), coping and sleep disturbances (Jones, Tai, Evershed, Knowles, & Bentall, 2006), and increased anxiety, excitability, and attentional problems (Shaw et al., 2005).

Family history of bipolar disorder and perinatal complications are both associated with early-onset illness. A positive family history is associated with a 15-fold greater risk for developing bipolar disorder; each perinatal complication increased the likelihood 6-fold (Pavuluri et al., 2006). Children with early-onset bipolar disorder are more likely than their peers to have attention-deficit/hyperac-tivity disorder or disruptive behavior disorders (Masi et al., 2006a). Conversely, children with substance-use disorders (Simkin, 2002), conduct disorder (Sultzer, & Cummings, 1989) or attention-deficit disorder (Faraone, Biederman, Mennin, Wozniak, & Spencer, 1997),were likely to have an eventual diagnosis of bipolar disorder if they had positive family histories, but not in the absence of a positive family history.

Early Detection of Bipolar Disorder

The clinical presentation of bipolar disorder may differ according to age at onset. In young adults with prominent affective symptoms caused by bipolar disorder, onset of illness or its prodromes are likely to have occurred during earlier in life, during adolescence or childhood. Patients with early onset differed from those with later onset by having more chronic episodes, more mixed states and polyphasic episodes, and higher rates of other behavioral disturbances (Craney & Geller, 2003). The course of bipolar disorder is heterogeneous, however (Turvey et al., 1999). Adults with bipolar disorder may have a largely episodic course that is considered to be classic for bipolar disorder, but a substantial number have an inherently unstable course of illness associated with frequent, long symptomatic periods with mixed and polyphasic features and high rates of complicating disturbances including, substance-use and anxiety/stress-related disorders (Duffy et al., 2002). This more malignant form of adult bipolar disorder strongly resembles childhood-onset illness (Craney & Geller, 2003).

Potential Interaction of Genes and Environment in Bipolar Disorder

Genetic expression mayby strongly influenced by environmental circumstances at specific times in development, referred to as gene by environment interaction (Caspi & Moffitt, 2006). Rutter and colleagues described four types of gene–environment interactions: (1) epigenetic mechanisms where environment altered gene effects, (2) (p. 385) variations in heredibility with environmental conditions, (3) gene–environment correlations, and (4) how specific identified genes interact with specific measured risks (Rutter, Moffitt, & Caspi, 2006). Several examples appear relevant to bipolar disorder, although they stem from other illnesses.

A classic example involves an abnormal allele of a gene coding for monoamine oxidase type A (MAO-A). Individuals who had experienced maltreatment during childhood were more likely than other children to develop antisocial behavior if they had the allele associated with lower levels of enzyme activity, but they appeared to be protected if they had the high-expression allele (Caspi et al., 2002). More generally, a study of 1,116 5-year-old British twin pairs and their families showed that maltreated children were more likely to develop conduct disorders if they were at high genetic risk (Jaffee et al., 2005). In another example, a functional polymorphism of the serotonin transporter gene, individuals with one or two copies of the short allele were morelikely to experience depressive symptoms, depressive episodes, and suicidal behavior related to stressors (Caspi et al., 2003). Susceptibility to development of psychotic symptoms after marijuana use was associated with the catecholamine O-methyltransferase valine 158 allele, while individuals with the methionine allele appeared not to have this complication of marijuana use (Caspi et al., 2005).

Effects of early exposure to severe stressors may be examples of gene–environment interaction relevant to bipolar disorder. For example, early severe stressful events are associated with early onset of bipolar disorder (Duffy et al., 2007b) and with a more malignant course of bipolar disorder throughout the life span (Garno, Goldberg, Ramirez, & Ritzler, 2005; Post et al., 2003), with severe mood instability and susceptibility to substance-use disorders, suicidal behavior, and other behavioral problems (Leverich et al., 2007).

Treatment Considerations

Acute Psychopharmacological Treatments

We know of no large treatment studies that have focused on early adulthood. Most large controlled treatment studies covered a broad range (generally 18–65 years) of ages, with mean ages of 38–40 years (Bowden et al., 1994; Calabrese et al., 2005; Cookson, Keck, Ketter, & Macfadden, 2007; Goodwin et al., 2004; Hirshfeld-Becker et al., 2003; Keck et al., 2003, 2006; Tohen et al., 2000). A few studies have focused on treatment of bipolar disorder in adolescence, though the evidence is limited (Findling, 2005). Randomized treatment trials in adolescents are summarized in Table 23-3. Based on the limited amount of evidence available, it is not surprising that many young adults with bipolar disorder have histories of inadequate or inappropriate treatment, even if they received an accurate diagnosis.

Table 23-3. Randomized Treatment Trials in Adolescents with Bipolar Disorder








DelBello, Schwiers, Rosenberg, & Strakowski, 2002







Geller et al., 1998




16.3 ± 1.2

Manic + substance abuse

Li+ > PBO mania and substance use

Kafantaris et al., 2004





Li+ = PBO

Tohen et al., 2007







DC, discontinuation study; DVP, divalproex; OLZ, olanzapine; PBO, placebo; QTP, quetiapine.

Lithium is considered to be a relatively ineffective treatment in early-onset bipolar disorder. Yet Geller and colleagues showed that, in a group of early adolescent subjects with mania and a substance-use disorder, lithium improved manic symptoms and reduced substance abuse (Geller et al., 1998). Lithium, however, was not (p. 386) more effective than placebo in a discontinuation study where subjects continued on lithium after 2 weeks and subjects switched to placebo had equally poor outcomes (52.6% relapse on lithium vs. 61.9% on placebo) (Kafantaris et al., 2004), or in an 18-month maintenance study (Findling et al., 2005). There are two positive studies of atypical antipsychotics in adolescents with mania (DelBello, Schwiers, Rosenberg, & Strakowski, 2002; Tohen et al., 2007).

Quetiapine and divalproex both appeared to improve impulsivity and reactive aggression in subjects with bipolar disorder combined with disruptive behavior (Barzman, DelBello, Adler, Stanford, & Strakowski, 2006). Divalproex was reported to be more effective than oxcarbazepine in patients with bipolar disorder and prominent aggressive behavior (MacMillan et al., 2006).

Many young adults with bipolar disorder were initially diagnosed with major depressive illness. Antidepressive agents may be associated with prominent mood instability in young patients. One study reported that 50% of patients receiving antidepressants experienced mania or hypo-mania, and 25% developed suicidal ideation (Baumer et al., 2006). Switch rates in antidepressants may be related to age, with SRIs having higher switch rates in younger patients, while switch rates were less related to age with tricyclics (Martin et al., 2004). One study comparing ‘‘pre-bipolar’’ depressed patients with unipolar patients of similar age found that outcomes were less favorable for ‘‘prebipolar’’ patients, with poorer antidepressive response and greater likelihood of treatment-emergent mixed states correlating with early age at onset (O’Donovan, Garnham, Hajek, & Alda, 2007). These results resemble a report in adults in which previously undiagnosed bipolar disorder was associated with loss of response to antidepressive treatments (Sharma, 2001).

Table 23-4 summarizes established treatments in bipolar disorder (Suppes et al., 2005; Swann, 2006a). As noted above, we know of no data differentiating response in young adults from other age groups. Young adults were prominently included in treatment trials with these agents, though mean ages were almost always 38–40 years. Several drugs and drug types have been found effective for treating acute manic episodes. Evidence for depression is less consistent; even when there have been placebo-controlled studies, results have been less consistent and quetiapine is the only FDA-approved mono-therapy for depression in bipolar disorder. For maintenance treatment, there are even fewer alternatives.

Table 23-4. Pharmacological Treatments in Bipolar Disorder

Drug or class



Relapse prevention

FDA approval






Mania, relapse

Family history, illness course






Carbamazepine; oxcarbazepine



C (M only)

Mania (ext release CBZ)





A typical antipsychotics


P (QTP only)

P,C (Ari, 6 mo, M only); OLZ)

M; D (QTP only); relapse (OLZ, Ari)

Antidepressive agents

P (as part of combination of fluoxetine-olanzapine)


None as monotherapy (D as part of combination)

*Only treatment shown to prevent relapse in subjects not originally treated/stabilized with the same treatment.

Ari, aripiprazole; C, comparator-controlled; D, depression; CBZ, carbamazepine; M, mania; OLZ, olanzapine; P, placebo-controlled; QTP, quetiapine.

Sources: Suppes et al. (2005); Swann (2006).

(p. 387) There is relatively little information comparing the effectiveness of individual approved treatments. Lithium appears to be most effective in patients with family histories of lithium response and with a relatively stable course of illness (fewer or less frequent episodes, fewer mixed states) (Duffy et al., 1998, 2002; Swann, Bowden, Calabrese, Dilsaver, & Morris, 2000).

In general, treatments effective for acute episodes are potentially effective for preventing relapse. Essentially every positive maintenance study was in subjects who had initially responded to the study treatment (Swann, 2006a). An exception is with antidepressive treatments, where, despite some evidence for effectiveness in acute episodes, maintenance or continuation studies have been consistently negative (Ghaemi, Lenox, & Baldessarini, 2001), with the potential for worsening of the course of illness (Ghaemi, Hsu, Soldani, & Goodwin, 2003; Ghaemi et al., 2004). A critical aspect in the long-term treatment of bipolar disorder is the transition between treatment of an acute episode and the establishment of maintenance treatment. This phase of treatment establishes the eventual long-term strategy, so we will discuss it in more detail.

Transition between Acute Episode and Maintenance

Pharmacological Transitional Strategies.

When acute symptoms have improved, functional impairment persists. It can take many months, or even years, for a patient to return to the level of function that preceded an episode of illness (Chengappa et al., 2005). The difficulty of this transitional period is compounded by the increase in responsibilities and reduction in structure and vigilance that tend to follow initial recovery. These considerations are especially crucial during young adulthood, when the individual is likely to still be establishing a social and occupational identity. The period directly after initial recovery is therefore a risky one for suicide (Sachs, Yan, Swann, & Allen, 2001), arrest (Quanbeck et al., 2004), substance abuse, and relapse (Perlis et al., 2006). Despite these considerations, the transitional period after an episode has not been extensively studied as an entity. There is indirect information, however, about treatment strategies for this period.

Manic episode.

The period following a manic episode is associated with increased risk for behavioral problems including arrest and incarceration (Quanbeck et al., 2004). There is little information available about treatment during this period. Among subjects whose manic episodes had responded acutely to a combination of lithium or valproate with olanzapine were randomized to continuation of the combination or replacement of olanzapine with placebo (Tohen et al., 2004), half of those who were randomized to placebo relapsed during the first 3 months. The other half had outcome similar to that of subjects on combination treatment (survival curves were parallel). This result implies that treatments that were necessary to induce remission of a manic episode should be continued, at least for several months, after symptomatic improvement. If it is thought that part of a combination is not necessary for maintenance, a gradual taper (Faedda, Tondo, Baldessarini, Suppes, & Tohen, 1993) should not be undertaken until after at least several months, with the patient at or approaching the level of function that preceded the episode (Sachs, 1996).

Depressive episode.

There is controversy over the continuation of antidepressants in a patient with bipolar disorder whose acute episode responded to these treatments. One contention is that antidepressive treatments should be discontinued as soon as possible, especially if a patient has experienced an unstable course of illness (Frye, Gitlin, & Altshuler, 2004). There is, however, the concern that hasty discontinuation of effective treatments could lead to increased mood instability, return of depressive symptoms, or increased suicide risk (already a feature of this recuperative period). In response to this dilemma, Altshuler and colleagues carried out two studies, one retrospective (Altshuler et al., 2001) and one prospective (Altshuler et al., 2003). The mean age of the subjects was about 42, though young adults were included. Both studies were naturalistic, without randomization. The patients in the study had required antidepressant treatment (therefore, they had not responded to mood-stabilizing agents that were generally given first) and had continued to tolerate antidepressant treatment after initial treatment. Among patients with these characteristics (about 20% of the total), patients in whom (p. 388) antidepressant were continued were compared to those whose antidepressants were discontinued. In both studies, patients whose antidepressants were discontinued experienced more relapses into depression than did those with continued antidepressant treatment, and they had no reduction in risk for mania. These results suggest strongly that, among that subgroup of patients who require, respond to, and tolerate antidepressive treatments, antidepressants should be continued for at least 6–12 months after recovery. It must be kept in mind that these results apply only to a minority of patients with bipolar depressive episodes, and that there was no information about reasons for discontinuation, so patients discontinuing antidepressants may have already been doing worse than those whose antidepressants were not discontinued, or they may have been more severely ill or had other differential clinical characteristics. Nevertheless, these studies are consistent with the results in mania in that, if part of a successful treatment combination is discontinued too early, risk of relapse is increased.

Nonpharmacological Transitional Strategies.

Treatment during the transitional, recuperative period after an episode has many goals, including return to the pre-episode level of social and occupational function, establishing methods to monitor and proactively address symptoms, and addressing other potential problems like substance abuse and other complications of bipolar disorder. They include the following:

  1. 1. Identification of prodromes of episodes (Fava & Kellner, 1991), which can improve outcome (Lam, Wong, & Sham, 2001; Perry, Tarrier, Morriss, McCarthy, & Limb, 1999).

  2. 2. Use of life-charting methods to monitor symptoms, side effects, medicine, and events (Post, Roy Byrne, & Uhde, 1988); this can be applied to identification of prodromes.

  3. 3. Behavioral and cognitive strategies (Otto, Reilly-Harrington, & Sachs, 2003); these can have particular value for complications of bipolar disorder like substance abuse (Schmitz et al., 2002), mild depressive symptoms (DeRubeis et al., 2005), or anxiety disorders (Simon et al., 2004), which would otherwise require potentially mood-destabilizing treatments. Similar strategies have been adapted for protection of sleep, activity, and social rhythms (Frank et al., 1997, 2005). Cognitive-behavioral therapies can reduce relapse and improve occupational function and quality of life (Lam, Hayward, Watkins, Wright, & Sham, 2005).

  4. 4. Education and support of the patient and significant others. Participation in treatment is more strongly related to understanding of the illness more than any other single factor, even side effects; unfortunately, clinicians seem not to recognize this fact (Scott, & Pope (2002). Similarly, stress to caregivers depends more on understanding of illness than on severity of symptoms (Perlick et al., 1999) and was shown to predict poor treatment outcome at 9 and 15 months better than acute symptom severity did (Perlick, Rosenheck, Clarkin, Raue, & Sirey, 2001). Psychoeducation is a cost-effective strategy for improving outcome and quality of life (Michalak, Yatham, Wan, & Lam, 2005). Comprehensive educational materials have been developed, in collaboration with the National Alliance for the Mentally Ill and Depression Bipolar Support Alliance, by the Texas Medication Algorithm Project (TMAP) (Suppes et al., 2002).

  5. 5. Once the transitional period is over, medicines not considered essential may be discontinued (Sachs, 1996). This process should be gradual. Even a rapid reduction in lithium level can increase the probability of relapse (Perlis et al., 2002). Rapid discontinuation of antidepressants can precipitate mania (Goldstein et al., 1999).

  6. 6. Insight-oriented treatments or planned major life changes should be deferred, if at all possible, until after this transitional, recuperative stage of treatment, when pre-episode function has been restored (Sachs, 1996).


Young adulthood is a crucial stage of life that is overlooked in treatment studies. The processes of brain maturation that were active during adolescence reach completion during this period. (p. 389) Individuals are establishing lifelong adaptive, social, and occupational patterns. In the context of the important transitions that occur during this period, bipolar disorder can be a challenging problem. Most patients with bipolar disorder have onset before adulthood, but early misdiag-nosis and inaccurate treatment are common. Fortunately, there are clues that can be useful to us in determining whether severe psychiatric symptoms might have been related to early-onset bipolar disorder (Table 23-1). The strongest are syndromal depressive or manic symptoms that began in the developmental context of childhood, and behavioral or symptomatic disturbance consistent with underlying susceptibilities of bipolar disorder (like anxiety, impulsivity, or depression) combined with a family history of bipolar disorder. A range of treatments is available, as summarized in Table 23-4, but evidence for effectiveness against depression or in long-term treatment is still relatively weak. As recovery from an episode progresses, the transition to long-term treatment is a vital step in establishing long-term adaptive function and mood stability. Treatment decisions must balance the severity of current and projected future impairment and strength of supporting diagnostic evidence against the potential toxicities and still-preliminary evidence supporting treatments, must consider the possibility of synergistic effects of pharmacological and nonpharmacological treatments, and must address the illness in the context of the transitions that characterize this stage of life.


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