Mood Disorders Research Paper

In the following research paper the topics discussed are unipolar depression and bipolar disorder, the two major forms of mood disorders, and their variants. Despite some similarities, the two disorders are viewed as distinct in their manifestations, underlying causes, and recommended treatments. Consequently, the paper presents information on these disorders in separate sections.

Defining and Diagnosing Unipolar Depression

The Experience of Depression

Depressed is a word in such common usage that it is often used interchangeably with upset, disappointed, or some similar term to refer to a negative emotion following a bad experience. Depression may be a mood state, lasting only a few moments or hours—occasionally a few days—but in which other elements of the person’s functioning are unchanged. It is, in fact, normal to have mild and brief depressed mood following an important loss or disappointment. Depression as a psychological disorder is more than a temporary, mild mood state. It is a constellation of experiences of mood, physical functioning, quality of thinking and outlook, and behaviors.

The depressed person may feel down or sad, but sadness may often be less apparent than a general lack of interest in activities that were once enjoyed. Irritability may be the dominant mood, rather than sadness. Changes in mood are accompanied by a gloomy outlook in which the future seems bleak and uninviting, and the person views himself or herself as flawed and inadequate, while circumstances may seem overwhelmingly difficult or unrelenting in their deprivation and capacity for disappointment. Because of the negative outlook, the sufferer’s motivation and persistence may be impaired. The negative interpretations of the self and world that are typical of depression may seem illogical or distorted to others, and there appears to be a focus on negative possibilities to the neglect of positive or even neutral alternatives: “Even though I got this promotion at work, I will fail”; “my family is supportive of me, but I don’t deserve it, and they will give up on me.” Bodily changes may become pronounced with increasing severity of depression; sleep is interrupted by awakening in the night or early morning—although sometimes people sleep even more than usual. Some individuals may focus extensively on aches and pains and physical debility and medical symptoms. Energy flags, and for some depression sufferers, it is an immense chore to get out of bed, shower, and get dressed. Appetite may be lost, and loss of weight may result, although some individuals do not experience such changes and may even eat more than usual. Behaviors mirror the inner suffering; depressed individuals may withdraw from others or discontinue typical activities, having little pleasure or energy to sustain them—and even finding that being around others makes them feel worse. Of course, others do indeed find it difficult to enjoy the company of a silent or suffering person who cannot be cheered, and may be frustrated with the depressed person’s seemingly willful exaggerations of negativity that they perceive inside and all around themselves. Some people experience depression as relentless suffering from which the only escape is death. For such sufferers, thoughts of death may be persistent, and unfortunately, for a significant minority of depressed people, suicidal acts may seem to be the only escape. What may seem to others as an irrational reaction or an excessive and selfish display of self-pity may even contribute to the depressed person’s feeling of abandonment at the time of greatest need. A vicious cycle of negative thoughts and more depressed mood and behaviors may contribute to a prolonged period of depressive suffering.

Diagnoses of Depression

The phenomenology of depression is relatively well recognized, and diagnostic systems have been developed to attempt to define key symptoms among the many possible manifestations, and to operationally define the point at which normal depressed mood becomes a clinical state. The current Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition (DSM IV; American Psychiatric Association [APA], 1994a) and International Classification of Diseases–10th Revision (ICD-10; World Health Organization, 1992) have evolved from various efforts to provide systematic, reliable definitions. There are four key features of diagnoses of depressive disorders: presence of more than depressed or negative mood—requiring a variety of additional syndrome manifestations; duration over a period of weeks or months to distinguish depression from temporary mood shifts; and impairment, indicating that the depression interferes with normal functioning. The fourth feature is critical to distinguishing between unipolar and bipolar mood disorders: There must be information about prior symptomatology sufficient to determine whether the individual has ever experienced a manic or hypomanic episode (described later). Only if there has never been such an experience could a person receive a diagnosis of unipolar depression. Those with histories of mania are diagnosed with bipolar disorder.

Major Depressive Episode and Dysthymic Disorder

The two most common unipolar diagnoses are major depressive episode (MDE) and dysthymic disorder.To meet diagnostic criteria for MDE, one must be depressed for at least two weeks, experience depressed mood nearly every day all day or have a loss of interest or pleasure, and at least four of the remaining nine symptoms (covering a range of cognitive, physical, and behavioral changes, such as diminished ability to think positively about the self or future or to concentrate; thoughts of death; changes in speed and spontaneity of movement). Dysthymic disorder is a milder, chronic form of depression that includes depressive experiences lasting for at least two years, accompanied by two or more of six milder depressive symptoms. Both MDE and dysthymic disorder diagnoses require the presence of impaired functioning in the person’s important roles. Some individuals experience double depression, a pattern observed in about 25% of clinical patients in which major depressive episodes are superimposed on dysthymic disorder, an especially adverse disorder in terms of course and impairment in adults (e.g., Keller, Lavori, Endicott, Coryell, & Klerman, 1983; Klein, Taylor, Harding, & Dickstein, 1988). Children who meet criteria for both MDE and dysthymia also appear to function significantly worse than children with either of the disorders alone (Goodman, Schwab-Stone, Lahey, Shaffer, & Jensen, 2000).

Depression in children may be diagnosed with the same criteria as for adults, with minor modifications. For instance, irritability may be substituted for depressed mood, and dysthymic disorder may be diagnosed with only one year’s duration.Although there may be developmental differences in expression of depressive symptoms (e.g., young children are unlikely to report subjective states), currently research suggests few reliable differences in symptom patterns in adults and children (reviewed in Garber & Flynn, 2001), and therefore the same criteria are to be used in the absence of validation of alternative procedures.At the same time, however, some have questioned the validity of distinguishing between MDE and dysthymic disorder in children and adolescents, noting that their correlates and impairments are similar (e.g., Goodman et al., 2000).

Subclinical Depression

Diagnostic criteria for defining MDEs and dysthymia are somewhat arbitrary in their establishment of a cutoff of number and duration of symptoms. Depressive experiences may include subsyndromal symptoms that are milder or briefer than these two diagnoses, or that are intermittent but frequent, or that are mild but enduring. Although mild and short-lived symptoms may have little significance for a person’s life and indeed might be considered normal reactions to losses and disappointments, even mild but persistent symptoms may be detrimental to a person’s adjustment. Research has shown, for example, that subclinical depressions may predict future diagnosed depressions or other emotional problems, and may result in significant impairment in functioning affecting employment and social roles (e.g., Gotlib, Lewinsohn, & Seeley, 1995; Horwath, Johnson, Klerman, & Weissman, 1992; Wells et al., 1989; Zonderman, Herbst, Schmidt, Costa, & McCrae, 1993). Moreover, persisting mild symptoms following major depression (indicating lack of total recovery) may portend a more severe future course of disorder, including more frequent episodes and chronic symptomatology (Judd et al., 2000).

Heterogeneity and Comorbidity of Depression

A particular challenge to the diagnosis of depression—and indeed, to the validity of diagnoses—is the fact that depressive experiences may be quite varied and they commonly overlap with or co-occur with other psychological disorders. The variability in presentation may range from premenstrual dysphoria to depressive delusions and psychotic states. Over the years, attempts to define meaningful subtypes have been based on the assumption that different forms of depression may result from different causes, and might have different effective treatments. A particular effort to define biologically based forms (endogenous rather than reactive or psychological forms) has permeated the field. The DSM-IV system defines a subtype of melancholic features of major depression based on phenomenology with emphasis on somatic symptoms. Although it is sometimes presumed to define a distinct form and perhaps biological origin, some have argued that it may simply represent a more severe version of depression. Another subtype distinction is a seasonal pattern of mood disorder, which may occur in both unipolar and bipolar patients. Further efforts to characterize potential etiological subtypes seem warranted, and an important corollary is that models of etiology or treatment methods that are successful with some depressions are unlikely to cover all depressions.

The diagnostic picture may be further complicated by comorbidity. The U.S. National Comorbidity Survey found that of all adult community residents who met criteria for current major depression, only 44% displayed pure depression, and the others had one or more additional diagnoses (Blazer, Kessler, McGonagle, & Swartz, 1994). Commonly co-occurring disorders are anxiety disorders (such as panic disorder, generalized anxiety, and posttraumatic stress disorder), substance abuse, and eating disorders. Moreover, Axis II pathology is extremely common among depressed individuals, with rates across different studies ranging from 23% to 87% (Shea, Widiger, & Klein, 1992). Such mixtures of depression and other disorders frequently portend more complicated courses of depression, and more difficulty in achieving success in treatment (Shea et al.).

In children, comorbidity is said to be the norm rather than the exception, with few children having pure depression rather than mixed with disruptive behavioral, anxiety, eating, and substance use disorders (e.g., reviewed in Angold & Costello, 1993; Hammen & Compas, 1994). High rates of comorbidity may reflect inadequacies in the diagnostic system in which some of the same symptoms may occur in different diagnoses, or over-narrowness in how disorders are conceived. Additionally, in children the indistinct boundaries of diagnoses may reflect a developmental reality in which nonspecific expressions of distress and behavioral disruption cannot readily be classified until further maturation and development occur. Continuing efforts to explore developmentally appropriate criteria for depression in children remain an important research priority (Garber & Flynn, 2001).

Assessment of Depression

There are presently several widely used instruments available to diagnose unipolar depressive disorders, and to characterize the severity of symptomatology.

Diagnosing Depressive Disorders

To meet the goal of reliable, systematic application of diagnostic criteria to determine a person’s past or current mood disorder, two methods have been widely used. The Structured Clinical Interview for DSM-IV Axis I Disorders (SCID; First, Spitzer, Gibbon, & Williams, 1995) has evolved from previous versions of research-oriented diagnostic criteria, including the Schedule for Affective Disorders and Schizophrenia (SADS; Endicott & Spitzer, 1978). It covers current and past symptomatology sufficient to diagnose most Axis I disorders, using semistructured questions and probes, administered by clinically trained interviewers whose task is to elicit examples and determine whether described experiences fulfill criteria to be included as definite symptoms. Interrater reliabilities for major depressive disorder and dysthymic disorder are high (First et al., 1995). The SCID is used in most research studies to select and define patient samples, and to evaluate the course of disorder.

The other major diagnostic instrument is the Diagnostic Interview Scale (DIS; Robins, Helzer, Croughan, & Ratcliff, 1981), developed for use in large epidemiological surveys. The major characteristic of the DIS is the highly structured administration of questions, eliciting yes-no answers from respondents, with no follow-up questions to determine the severity or significance of experiences with each symptom. Hence, the DIS requires relatively little training for administration, and does not require clinical experience. A computer algorithm is used to score the DIS, yielding diagnoses independent of clinician judgment. Thus, the DIS is used principally for epidemiological samples that are very large and for which costs of clinically trained interviewers would be prohibitive. The DIS has been reported to yield adequate reliabilities for depressive disorders. Some have feared that the DIS tends to overdiagnose depression because respondents may say yes to certain questions based on trivial negative emotional experiences. However, perhaps somewhat surprisingly, comparisons of rates of depressive diagnoses obtained from the DIS compared with a clinician-based interview indicated a tendency of the DIS to result in fewer diagnoses (Eaton, Neufeld, Chen, & Cai, 2000). The authors suggest that the procedures vary by the threshold at which diagnoses are made, although agreement at the level of reporting syndrome features was fairly good.

It should be noted further that different diagnostic instruments, owing to differences in wording and procedures, may yield different estimates of rates of depression in the population. A recent modified version of the DIS, called the Composite International Diagnostic Interview (CIDI; e.g., Kessler et al., 1994) was used in the National Comorbidity Survey. Resulting data on incidence and prevalence of depression were notably higher than for the prior DIS-based Epidemiological CatchmentArea studies.As Blazer et al. (1994) noted, the instruments differed slightly on the stem questions, with the CIDI asking more stem questions so that there were more opportunities for people to acknowledge a depressive mood. As Regier et al. (1998) observed, actual information about the occurrence of depressive (and other) disorders may be substantially affected by how the information is obtained.

Assessing Severity of Depressive Symptoms

There are a number of instruments available for research and clinical use to evaluate severity of current depressive symptoms. One type is a self-report questionnaire, exemplified by the Beck Depression Inventory (BDI), the most widely used such scale. Developed by Beck, Ward, Mendelsohn, Mock, and Erbaugh (1961), and recently revised as the BDI-II to be consistent with the DSM-IV (Beck, Steer, & Brown, 1996), the scale consists of 21 items, each containing four response options differing in severity. Individuals select the one response per item that corresponds most to their current clinical state “over the past two weeks.” Total scores indicate level of depression, but like all self-report scales for which a cutoff is used to indicate significant symptoms, the scale is not a diagnostic instrument, and scores may be elevated temporarily due to environmental, medical, or other emotional difficulties. The BDI and BDI-II have been well studied and have excellent reliability and validity for measuring severity of depression (Beck, Steer, & Garbin, 1988; Beck et al., 1996). Further detailed information on additional self-report methods is reviewed in Nezu, Ronan, Meadows, and McClure (2000), Practitioner’s Guide to Empirically Based Measures of Depression. Also, many instruments have been developed for use with specific populations, such as children and adolescents, geriatric samples, and with specialized content areas related to depression, such as hopelessness, suicidality, selfesteem, and others. There are also measures of depressed mood state, exclusive of additional symptomatology. These are beyond the scope of the current discussion.

Another type of assessment procedure for depression severity involves clinician-based interviews, representing the view that some of the symptoms of depression are more objectively characterized by a trained observer than by subjective selfreport. The most widely used such instrument is the Hamilton Rating Scale for Depression (HRSD; Hamilton, 1960). It has been amended and altered several times over the years. It is focused much more on somatic and behavioral symptoms than on mood and cognitive symptoms as is typical in self-report questionnaires. In its most commonly administered form, the Hamilton is a 17-item scale measuring mood, guilt, suicidal ideation, sleep disorders, changes in work and interests, psychomotor agitation and retardation, anxiety, somatic symptoms, hypochondriasis, loss of insight, and loss of weight. It has been shown to have solid psychometric properties, and is nearly always included in clinical studies and treatmentoutcomes research. Nevertheless, it does not cover all symptoms of the DSM-IV syndrome of depression, and has been criticized therefore as less adequate for assessing severity of bipolar depression. Revisions include the Inventory of Depressive Symptomatology–Clinician rated (IDS-C; Rush, Gullion, Basco, Jarrett, & Trivedi, 1996) and the Revised Hamilton Rating Scale for Depression (RHRSD; Warren, 1994).

Course and Consequences of Unipolar Depression

Much of what clinicians once believed about depression— that it occurs mostly in middle and older adulthood and rarely in youngsters and that it is commonly expressed as a single episode with full recovery—has been found to be untrue. The following sections discuss key features of depression, and its consequences in the lives of sufferers and their families.

Features of Unipolar Depression

Age of Onset

Researchers have documented that the most typical age of onset of major depression is adolescence and young adulthood (Burke, Burke, Regier, & Rae, 1990). Young women in particular have enormous liability for depression onset between ages 15 and 19 (Burke et al., 1990); 50% of respondents with depression histories reported onset by age 25 (Sorenson, Rutter, & Aneshensel, 1991). Generally speaking, the risk of first episode is significantly higher before age 40 than earlier (Coryell, Endicott, & Keller, 1992a). There are two important implications. One is that depression is especially likely to affect young people during critical periods of their development, including marriage, childbearing, and establishment of careers. Impairment during these important functions might have persisting maladaptive consequences. Asecond implication is that relatively early onset of depression—or perhaps of any psychological disorder—may portend a relatively worse course of illness, both because of developmental disruptions and because earlier onset may reflect a more severe form of the disorder.

The issue of whether childhood or early adolescent onset of depression predicts higher rates of depression in adulthood has been examined in a small number of longitudinal studies. In the largest follow-up study of the continuity of childhood depression into adulthood, Weissman, Wolk, Wickramaratne, et al. (1999) determined that although the youngsters had relatively high rates of psychological disorders and maladjustment, there was poor specificity for depressive disorders— except in a small sample that had recurrent episodes in childhood and high rates of depressed relatives. Similar results were reported by Harrington, Fudge, Rutter, Pickles, and Hill (1990) in a follow-back study. Thus, childhood onset of depression may predict significant disorder, but not specifically recurring depression—suggesting that many cases labeled as childhood depression may reflect marked emotional and behavioral dysregulation. In contrast, several follow-up studies of adolescent-onset depression have shown relatively high risk for recurring episodes in adulthood (e.g., Bardone, Moffitt, Caspi, Dickson, & Silva, 1996; Harrington et al., 1990; Lewinsohn, Rohde, Klein, & Seeley, 1999; Rao, Hammen, & Daley, 1999; Weissman, Wolk, Goldstein, et al., 1999).

Episode Length

Two trends are noteworthy concerning duration of major depressive episodes. One is that the majority of episodes appear to resolve within 6 months (including untreated depressions), as shown by longitudinal studies of the natural course of unipolar disorder. For instance, Coryell et al. (1994), in the National Institute of Mental Health (NIMH) Collaborative Depression Study (CDS), found that 55% of patients and 57% of nonclinical relatives who developed depression recovered by 6 months. The second trend, however, is that a substantial minority of depressions persist for long periods, and may even be chronic. For instance, the CDS follow-up reported that after 5 years, 12% of patients had still not recovered (Keller et al., 1992). Even among those who no longer meet diagnostic criteria for an episode, there may continue to be considerable residual symptomatology. Data from the CDS indicate that unipolar patients manifested symptoms during 59% of the weeks of the follow-up, with many never being free of some level of depressive symptoms (e.g., Judd et al., 1998).

Risk for Recurrence of Depression

Whereas depression, except in its most severe forms, was once considered a relatively benign disorder with recovery as the norm, it is now recognized that depression is especially pernicious not only because of protracted symptomatology, but also because it is highly recurrent. More than 80% of depressed adults experience at least one recurrence—a figure increasing to 100% if minor or subsyndromal episodes are included; and the median number of MDEs is four (reviewed in Judd, 1997). Recurrent episodes of MDE last about 20 weeks (Solomon et al., 2000). An international study conducted under the auspices of the World Health Organization found that over 10 years, affected individuals experienced a mean of 2.7 episodes of major depression, and spent an average of 27.5% of their lives in depressive episodes (Thornicroft & Sartorius, 1993). Similar frequencies and probabilities of recurrent MDE have been observed in adolescent depressed populations including both community and clinical samples (e.g., McCauley et al., 1993; Rao et al., 1999).

Another feature of the recurrent nature of depressive episodes is the observation that each recurrence increases the probability of further episodes. Solomon et al. (2000) followed patients over a 10-year period, and found that the probability of recurrence after recovery from the index episode was 25% in the first year, 42% by two years, and 60% by 5 years. Moreover, as predicted, median time to recurrence decreased with subsequent episodes, and the converse also occurred: The longer the person remained well, the less likely he or she was to experience recurrence. The results suggest that episodes themselves increase likelihood of disorder, and the hypothesized mechanisms of the process are discussed in later sections.

Impairment Associated With Depressive Disorders

It is hardly surprising that the low mood, loss of interest, decreased energy, sense of futility, and low self-esteem associated with depressive disorders would result in dysfunction in important roles such as work, marital, and parental adjustment. What is more surprising is the extent of debility, resulting in as much or even more self-reported impairment than many serious medical disorders (e.g., Wells et al., 1989). In the language of illness burden to society due to economic and social disability as well as mortality, the World Health Organization has termed major depression the number-one cause of disability in the world, and the fourth greatest cause of disease burden (expected to move to second most important by the year 2020; Murray & Lopez, 1996). Depression is one of the few psychological disorders that can be said to be fatal. Mortality due to suicide has been estimated to affect about 15% of those with a diagnosis of major depressive episode (Clark & Fawcett, 1992), and some studies suggest that depression is also predictive of increased mortality associated with medical disorders such as heart attacks (e.g., Musselman, Evans, & Nemeroff, 1998).

In more specific terms of social disability, patients with major depression in the CDS sample compared with controls achieve lower educational and income levels, and have lower rates of employment and decreased occupational status (Coryell et al., 1993). Moreover, fewer of those with unipolar depression were married, and those who were married reported worse quality of relationships. Even relatively minor or subsyndromal depressions are also associated with impairment as noted previously (e.g., Gotlib et al., 1995;Wells et al., 1989). Detailed analyses of level of work and social adjustment as a function of level of symptomatology over several years of follow-up in the CDS sample indicated a fairly linear relationship between impairment and severity of depression (Judd et al., 2000). Individuals who suffer from double depression appear to be especially likely to have occupational and social impairment, and those with dysthymic disorder (including double depression) are more likely never married (Evans et al., 1996). Of additional interest is the finding in the Judd et al. study, as well as other reports, that impairment in role functioning persists, even when the person is no longer in an episode (e.g., Billings & Moos, 1985; Judd et al., 2000).

Not surprisingly, studies of the consequences of depression in children and adolescents also indicate significant impairment of functioning. Those with childhood or adolescent depression show relative difficulties in school performance and conduct, and problematic relationships with peers and family members (e.g., Lewinsohn et al., 1994; Puig-Antich et al., 1993; see reviews in Birmaher et al., 1996; Hammen & Rudolph, 1996). In addition to impaired current functioning, a unique concern for depressed youngsters is the possibility that depression interferes with acquisition of developmentally appropriate skills and attainments. As a consequence, depressed youngsters may be left behind in ways that may contribute to further stress and depressive experiences.

Effects of Depression on Others

There has been considerable research on a further aspect of depression’s toll: the effects of depression on others. A great deal of the social disability of depression is due to two particular aspects of impairment: maladaptive marital relationships and high risk for offspring of depressed parents to develop depression and other disorders. As noted previously, there is evidence of less frequency of marriage, or of greater marital dissatisfaction or divorce among depressed patients than nondepressed controls (Coryell et al., 1993; reviewed in Gotlib & Hammen, 1992). The romantic relationships of young women assessed over a 5-year period indicated that lower quality of the relationship at the end of the follow-up and the boyfriends’ dissatisfaction were significantly correlated with the amount of time the woman had spent in major depressive episodes (Rao et al., 1999). Other research has indicated that depressed women are more likely to be romantically involved with men who themselves have psychological disorders (assortative mating), potentially creating a stressful home environment (e.g., Hammen, 1991a; Merikangas, Weissman, Prusoff, & John, 1988). The important question of whether intimate relationship difficulties are unique and specific to depressive disorders has been addressed by Zlotnick, Kohn, Keitner, and Grotta (2000) with community data from the National Comorbidity Survey. These investigators found that participants with current diagnoses of major depressive episode or dysthymic disorder were significantly more likely to report more negative and less positive quality of their marital or intimate relationships than participants with nonaffective disorders. Moreover, the relative negativity was especially pronounced in their romantic relationships, and not seen in their attitudes about friendships.

Overall, it appears that depressed persons themselves—as well as their spouses—experience difficulties in the marital relationship. The processes by which such problems occur are not fully understood. Certainly, depression symptoms themselves may create friction and mutual dissatisfaction. Depressed people may also have impaired interpersonal skills and dysfunctional cognitions that reflect poor interpersonal problem-solving, often leading to conflict (e.g., Hammen, 1991b). They are often dependent on others, and seek reassurance in ways that distance others (Barnett & Gotlib, 1988; Joiner & Metalsky, 1995). Spouses and significant others may view the depressed person as a burden, causing worry, reducing the sharing of pleasurable activities, and rejecting suggestions for help or support. A survey of the attitudes of spouses toward their depressed partners found that they acknowledged numerous such problems, and 40% of them were sufficiently distressed by the depressed person to warrant treatment themselves (Coyne et al., 1987).

The other major area of difficulty for depressed people is high likelihood that their children will have depressive or other disorders. Numerous studies have now shown that the risk to offspring for developing depression and other disorders is very high, likely greater than 50% (reviews in Beardslee, Versage, & Gladstone, 1998; Downey & Coyne, 1990). Indeed, the risk is so pronounced that being a child of a depressed parent is often said to be the strongest predictive factor for youth depression. Numerous studies have attempted to shed light on the mechanisms by which risk is imparted. Certainly, genetic transmission may be one pathway. Additionally, however, it seems apparent from many observational studies of depressed women with their infants, toddlers, and school-age children that the quality of the parent-child interaction is relatively more negative than for nondepressed mothers and their youngsters (e.g., reviewed in Goodman & Gotlib, 1999; Kaslow, Deering, & Racusin, 1994). Similarly, depressed children and adolescents have more negative relationships with their parents (Kaslow et al., 1994). Being a child in a family with a depressed parent also typically subjects the child to elevated levels of chronic stress (including parent marital disorder) and episodic life events, which may also contribute to children’s risk for disorder (e.g., Hammen, 2002).

An important consequence of impaired marital and family relationships is that the impact of the depressed person on family members may create a context that endures even when the person is no longer depressed. Difficult marital issues and problematic relationships with ill children may present enduring challenges to depressed adults, contributing not only to the persistence of impairment but also to the risk for further depression.

Who Is Affected by Unipolar Depression?

Rates of Depression

In the United States, the most recent epidemiological survey of adults between the ages of 15 and 54, using the CIDI as described earlier, reported a rate of 4.9% current major depression, and 17% lifetime major depression (Kessler et al., 1994). Earlier surveys had reported substantially lower rates but used different methods as noted previously. An international collaborative study, using various methods to arrive at DSM-III diagnoses, indicated an annual rate of major depression ranging from 0.8% in Taiwan to 5.8% in New Zealand (with the United States at 3% annually; Weissman et al., 1996). This study also reported lifetime rates of MDE between 1.5% and 19% across the various sites. Additionally, dysthymic disorder is estimated to affect 2–4% of the population internationally (Smith & Weissman, 1992).

Depressive disorders in young children are relative rare, possibly affecting 2–3% of preadolescents and 1% of preschoolers (Angold & Costello, 1993; Kashani & Carlson, 1987). However, epidemiological surveys of diagnoses among children have been much more limited in scope than those for adults. Data on rates of adolescent depression generally indicate much higher rates than in childhood. For instance, the Oregon Adolescent Depression Study found that 3% met criteria for current major depression or dysthymia, and a total of 20% had a lifetime diagnosis of depressive disorder (Lewinsohn, Hops, Roberts, Seeley, &Andrews, 1993).

Gender, Age, and Depression

Sex Differences in Depression

For many years a striking gender difference has been noted, with many more women reporting—or being treated—for depressive disorders than men. The Cross-National Collaborative Group (Weissman et al., 1996) found a gender difference in every culture studied, and overall, the rate of approximately 2:1 is cited indicating women’s prevalence among those with unipolar depressive disorders.

The gender gap appears to emerge in early adolescence (e.g., Angold & Rutter, 1992; Cohen et al., 1993). The magnitude of the gender difference—and its emergence in early adolescence—have stimulated many theories and research efforts to explain the patterns (e.g., reviewed in Cyranowski, Frank, Young, & Shear, 2000; Nolen-Hoeksema, 1990; Nolen-Hoeksema & Girgus, 1994). A variety of biological and psychosocial perspectives have been pursued with no final resolution, including hormonal effects and timing of puberty; differential exposure to stressors; gender differences in self-esteem, cognition, and coping; societal expectations and access to achievement; and many others. A review of this literature is beyond the scope of this research paper, but the implications are significant for theoretical models of depression, treatments, and prevention programs.

Age Trends in Depression

A further challenge to models of understanding depression concerns evidence that young people are experiencing increasing rates of depression. Not only is the age of onset of depression now known to be in the teens or early 20s for most sufferers, but the rates of depression appear to be higher in more recently born people. For instance, the Cross-National Collaborative Group (1992) found that rates of depression increased in birth cohorts such that they were highest by age 25 in those who had been born since 1955. The rate appears to be continuing to increase in more recently born youngsters, with rates in adolescent and young women higher than 30% (e.g., Lewinsohn, Rohde, Seeley, & Fischer, 1993; Rao et al., 2000). Although methodological artifacts such as memory bias have been argued to be a partial cause, recent evidence based on use of the same instrument over a 40-year period in the same community confirms that rates of depression have indeed increased in young women (Murphy, Laird, Monson, Sobol, & Leighton, 2000). Conversely, many studies have suggested that the rates of depression in older adults have been declining—although information on the very old is typically absent from most surveys (e.g., Murphy et al., 2000; see Wallace & O’Hara, 1992).

Theories of the origins of increased rates of depression in young people, especially females, abound. It has been suggested that changing cultural trends including family breakups and increasing social mobility diminishing supportive resources plus increased stress in the form of heightened expectations and increased competition for careers may have contributed. Such age trends appear to be a particular challenge to theories emphasizing biological diatheses. Nevertheless, the issue remains unresolved, while its consequences continue to be of considerable concern and interest.

Unipolar Depression: Theories of Etiologyand Vulnerability

There are numerous biological and psychosocial perspectives on the origins of depression, and new findings emerge frequently following advances in the technologies for evaluating genetic and neurobiological processes. Consequently, the etiology sections can attempt only a brief statement of these approaches, and the current directions in which research is proceeding. It is safe to say that nearly all models adopt a diathesis-stress perspective, and many assume a biological predisposition that may require activation by environmental stressors. It is noted, however, that few studies have tested such interactions.

Biological Approaches

Genetic Vulnerability to Unipolar Depression

Depression undeniably runs in families. Many studies of the first-degree relatives of depressed patients have reported rates of depression ranging between 7% and 30% across studies— considerably in excess of rates in the general population (Gershon, 1990; Winokur, Coryell, Keller, Endicott, & Leon, 1995). Studies of the children of depressed parents, as noted previously, have indicated that having a parent with a depressive disorder is one of the strongest predictors of youth depression (reviewed in Beardslee et al., 1998).

Of course, family studies do not prove a genetic mechanism of transmission, given potential effects of the family environment. Moreover, there is no evidence of a single depressive gene or defect—and likely never will be, given the apparent heterogeneity of depression and multiple causal pathways. However, genetic strategies that are less confounded with environmental factors are also suggestive. Twin studies using modern biometric model-testing analyses have proven to be highly suggestive. Kendler and colleagues (e.g., Kendler, Neale, Kessler, Heath, & Eaves, 1992) have published a series of studies based on a population-based twin registry in Virginia. Initially focused on female twins (Kendler et al., 1992), the authors found significantly higher monozygotic (MZ) concordance than dizygotic (DZ) concordance, recently replicated with male twin pairs (Kendler & Prescott, 1999). Biometric twin-modeling statistical analyses concluded that the genetic liability accounted for 39% of the risk for MDE in both male and female twin pairs, with the remaining 61% of the variance attributable to individual-specific factors (such as stressful events). McGuffin, Katz, Watkins, and Rutherford (1996) also conclude that there is a moderate role of genetic factors in depression, based on their inpatient sample.To date, however, there is no consensus on whether more severe forms of depression are especially likely to be genetically related (e.g., Kendler, Gardner, & Prescott, 1999; Lyons et al., 1998; McGuffin et al., 1996).

Psychoneuroendocrinology of Depression

Even though suggestive, genetic studies to date do not tell what it is that might be transmitted. Brain functioning and neuroendocrine processes may provide possible mechanisms. Considerable evidence implicates dysregulation of the human stress response of the hypothalamic-pituitaryadrenal (HPA) axis in depressive disorders. Numerous studies have found elevated levels of cortisol, a hormone resulting in various forms of physical arousal and activation, in acutely depressed people compared to nondepressed people (as well as increased levels of corticotropin releasing factor, or CRF). When individuals are no longer depressed, cortisol levels return to normal. In addition to hypersecretion of cortisol, investigators have observed abnormalities in the regulation of cortisol. A review of 100 studies of abnormal cortisol regulation and clinical course concluded that the abnormalities themselves did not predict treatment outcome, but when the abnormalities continued even after treatment, they portended poorer prognosis and high likelihood of relapse (Ribeiro, Tandon, Grunhaus, & Greden, 1993). Thus, the subset of depressed people with abnormal HPA functioning may have a worse type of depression, or at least a form that perhaps stems from an underlying disorder of the stress response system.

Stress-related neuroendocrine processes may also affect brain development, predisposing to depression. Plotsky, Owens, and Nemeroff (1998) recently reviewed research on stress and HPA-related hormones and their effects on the brain. They speculated that early stress experiences may sensitize specific neural circuits, resulting in depressive reactions in later life in response to stressful life events (see also Gold, Goodwin, & Chrousos, 1988; Sapolsky, 2000). Most of the relevant research has been conducted on animals, but a growing body of human research has shown abnormal HPA axis functioning associated with adverse childhood experiences such as insecure attachment and abuse experiences (e.g., Gunnar, 1998; Heim, Ehlert, Hanker, & Hellhammer, 1998). However, information about continuity of effects into childhood or their direct and specific link with depressive reactions has yet to be established.

Neurotransmitters and Depression Vulnerability

There has been considerable historical interest in the potential role of monoamine neurotransmitters such as serotonin, norepinephrine, and dopamine in mood disorders. These neurotransmitters are especially important in the limbic system of the brain, areas affecting drives and emotions, and pathways to other parts of the brain. The original catecholamine hypothesis of depression (Schildkraut, 1965) emphasizing relative deficits of these substances has proven to be far too simplistic, yielding to greater focus on amine receptor systems (McNeal & Cimbolic, 1986) and models of dysregulation of neurotransmitters (e.g., Siever & Davis, 1985). Recently, attention has turned particularly to serotonin (5-HT) models of depression (reviewed in Maes & Meltzer, 1995), suggesting that vulnerability to depression may arise from alterations in presynaptic 5-hydroxytryptamine (5HT) activity and postsynaptic serotonin receptor functioning. Moreover, since the hippocampus is a site of serotonergic innervation of the regulation of the HPA axis, it has been speculated that lowered central 5HT activity in depression may attenuate hippocampal feedback control over the HPA axis, inducing excessive corticosteroid secretion (Maes & Meltzer, 1995). Experimental analogue studies involving challenges with depletion of serotonin precursors that induce temporary depression in remitted patients (e.g., Smith, Fairburn, & Cowen, 1997) provide further suggestive evidence that serotonin processes may be involved in some forms of depression. Recent data also implicate a role of other neurotransmitters, such as norepinephrine and dopamine. It should be kept in mind that neurotransmitters are intimately interrelated with other neuroendocrine processes in the brain, and the interactions among them are extremely difficult to tease apart. Moreover, most of the cross-sectional designs of such studies make it difficult to draw definitive conclusions about whether depression results from—or causes—abnormalities of brain functioning.

Functional and Structural Brain Changes in Depression

It has long been known that certain medical conditions with brain lesions cause depression (e.g., certain strokes, neurodegenerative diseases), prompting a search for particular areas of the brain associated with depressive symptoms. Neuroimaging studies have reported some evidence of structural abnormalities in the brains of depressed people, such as reduced frontal volume (Coffey et al., 1993). A review by Kennedy, Javanmard, and Vaccarino (1997) concludes that the evidence shows reduced metabolic rate and reduced blood flow during depressive states, and consistent evidence of abnormalities in the functions of the prefrontal and cigulate cortices—areas closely linked with limbic and paralimbic structures. However, as noted earlier, research designs have been unable to demonstrate when such observed abnormalities are stable, and whether they are the cause or the result of depressive disorders.

Electrophysiological research on frontal brain activity by Davidson and colleagues has resulted in a model of emotional reactivity that may have considerable promise as a vulnerability factor in negative emotional states such as depression (e.g., Davidson, 1993). He observed that depressed patients and even previously depressed but remitted patients showed relative left frontal hypoactivation. Davidson proposed that decreased left prefrontal activation represents an underactivation of an approach system, thus reducing the person’s tendency to experience pleasure and positively engagement with the environment while enhancing the likelihood of developing depressive symptoms. Interestingly, several studies have found that infants and toddlers with depressed mothers display relative left frontal hypoactivation (e.g., Jones, Field, Fox, Lundy, & Davalos, 1997). Investigators have speculated that the patterns may be genetically transmitted—or acquired prenatally or in early stressful interactions with a depressed mother—andmayrepresentamechanismofriskfor development of depression.

Additional Topics in the Biology of Depression

Abnormalities of the circadian rhythms affecting the sleepwake cycle as well as cortisol and other bodily processes have been hypothesized to contribute to mood disorders. Numerous studies have demonstrated not only clinical complaints of sleep disturbances but also abnormalities of sleep waves—in stages such as rapid eye movement (REM) and slow-wave sleep. Research on circadian rhythm abnormalities is discussed further in the section on bipolar disorder.

The relatively higher rates of depression among women has stimulated much speculation on a hormonal component to vulnerability to depression. To date, however, there is little evidence of a major role of hormones in clinical mood disorders. It has been noted that even massive changes in hormonal levels such as those accompanying childbirth are associated with only minor depressive symptoms, called postpartum blues. A recent review of changes involving such hormones as progesterone, estrogen, prolactin, and others associated with postpartum major depression notes the negative or inconsistent findings (Hendrick, Altshuler, & Suri, 1998). The authors conclude that while there is no evidence of an etiologic role for the hormones, some women may experience mood changes because they are extremely sensitive to hormone levels. It is noteworthy that this field of study has focused mainly on levels of hormones, while degrees of change and the interactions among ovarian and stress-related hormones are promising topics that merit further study pending methodological improvements.

Psychological Models of Depression

Historically, psychodynamic theories of depression (melancholia) variously emphasized the experience of loss and intrapersonal dynamics including self-esteem and close relationships. Many of these same themes have been studied in more modern models of depression, and several themes are recognized as important contributors to depression vulnerability: stressful life events including loss; negative cognitive representations of the self and the world; quality of close relationships including childhood experiences.

Cognitive Vulnerability to Depression

Aaron Beck’s original (1967) cognitive model of depression was the first to illuminate the characteristically negative thinking of depressed people, and to assign causal significance in the phenomenology of depressive disorders to selfcritical, pessimistic, helpless, and hopeless interpretations of the self and the world. Beck’s approach gave rise to a veritable paradigm shift in clinical science in its focus on the significance and measurement of conscious thoughts and cognitive processes in psychopathology. Beck’s approach was highly successful in describing depressive thinking, and stimulated the development of related but somewhat different approaches to understanding vulnerability to depression in adults (e.g., Abramson, Alloy, & Metalsky, 1989; see reviews in Ingram, Miranda, & Segal, 1998; Segal & Ingram, 1994) and in children (e.g., reviews in Garber & Flynn, 2001; Hammen & Rudolph, 1996). Both questionnaire-based and experimental information-processing methods are presently being employed by researchers to test the power of the cognitive vulnerability models to predict who is at risk for depression and under what conditions it might develop (e.g., Alloy et al., 2000).

The cognitive perspective has been the dominant psychological model of depression for more than two decades, and is bolstered both by research and common sense (i.e., that the way people think about the misfortunes that may befall them is what determines reactions to stressors, and that some people are prone to magnify the sense of being incompetent or diminished by negative events). However, these approaches have not been well supported as playing a causal role in the origin of depression, nor is it established that their contributions are necessary, substantial, and specific to depression (e.g., Hammen, 2000). Hammen emphasized the need for greater integration of the cognitive perspectives with developmental, contextual, and biological approaches.

Stressful Life Events

There is strong empirical support for an association between significant stressful life events and depressive syndromes, in both community and clinical samples (e.g., Dohrenwend, Shrout, Link, Martin, & Skodol, 1986; Shrout et al., 1989). For instance, in Brown and Harris’s (1989) review of seven community studies, approximately 70–95% of individuals who developed cases of depression experienced a prior severe life event, compared with 25–40% among those who did not develop depression.

Although these studies indicate that most depressions are triggered by a significant negative life event, the obverse raises the critical question of vulnerability: Most people who do experience even major negative events do not become depressed. Why do some people become depressed and others do not? One approach, a multiple risk-factor model, suggests that depression occurs in the context not only of stressors, but also of chronic strains and diminished resources for coping, such as social support (e.g., Lewinsohn, Hoberman, & Rosenbaum, 1988; Moos, Cronkite, & Moos, 1998). Brown and colleagues (e.g., Brown & Harris, 1978, 1989; Brown, Andrews, Harris, Adler, & Bridge, 1986) have shown empirical support for their model that includes life-event occurrence in the context of chronic stressors, reduced support, and psychological conditions such that the negative event is especially meaningful in terms of the person’s values, commitments, and self-esteem.

Many studies have indicated that severe childhood adversities, such as physical or sexual abuse, may predict adult histories of depression among women (e.g., Kessler & Magee, 1993; McCauley et al., 1997). Such work has not revealed the mechanisms by which such experiences result in risk for depression, and depression is by no means the specific consequence of childhood adversities.

A refinement of the life-stress approaches suggests that individuals may be particularly vulnerable to some stressors more than to others. Specifically, individuals differ in the sources of their self-esteem and sense of mastery, with some individuals experiencing personal worth as deriving from the achievement of highly valued goals and control (autonomy), whereas others are more likely to invest themselves and their self-definitions in personal relationships with others (sociotropy). Negative events occurring in the vulnerable domain may be especially interpreted as depletions of the sense of worth and competence, leading to depression. Several studies have found support for the life event–vulnerability matching approach in adults(e.g.,Hammen,Marks,Mayol,& DeMayo, 1985; Segal, Shaw, Vella, & Katz, 1992) and children (Hammen & Goodman-Brown, 1990).

Another focus on stressful life events has emphasized the role that depressed people may play in the occurrence of stressful events. While research has clearly demonstrated the effects of stressors in precipitating depression among those who are vulnerable, other studies have shown that the behaviors of depressed women—even when not currently in a depressive episode—may contribute to the occurrence of stressors, especially stressors with interpersonal conflict themes (Daley et al., 1997; Hammen, 1991a). Depressed women may have difficult relationships with their children—and with their own spouses (e.g., Gotlib, Lewinsohn, & Seeley, 1998)—and may lack the skills to deal with problematic personal relationships. More over, depressed women are especially likely to marry men with psychopathology (e.g., Hammen, 1991b), thereby contributing to a stressful personal environment that may cause further depressive reactions. In a family or interpersonal context marked by conflict, repeated depressive experiences may occur.

An additional form of vulnerability to stressful life events may result from a sensitization process in which early exposure to significant stressors may increase the likelihood that subsequent stressors may trigger depression. Both psychological mechanisms of cognitive sensitization, as well as neurobiological changes in the developing brain, have been posited to account for such processes (e.g., Post, 1992; Sapolsky, 2000; Segal, Williams, Teasdale, & Gemar, 1996). Hammen, Henry, and Daley (2000) showed that young women’s reports of early childhood adversity were associated with lowered levels of stress prior to depression onset compared with women who developed depression but who did not have early adversity. Clinical lore, and a few empirical studies, have suggested that repeated episodes of depression are progressively less associated with stress, such that triggering stressors may eventually become unnecessary for episodes to occur (e.g., Post, 1992). One recent longitudinal study appeared to support this model (Kendler, Thornton, & Gardner, 2000). Direct evidence of the neurobiological consequences of children’s exposure to severe stressors, as well as for animal models (e.g., reviewed in Plotsky et al., 1998; Sapolsky, 2000) suggest that this integrative stress-biology perspective may hold considerable promise for understanding depression vulnerability.

Interpersonal Approaches to Depression Vulnerability

There has been increasing research and theoretical interest in interpersonal aspects of depression. Initially, work in this area emphasized the debilitating social consequences, such as the effects of depression on marital relations and children’s development, as noted previously. More recently, investigators have explored the role of interpersonal factors in the origin of depression, not only as social stressors precipitating episodes, but also in terms of the role that early parent-child relationships and interpersonal styles, needs, and cognitions may play in creating vulnerability to depression. No single model or theory defines this area, and readers may be referred to Gotlib and Hammen (1992), Psychological Aspects of Depression: Toward a Cognitive-Interpersonal Integration, and Joiner and Coyne (1999), The Interactional Nature of Depression, for more extended reviews. In the following sections, two interpersonal topics are discussed briefly.

Dysfunctional Parent-Child Relations

From various theoretical perspectives, including psychodynamic (e.g., Bowlby’s attachment theory; Bowlby, 1978, 1981) and social learning perspectives emphasizing the acquisition of interpersonal skills and self-views in the context of interactions with parents, many investigators have emphasized the important role of the quality of parent-child relations in vulnerability to depression. Studies have shown that depressed adults, as well as children and adolescents, report more negative relationships with their parents and show more evidence of insecure attachment (e.g., Kobak, Sudler, & Gamble, 1991; Rosenfarb, Becker, & Khan, 1994; reviewed in Gerlsma, Emmelkamp, & Arrindell, 1990; Kaslow et al., 1994). Insecure attachments are presumed to determine later beliefs, expectations, and behaviors in intimate relationships; maladaptive patterns may create vulnerability to depression. For example, a study of young women found that those with more negative cognitions about their ability to trust and depend on others were more likely to experience depression following a negative interpersonal life event than women who did not have such beliefs (Hammen et al., 1995).Although more longitudinal and prospective studies are needed to further validate the role of such experiences in risk for depression, the sheer volume of supportive findings indicates that parent-child relationships, especially those characterized by negative affect and harsher parental control, may contribute to a sense of personal inadequacy that promotes susceptibility to depression.

Dependency and Reassurance-Seeking

Dependency has long been recognized as a concomitant and risk factor for depression—as a trait, or as the diathesis in a diathesis-stress interaction (e.g., reviews by Barnett & Gotlib, 1988; Nietzel & Harris, 1990). As noted earlier, measures of sociotropy or dependency represent beliefs and schemas about the importance of contact and value by others, and when individuals high in such cognitions encounter negative interpersonal relationships, depressive reactions may result. Recently, Joiner and colleagues have speculated that reassurance-seeking may be an individual difference variable that serves as a vulnerability to develop depression. Reassurance-seeking is related to the construct of dependency—emotional reliance on others and the belief that affection, acceptance, and support of others are essential to well-being. Joiner and Metalsky (1995; see also Potthoff, Holahan, & Joiner, 1995) showed that a measure of reassurance-seeking predicted future depressive symptoms in students experiencing stressful situations.

Treatment of Depression

Since this research paper’s focus is psychopathology rather than treatment, only a brief overview of treatment issues is noted. Only 25 years or so ago, there were few effective treatment options for depression. However, there is now solid empirical evidence for success in treating the acute phase of depression with short-term structured psychotherapy or with a variety of antidepressant medications. Cognitive-behavioral therapy (CBT; see review in Hollon, Haman, & Brown, 2002) and interpersonal psychotherapy (IPT; see review in Weissman & Markowitz, 2002), as well as various tricyclic and selective serotonin reuptake inhibitors (SSRIs) and atypical medications (reviewed in Gitlin, 2002) are all approximately equally effective. Recently, evidence has suggested that CBTand IPT, as well as SSRI medications, may also be effective in reducing depression in children and adolescents (e.g., Brent et al., 1997; Emslie et al., 1997; reviewed in Kaslow, McClure, & Connell, 2002). Overall, medication studies indicate about 60–70% effectiveness in reducing depressive symptoms.

Since depressive episodes tend to recur, a critical question is whether treatments prevent relapse and recurrence. It has become standard pharmacotherapy practice to continue medications for 6 to 9 months beyond symptom remission to prevent relapse, and maintenance medication at full dosage may be recommended for those whose histories indicate a significant risk for recurrence. Among the psychotherapies, CBT is especially oriented toward teaching patients skills they can use to prevent future episodes, and some evidence of the success in reducing rates of relapse has been reported especially for CBT (e.g., Hollon et al., 2002). Maintenance (periodic) IPT sessions have also been shown to lower recurrence rates (e.g., Frank, Kupfer, Wagner, McEachran, & Cornes, 1991). Remaining questions about whether there are some kinds of depression (e.g., more severe, more vegetative) that respond better to medications than to therapy are largely unresolved. Also, the question of whether combined medication-psychotherapy treatments are better than either alone has resulted in mixed results (Hollon et al., 2002).

Accordingly, future research is needed to refine the issue of the best match between treatment type and patient characteristics. Moreover, additional challenges remain. For one thing, most people do not seek treatment for depression, and those who do often are the ones most likely to be impaired and to have comorbid conditions. Adolescents, for example, may require more than medication alone to resolve their complex symptoms and maladjustment in social and academic roles. Also, many individuals are not adherent to the medication regimens, or may require unique combinations of treatments. Thus, finding ways to disseminate treatments to those in need, helping them to improve their lives as well as reduce depressive symptoms, improving treatments for more complex cases, and improving methods of preventing relapse are all important priorities in the treatment field.

Bipolar Disorder

Compared with unipolar depression, bipolar disorder is much more rare and is presumed to have a fundamentally biological origin with a genetic diathesis. Its severe, recurrent course necessitates lifelong pharmacological treatment for most sufferers. Also in comparison to unipolar depression, bipolar disorder has been less studied, in part because its diagnostic boundaries and differences from unipolar disorders were defined only relatively recently (in the late 1970s). Nevertheless, efforts to treat this potentially severe disorder with empirically tested medications helped to usher in an era of clearer diagnostic criteria and the study of neural mechanisms of pharmacotherapy effects, which in turn played an important role in the development of modern neuroscience (Goodwin & Ghaemi, 1999).The following sections are relatively brief and descriptive, attempting to highlight the current understanding of this disorder and ongoing research activity on unresolved issues. A detailed account of bipolar disorder is presented in Goodwin and Jamison (1990), Manic-Depressive Illness.

Defining and Diagnosing Bipolar Disorder

Bipolar Diagnoses

The defining feature of bipolar disorder is the occurrence of a manic or hypomanic episode, or mixed states of mania and depression. The classical term manic-depressive illness has been replaced in recent years by the term bipolar disorder, because the former sometimes referred to recurrent depressive episodes in the absence of mania—a condition that nowadays would be called unipolar depression. Because both bipolar and unipolar disorder employ the same diagnostic criteria for presence of depressive episodes, diagnostic errors may occur. Individuals with current depression must be evaluated carefully for past history of mania or hypomania. Mania is defined as a period of persistently expansive, elevated, or irritable mood that is accompanied by at least three additional symptoms reflecting inflated self-esteem or grandiose thinking, marked cognitive changes such as distractibility or flight of ideas, pressured speech, decreased need for sleep, agitation or increased activity, and excessive involvement in pleasurable activities that have potentially harmful consequences. When similar symptoms are present but not severe enough to cause significant impairment of functioning or require hospitalization, the condition is termed hypomania. Mania must persist for at least a week, and hypomania for at least 4 days. Mania can be so severe as to include psychotic experiences and extremely destructive behaviors clearly signifying need for hospitalization, whereas hypomania may be brief and relatively mild—and therefore sometimes difficult to diagnose or recall. Mixed episodes refer to seemingly simultaneous or rapidly alternating manic and depressive symptoms. Bipolar I disorder is defined by presence of one or more manic episodes, whereas bipolar II disorder signifies history of hypomanic episodes and major depressive disorders.

Less severe mood swings that include numerous periods of highs and lows that do not meet criteria for mania or major depression may be diagnosed as cyclothymic disorder. Others have suggested that there may be additional variants of bipolar disorder in the subclinical bipolar spectrum, possibly portending risk for future bipolar I or II disorder or indicating stable bipolar temperaments or personalities (Akiskal, 1996; Depue, Krauss, Spoont, &Arbisi, 1989; Eckblad & Chapman, 1986; Lewinsohn, Klein, & Seeley, 1995). Research interest in further validation of bipolar diagnostic criteria or possible subtypes continues (e.g., Cassidy, Forest, Murry, & Carroll, 1998).

Diagnostic accuracy may be compromised by misperception of acute depressive episodes as unipolar when they are actually bipolar. Further problems may occur when severe psychotic symptoms of grandiosity or paranoia are misconstrued as schizophrenia. Also, the features of substance abuse and intoxication-related behaviors may make it difficult to recognize bipolar disorder. Such comorbid conditions or psychotic features may all contribute to the failure to recognize, accurately diagnose, and appropriate treat bipolar disorder. Indeed, as Goodwin and Ghaemi (1999) noted, about 40% of hospitalized patients they and colleagues had diagnosed as bipolar had not been diagnosed as bipolar by previous psychiatrists.

Substance abuse is an especially problematic comorbid condition (e.g., Kessler, Rubinow, Holmes, Abelson, & Zhao, 1997). For instance, Helzer and Pryzbeck (1988) found that individuals with bipolar I disorder had 6.2 times the likelihood of alcohol abuse as those in the general U.S. population. Not only may substance abuse problems prevent accurate diagnosis, but they are commonly associated with worse outcomes (e.g., Strakowski et al., 1998)—perhaps because they interfere with treatment adherence, but also because substances may affect biological brain processes that underlie the disorder. Personality disorders are also a common cooccurring problem among samples of bipolar patients, although potentially overlapping mood and behavioral symptoms require caution in interpretation. Studies that have attempted to examine personality disorder symptoms during remission of bipolar episodes have found particularly high rates of Cluster B disorders (e.g., Dunayevich et al., 1996; Peselow, Sanfilipo, & Fieve, 1995). Generally, as with other disorders, Axis II pathology generally predicts greater psychosocial maladjustment and more severe clinical course (e.g., Barbato & Hafner, 1998).

Diagnosis of Bipolar Disorder in Children and Adolescents

Diagnosis of bipolar disorder in adolescents is now relatively well accepted, although it is potentially challenging if the first episode is depression. The disorder is frequently either misdiagnosed because of confusing comorbid conditions, or mislabeled as schizophrenia, substance abuse, or disruptive behavioral disorders. Some investigators have reported relatively higher rates of mixed episodes and more rapid cycling in adolescent bipolar patients than in adults (e.g., Kutcher, Robertson, & Bird, 1998; McElroy, Strakowski, West, Keck, & McConville, 1997). Such cases may portend a relatively more difficult course of disorder than those who have relatively classic bipolar disorder (e.g., Stober et al., 1995).

Considerable controversy surrounds the question of childhood bipolar disorder (e.g., mania). Most investigators agree that such cases, although rare, definitely occur. Disagreement, however, concerns the frequency of occurrence and the accurate diagnosis of potentially ambiguous presentations, especially when longitudinal data are not available. A key problem is that childhood mania typically does not have features that help define adult mania: an acute onset, periods of relatively good functioning between episodes, and distinct periods of elevated mood or irritability. Geller et al. (1998) followed a well-defined sample of manic children with a mean onset age of 8.1 years, and reported that 75% had ultradian cycles (variation within 24 hr) and were chronically ill. Many presumed manic children show what appear to be mixed states, with intensely irritable moods and rages (e.g., Carlson & Kelly, 1998; Faraone, Biederman, Wozniak, et al., 1997). They are often aggressive and viewed as out of control, with severe impairment, and less evidence of euphoria and grandiosity than adults show (Faedda et al., 1995).

The apparent overlap of symptoms of mania and attentiondeficit/hyperactivity disorder (ADHD) is especially confusing. Symptoms of hyperactivity, heightened energy and restlessness, distractibility, racing thoughts and pressure to talk, and impulsivity may make it difficult to distinguish between ADHD and mania. However, systematic comparisons indicate significantly higher scores for mania symptoms in bipolar children with ADHD than in children with ADHD alone (Geller et al., 1998). In contrast to typical ADHD, children with bipolar disorder may be purposefully destructive; may have prolonged rages, temper tantrums, and rapidly shifting moods; and may even show gross distortions in the perception of reality (Papolos & Papolos, 1999; Weller, Weller, & Dogin, 1998).

Biederman and colleagues (Biederman, 1998; Faraone, Biederman, Mennin, et al., 1997; Faraone, Biederman, Wozniak, et al., 1997) argue that ADHD and bipolarity are comorbid disorders, possibly reflecting an etiological genetically transmitted subtype of bipolar disorder. These investigators argue that comorbidity with ADHD may be a marker of childhood-onset bipolar disorder. Biederman (1998) further suggests that many cases of juvenile bipolar disorder may be missed or misdiagnosed because they are mistaken for severe cases of ADHD, when in fact they are a subtype of bipolar disorder. Geller et al. (1998), however, have suggested thatADHD in young bipolar samples may be a phenocopy ADHD, driven by developmentally prevalent high energy in children. Geller predicts that, with age, the ADHD will decrease to population levels by adulthood. Thus,ADHD may be either a prodrome or developmentally expressed version of bipolarity in children, rather than a separate disorder. On the other hand, some have argued that what is called mania in children may often be a mislabeled, nonspecific severe psychopathology found in children, possibly a “multiple complex developmental disorder”—which suggests that there are conditions of severe emotional and behavioral dysregulation that we simply have yet to characterize adequately (e.g., Carlson & Kelly, 1998; Carlson, Loney, Salisbury, & Volpe, 1998). Clearly, longitudinal studies of purported bipolar disorder in children are needed to help resolve the diagnostic issues. Meanwhile, some suggest that at the very least, diagnosis of prepubertal bipolar disorder be made only by very experienced clinicians (e.g., Nottelman & Jensen, 1998).

Course of Bipolar Disorder

By definition, bipolar disorder is recurrent, with multiple lifetime episodes. One 5-year follow-up of patients with mood disorders indicated more total episodes for those with bipolar than for those with unipolar disorders (Winokur, Coryell, Keller, Endicott, & Akiskal, 1993). A subgroup of bipolar I patients (possibly 20–30%) seemingly do not experience depression, and therefore have only manic episodes (Kessler et al., 1997). Individuals vary additionally in whether they have depression following or preceding mania, whether they have polyphasic course patterns, and whether their patterns are consistent or inconsistent. Several studies have suggested that there may be prognostic significance to the patterning of episodes. The most extensive longitudinal study, the NIMH CDS, examined the association with patterning and outcome in patients with bipolar I over a period of up to 15 years (Turvey et al., 1999). They found that most bipolar patients had consistent polarity patterns, especially those whose episodes started with mania. Those with cycles that commenced with depressive episodes tended to have longer episodes and spent an average of 30% of the follow-up in an affective episode, compared to 18% in those with maniconset patterns. Also, those whose episodes began with depression were more likely to have chronic illness courses over time. Based on close analysis of symptom patterns in bipolar patients in the same sample over a 15-year period, Coryell et al. (1998) concluded that there may be a depressive subtype of bipolar I disorder, marked by persistent depressive symptoms observable during the first 2 years of follow-up and continuing over the entire period, accompanied by poor prognosis in psychosocial adjustment.

Two additional bipolar I patterns have been especially associated with poor prognosis, as defined by multiple and frequent episodes, incomplete recovery, and psychosocial impairment. One concerns rapid cycling, defined as four or more episodes in a year’s time. Rapid cycling is found to occur in approximately 5–15% of patients in treatment, and is more common among women (e.g., Coryell et al., 1992b). It is sometimes a side effect of antidepressant treatment, especially if treatment is administered in the absence of concurrent mood stabilizers. Also, mixed state episodes of concurrent manic and depressive symptoms also appear to portend worse outcomes (e.g., Keller, Lavori, Coryell, Endicott, & Mueller, 1993).

It has often been noted, since Kraepelin (1921), that episodes become more frequent after the first few, up to a point at which frequency may stabilize (see also Goodwin & Jamison, 1990). This pattern has implications that are discussed later, concerning kindling and the pathophysiology of bipolar disorder.

Age of onset of bipolar disorder has classically been viewed as occurring commonly in late teens and young adulthood. Kraepelin (1921) concluded that the greatest frequency of first episodes of manic depression occurs between the ages of 15 and 20. Supporting this observation, Faedda et al. (1995) summarized 28 studies that reported onset by age; overall, 25% of bipolar patients had onset before the age of 20. The authors suggest that this figure is probably inaccurate, noting that many of the original samples may have excluded child and early-onset cases owing to diagnostic biases and practices of the time. These findings are consistent with a retrospective self-report survey of 500 members of the National Depressive and ManicDepressive Association (Lish, Dime-Meenan, Whybrow, Price, & Hirschfeld, 1994). When individuals with bipolar disorder were asked to indicate their best estimate of age of symptom onset, 60% reported onset in childhood and adolescence. Research on age of onset is, of course, also hampered by definitions of onset. As Carlson, Bromet, and Sievers (2000) asked, does one date onset of bipolar disorder from first symptoms, first episode, first treatment, or first hospitalization—or first diagnosis? Establishing age of onset of bipolar disorder may have the further complication that first episodes may be depression, followed by an indeterminate interval before manic episodes occur and thus establish the diagnosis. Exemplifying the potential difficulty of accurate diagnosis if the first episode is major depression, several longitudinal studies have shown a switch rate of about 15% from apparent unipolar depression to bipolar disorder (e.g., Akiskal et al., 1995; Coryell et al., 1995). For childhood- or adolescent-onset depression the rates may be even higher. A review of seven studies of more than 250 depressed children and adolescents followed for 2–4 years reported a mean switch rate from depression to mania of about 25% (Faedda et al., 1995; see also Kovacs, 1996; Weissman, Wolk, Wickramaratne, et al., 1999).

The implications of accurate diagnosis may be especially important for those with childhood or adolescent onset. Several studies have indicated that earlier onset of bipolar disorder portends a more pernicious clinical course with more social impairment (Carlson et al., 2000; Lish et al., 1994; Schurhoff et al., 2000). Moreover, it is commonly hypothesized that early detection and appropriate treatment may lessen the course of illness, based on the presumed neurobiological processes in which episodes actually alter the brain and accentuate a possible kindling mechanism (as will be discussed further).

Whereas bipolar I patients may experience both mania and hypomania along with major depressive episodes, bipolar II patients experience only hypomania and major depressive episodes. Over time, the pattern appears to be stable—this is, such individuals do not switch to manic episodes (Coryell et al., 1989). Episodes of depression are especially characteristic, and associated with impaired functioning.

Impairment and Consequences of Bipolar Disorder

It was once believed that most bipolar patients were relatively symptom free between episodes, and that the disorder could be relatively successfully treated with lithium monotherapy. However, in recent years several longitudinal studies have demonstrated considerable variability in bipolar I patients’ courses and social functioning, with a far less rosy picture of treatment success. Harrow, Goldberg, Grossman, and Meltzer (1990) and Tohen, Waternaux, and Tsuang (1990) found that only a minority of bipolar I patients had good clinical and functional outcomes, despite apparently adequate lithium treatment. Gitlin, Swendsen, Heller, and Hammen (1995) followed patients for a mean of more than 4 years, and found that despite adequate treatment with mood stabilizers, 73% had at least one major episode of depression or mania, and most had multiple episodes. Moreover, there was considerable subclinical symptomatology, paralleled by impaired work and social adjustment.

Epidemiology of Bipolar Disorder

The rate of bipolar I disorder is generally about 1% of the population, although rates vary somewhat by country, and presumably, by diagnostic practices (Weissman et al., 1996). In the United States, somewhat different instruments in epidemiological surveys—the DIS versus the CIDI (as previously noted)—resulted in different rates. The former yielded a rate of bipolar I disorder of 0.8%, while the National Comorbidity Survey reported a rate of 1.6% (Kessler et al., 1994). These variations reflect not only diagnostic method differences and unreliability, but also, as observed previously, the fact that diagnostic distinctions regarding bipolar disorder may be difficult, compounded by the relatively poor recognition or insight of affected individuals about their own manic and hypomanic experiences. Bipolar II disorder is estimated to affect somewhere between 0.3 and 3.0% of the population, and bipolar spectrum disorders, depending on how defined, may affect between 3.0 and 6.5% (Angst, 1998).

Unlike the rates of unipolar depression, the rates of bipolar I disorder are approximately the same for men and women (Weissman et al., 1996), although bipolar II disorder is diagnosed more frequently in women than men. Absence of striking gender differences is often seen as consistent with the view of a biological basis of bipolar disorder.

Etiological Approaches to Bipolar Disorder

Genetic Studies

There is solid evidence of heritability of bipolar disorder. Family studies have consistently revealed an interesting pattern: Both unipolar and bipolar disorders (mania) occur in relatives of bipolar patients, whereas only unipolar disorder is found among relatives of unipolar patients (e.g., Winokur et al., 1995). This distinctive pattern has helped to confirm that bipolar disorder is a separate disorder from unipolar depression. In addition to family studies, twin studies indicate heritability. A review by NIMH (1998) indicated that concordance rates for bipolar I disorder in monozygotic twins range between 33 and 80%.

For several years the focus of genetic research was on discovery of a single genetic locus, often based on isolated extended families with high rates of bipolar illness (e.g., Baron et al.,1987;Egelandetal.,1987).Mostfindings,however,were not replicated, and modern genetic techniques have identified multiple possible chromosome locations, including chromosomes 18, 21q, 11, and others (e.g., Bellivier et al., 1998; see review in Kelsoe, 1997). Despite interest in single-locus approaches, most research now suggests a polygenic disorder (Goodwin & Ghaemi, 1999). Current major bipolar genetic studies are underway to help resolve the genetic issues.

In addition to genetic research, there is considerable interest in discovery of potential markers of risk for bipolar disorder in children of bipolar parents. A meta-analysis of high-risk studies indicated that children of bipolar parents had a 52% likelihood of some diagnosis, with a risk of 26.5% of mood disorders (Lapalme, Hodgins, & LaRoche, 1997). Bipolar disorder occurred in 5.4% of the offspring of bipolar parents, whereas none of the children of non-ill parents were bipolar. Obviously this figure cannot be taken as the final estimate of risk for bipolarity, because most of the children had not passed—or even entered—the age of risk. The figure of 15–20% is often cited as the risk for developing bipolar disorders in offspring of a bipolar parent (e.g., Goodwin & Ghaemi, 1999). To date, high-risk research has yet to identify symptom, psychological, genetic, or biological markers of potential bipolar diathesis. Discovery of bipolar-related genes, for example, could help to identify children who might benefit from early treatment (see treatment section, later).

Neuroregulatory Processes in Bipolar Disorder

Presuming genetic predisposition to bipolar disorder, the mechanism of the illness is unknown. However, any model must be able to explain clinical features of the disorder, suchas recurrent episodes and the switches from one state to another, as well as apparent progression in severity and frequency of episodes. On the basis of animal research, Post (e.g., Post, 1992; Post, Rubinow, & Ballenger, 1984) has speculated that processes resembling kindling or behavioral sensitization may operate in which the brain is altered by repeated episodes of mood disorder, resulting in increased sensitivity to neurotransmitter and neurohormonal regulation of mood in response to stressors or other triggering experiences. This hypothesis is consistent with the clinical observation that the severity of untreated episodes worsens over time, and that early episodes are more likely triggered by stressors whereas later episodes are not. Several studies have shown nonspecific brain abnormalities but present conflicting evidence of correlation of extent of abnormality with length of illness (e.g.,Altshuler et al., 1995; Dupont et al., 1995; Strakoswki et al., 1999). Recently, a study found neurocognitive impairments, especially those of memory and learning, that were strongly correlated with total duration of lifetime episodes (Van Gorp, Altshuler, Theberge, Wilkins, & Dixon, 1998). Consistent with Post’s model, these authors speculated that repeated bipolar episodes may induce hippocampal dysfunction (with memory and learning impairment) through the toxic effects of episode- or stress-induced hypercortisolemia. Although the kindling model is intriguing, its empirical basis remains to be further developed.

Other models of brain and neurotransmitter functioning have been articulated over the years (e.g., Schildkraut, 1965; dopamine and the behavioral facilitation system, according to Depue & Iocono, 1989; and others). Simple neurotransmitter approaches have not captured much recent attention in isolation. However, relatively recent research on the mechanisms responsible for the effectiveness of lithium and antidepressants has led to important advances in understanding complex neurobiological processes. As Goodwin and Ghaemi (1999) phrase it, current thinking favors “the evolution from synaptic neurotransmitter-based hypotheses to . . . postsynaptic second messenger-based hypotheses” (p. 47). Research in this area promises to shed new light not only on possible bipolar illness–related abnormalities but on other disorders as well.

Circadian-Rhythm Abnormalities

Neurotransmitter systems also may be a mechanism through which hypothesized abnormalities in circadian rhythms cause episodes. Wehr (e.g., Wehr & Goodwin, 1983) suggested that brain abnormalities affecting regulation of daily biological rhythms may cause desynchronization of the cycles, leading to clinical symptoms—as well as to seasonal patterns of mood episodes. Patterns of seasonal variation of mood and associated biological states—in both unipolar and bipolar patients—have contributed to considerable research interest in chronobiological processes in mood disorders (Goodwin & Jamison, 1990). Interestingly, disrupted sleep cycles are well known to trigger manic episodes in some bipolar patients, leading clinicians to urge individuals with bipolar I disorders to be cautious about sleep loss, international travel, and other sleep-altering patterns.

Psychosocial Processes in Bipolar Disorder

Although modern theories of bipolar disorder do not view it as fundamentally caused by psychological processes, a small but growing body of research emphasizes the importance of such factors in potentially influencing the course of illness. It is also possible that psychological and environmental factors play a role in triggering the disorder among those who may be biologically predisposed. It is clear that psychological factors play a role in treatment outcome and adherence to medication.

A number of studies have shown that stressful life events may affect the course of disorder by triggering episodes of depression and mania (e.g., reviewed in Johnson & Roberts, 1995). Quality of family and spouse support also appear to affect outcome, in that more negative family attitudes toward the patient significantly predict increased likelihood of relapse (Miklowitz, Goldstein, Nuechterlein, Snyder, & Mintz, 1988), and better social support in general appears to predict a more favorable course of disorder (Johnson, Winett, Meyer, Greenhouse, & Miller, 1999). To date, however, research has not been designed to test potentially important predictors of manic versus depressive experiences, and such questions are important. Also, considerably more work is needed to help understand the psychosocial predictors of the vastly different outcomes—both clinical and functional—that are observed among bipolar patients.

Treatment of Bipolar Disorder

Medications are the primary treatment for bipolar disorders, and are indicated for reduction of manic (antimanic drugs) or depressive (antidepressant drugs) symptoms in the short run, and prevention of episodes over time (mood stabilizers). Lithium is the most frequently used and effective antimanic and mood stabilizer medication. Up to 2 weeks of lithium treatment may be needed to achieve significant reduction of manic symptoms (APA, 1994b), and treatment of acute mania may also include use of neuroleptics. Regarding lithium’s prophylactic effect, a review of 10 double-blind, placebo-controlled studies indicated a significantly lower probability or intensity of an episode in those taking lithium, compared with placebo (Goodwin & Jamison, 1990). Despite the enormous treatment advances that lithium brought about in the early 1960s, however, recent studies, as indicated previously, have shown that many patients have relatively high rates of relapse and symptoms despite adequate lithium treatment. It has been argued that recent investigations may include many patients who have more treatment-resistant forms of disorder, or who have problems with medication compliance. It is also suspected that lithium is especially effective for those who have classic bipolar I disorder, with manic and depressive episodes, but less so for those with mixed or cycling episodes. Moreover, due to lithium’s potential toxicity and various side effects—as well as to patients’ reduced insight about the need for continuous medication—compliance with lithium may be problematic, requiring continuing medical monitoring and support. It has also been suggested, although not empirically resolved, that periodic discontinuation of lithium may reduce its effectiveness in episode prevention.

In recent years, several additional mood stabilizer medications that are pharmacological antiseizure drugs have been used with apparently good results in treatment of acute mania—and apparently (although less well established empirically) with prophylactic effects as well. Sodium valproate, for example, is suspected to be more effective than lithium for patients who have mixed states and rapid cycling (APA, 1994b). Although it, too, is associated with bothersome side effects (such as weight gain), it is not toxic. Carbamazepine is also apparently effective as an antimanic and mood stabilizer medication, but may have serious adverse side effects including fatal toxicity.

Use of antidepressants to treat depression in bipolar patients is problematic, because they may trigger manic episodes and have been implicated in the emergence of rapidcycling bipolar episodes. Indeed, it has been speculated that recent studies of the relatively poor showing for lithium prophylaxis may reflect illness courses that are more difficult to treat in part because of the widespread use of antidepressants without concurrent mood stabilizers (e.g., Goodwin & Ghaemi, 1999). Psychiatrists are urged to use antidepressants with caution in bipolar patients. New drugs with safer antidepressant properties are currently being evaluated.

An intriguing issue in treatment concerns the implications of the previously mentioned kindling hypothesis: the idea that early intervention in the course of disorder may prevent the development of future episodes by eliminating the cumulative pathological effects of episodes themselves. There is considerable interest in detection of bipolar disorder in children and those at risk due to genetic factors to enable early intervention. Lithium treatment of children and adolescents is relatively well established, but the long-term effects have not been evaluated in terms of the kindling hypothesis.

There is also increasing interest in psychotherapy and psychosocial interventions for bipolar patients as an adjunct to pharmacological treatment (e.g.,APA, 1994b).Anumber of issues have been targeted: education about the illness, identification of prodromal signs of impending episodes, management of lifestyles to promote stable sleep and social patterns conducive to more stable moods, dealing with issues of personal identity and self-esteem in the face of destructive mood swings, encouragement of adherence to medication, and improved personal and family communications and problem solving. Family process, cognitive-behavioral, and interpersonal psychotherapy models are currently being applied and studied (e.g., Frank, Swartz, & Kupfer, 2000; reviewed in Johnson, Greenhouse, & Bauer, 2000).

Conclusions and Future Directions

The past two decades have seen enormous amounts of research on mood disorders, contributing substantially to the understanding of unipolar and bipolar disorders in children, adolescents, and adults. Future work on the further identification of the disorder, the clarification of risk markers, and the longitudinal course of disorders in children will be a high priority, especially to test the hypotheses that early intervention may quell the severity of the course of recurrent mood disorders. High-risk studies of the offspring of unipolar parents have been highly informative, but new ground will be broken by more integrative approaches that include multiple and interacting factors, including both biological and psychosocial variables. High-risk research in bipolar families is of great interest but in need of further attention.

Additional clarification of possible subtypes of unipolar and bipolar disorders, including subclinical variants, will be necessary to fully understand the ranges and courses of the disorders and their distributions in the population. However, it would be unfortunate to focus only on syndromal conditions, since specific symptoms and constellations of characteristics— such as negative affectivity or behavioral activation—may also be productive for further study.

Research on etiological factors will continue to mine the advances in genetic and neuroscience models and techniques. However, a hugely important issue is the integration of biological and psychosocial models. Although there are increasing signs of such integration, important advances in mood disorders will require developments in conceptualization and methods that employ strategies from multiple fields.

Both pharmacological and psychological treatments have proven to be successful in reducing depressive symptomatology. The challenge in this topic is to extend the effectiveness of such interventions to reduce recurrence and prevent future episodes. Among bipolar patients, treatment options are somewhat more limited, but advances are being made on both the medication and psychotherapy fronts. However, an important consideration in both unipolar and bipolar populations is dissemination of treatments, and encouragement of those in need to get treatment. Surprisingly large numbers of both depressed and bipolar patients are not being treated at all, or are not being treated aggressively enough. The obstacles appear to include recognition of the illnesses as well as lack of widespread use of treatment guidelines and limited availability of empirically supported therapies outside the university communities. Treatments of children are particularly challenging and important, and preventive interventions require continued exploration.

Finally, the demographics of mood disorders command ongoing interest: Depression has increased in young people and continues to affect women disproportionately. All our assessment, etiological models, and treatments need to contend with and shed further light on this reality.

Bibliography:

1. Abramson, L. Y., Alloy, L. B., & Metalsky, G. I. (1989). Hopelessness depression: A theory-based subtype of depression. Psychological Review, 96, 358–372.
2. Akiskal, H. S. (1996). The prevalent clinical spectrum of bipolar disorders: Beyond DSM-IV. Journal of Clinical Psychopharmacology, 16, 4S–14S.
3. Akiskal, H. S., Maser, J. D., Zeller, P. J., Endicott, J., Coryell, W., Keller, M., Warshaw, M., Clayton, P., & Goodwin, F. (1995). Switching from “unipolar” to bipolar II: An 11-year prospective study of clinical and temperamental predictors in 559 patients. Archives of General Psychiatry, 52, 114–123.
4. Alloy, L. B., Abramson, L. Y., Hogan, M. E., Whitehouse, W. G., Rose, D. T., Robinson, M. S., Kim, R. S., & Lapkin, J. B. (2000). The Temple-Wisconsin Cognitive Vulnerability to Depression Project: Lifetime history of Axis I psychopathology in individuals at high and low cognitive risk for depression. Journal of Abnormal Psychology, 109, 403–418.
5. Altshuler, L. L., Curran, J. G., Hauser, P., Mintz, J., Denicoff, K., & Post, R. (1995). T₂ hyperintensities in polar disorder: Magnetic resonance imaging comparison and literature meta-analysis. American Journal of Psychiatry, 152, 1139–1144.
6. American Psychiatric Association. (1994a). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: Author.
7. American Psychiatric Association. (1994b). Practice guideline for the treatment of patients with bipolar disorder. Supplement to the American Journal of Psychiatry, 151, 1–36.
8. Angold, A., & Costello, E. J. (1993). Depressive comorbidity in children and adolescent: Empirical, theoretical, and methodological issues. American Journal of Psychiatry, 150, 1779–1791.
9. Angold, A., & Rutter, M. (1992). Effects of age and pubertal status on depression in a large clinical sample. Development & Psychopathology, 4, 5–28.
10. Angst, J. (1998). The emerging epidemiology of hypomania and bipolar II disorder. Journal of Affective Disorders, 50, 143–151.
11. Barbato, N., & Hafner, R. J. (1998). Comorbidity of bipolar and personality disorder. Australian and New Zealand Journal of Psychiatry, 32, 276–280.
12. Bardone, A., Moffitt, T., Caspi, A., Dickson, N., & Silva, P. (1996). Adult mental health and social outcomes of adolescent girls with depression and conduct disorder. Development and Psychopathology, 8, 811–829.
13. Barnett, P. A., & Gotlib, I. H. (1988). Psychosocial functioning and depression: Distinguishing among antecedents, concomitants, and consequences. Psychological Bulletin, 104, 97–126.
14. Baron, M., Risch, N., Hamburger, R., Mandel, B., Kushner, S., Newman, M., Drumer, D., & Belmaker, R. H. (1987). Genetic linkage between X-chromosome markers and bipolar affective illness. Nature, 326, 289–292.
15. Beardslee, W. R., Versage, E. M., & Gladstone, T. R. (1998). Children of affectively ill parents: A review of the past 10 years. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 1134–1141.
16. Beck, A. T. (1967). Depression: Clinical, experimental, and theoretical aspects. New York: Harper & Row.
17. Beck, A. T., Steer, R. A., & Brown, G. K. (1996). Manual for the BDI-II. San Antonio, TX: Psychological Corporation.
18. Beck, A. T., Steer, R. A., & Garbin, M. G. (1988). Psychometric properties of the Beck Depression Inventory: Twenty-five years of evaluation. Clinical Psychological Review, 8, 77–100.
19. Beck, A. T., Ward, C. H., Mendelsohn, M., Mock, J., & Erbaugh, J. (1961). An inventory for measuring depression. Archives of General Psychiatry, 4, 561–571.
20. Bellivier,F.,Leboyer,M.,Courtet,P.,Buresi,C.,Beaufils,B.,Samolyk, D., Allilaire, J., Feingold, J., Mallet, J., & Malafosse, A. (1998). Association between the tryptophan hydroxylase gene and manicdepressive illness. Archives of General Psychiatry, 55, 33–37.
21. Biederman, J. (1998). Resolved: Mania is mistaken for ADHD in prepubertal children. Journal of the American Academy of Child and Adolescent Psychiatry, 37(10), 1091–1093.
22. Billings, A. G., & Moos, R. H. (1985). Psychosocial processes of remission in unipolar depression: Comparing depressed patients with matched community controls. Journal of Consulting and Clinical Psychology, 53, 314–325.
23. Birmaher,B.,Ryan,N.D.,Williamson,D.E.,Brent,D.A.,Kaufman, J., Dahl, R. E., Perel, J., & Nelson, B. (1996). Childhood and adolescent depression: Pt. 1. A review of the past 10 years. Journal of the American Academy of Child and Adolescent Psychiatry, 35, 1427–1439.
24. Blazer, D. G., Kessler, R. C., McGonagle, K. A., & Swartz, M. S. (1994). The prevalence and distribution of major depression in a national community sample: The national comorbidity survey. American Journal of Psychiatry, 151, 979–986.
25. Bowlby, J. (1978). Attachment and loss: Vol. 2. Separation: Anxiety and anger. Harmondsworth, England: Penguin.
26. Bowlby, J. (1981). Attachment and loss: Vol. 3. Loss: Sadness and depression. Harmondsworth, England: Penguin.
27. Brent, D. A., Holder, D., Kolko, D., Birmaher, B., Baugher, M., Roth, C., Iyengar, S., & Johnson, B. A. (1997). A clinical psychotherapy trial for adolescent depression comparing cognitive, family, and supportive therapy. Journal of the American Academy of Child and Adolescent Psychiatry, 54, 877–885.
28. Brown, G. W., Andrews, B., Harris, T. O., Adler, Z., & Bridge, L. (1986). Social support, self-esteem, and depression. Psychological Medicine, 16, 813–831.
29. Brown, G. W., & Harris, T. O. (1978). Social origins of depression. London: Free Press.
30. Brown, G. W., & Harris, T. O. (1989). Depression. In G. W. Harris & T.O.Harris(Eds.),Lifeeventsandillness(pp.49–93).NewYork: Guilford Press.
31. Burke, K. C., Burke, J. D., Regier, D. A., & Rae, D. S. (1990). Age at onset of selected mental disorders in five community populations. Archives of General Psychiatry, 47, 511–518.
32. Carlson, G. A., Bromet, E. J., & Sievers, S. (2000). Phenomenology and outcome of subjects with early- and adult-onset psychotic mania. American Journal of Psychiatry, 157(2), 213–219.
33. Carlson, G. A., & Kelley, K. L. (1998). Manic symptoms in psychiatrically hospitalized children—what do they mean? Journal of Affective Disorders, 51, 123–135.
34. Carlson, G.A., Loney, J., Salisbury, H., &Volpe, R. J. (1998).Young referred boys with DICA-Pmanic symptoms vs. two comparison groups. Journal of Affective Disorders, 121, 113–121.
35. Clark, D. C., & Fawcett, J. (1992). Review of empirical risk factors for evaluation of the suicidal patient. In B. M. Bongar (Ed.), Suicide: Guidelines for assessment, management, and treatment (pp. 16–48). New York: Oxford University Press.
36. Coffey, C. E., Wildinson, W. E., Weiner, R. D., Parashos, I. A., Djang, W. T., Webb, M. C., Figiel, G. S., & Spritzer, C. E. (1993). Quantitative cerebral anatomy in depression: A controlled magnetic resonance imaging study. Archives of General Psychiatry, 50, 7–16.
37. Cohen, P., Cohen, J., Kasen, S., Velez, C. N., Hartmark, C., Johnson, J., Rojas, M., Brook, J., & Streuning, E. L. (1993). An epidemiological study of disorders in late childhood and adolescence: I. Age and gender-specific prevalence. Journal of Child Psychology and Psychiatry, 34, 851–867.
38. Coryell, W., Akiskal, H., Leon, A., Winokur, G., Maser, J., Mueller, T., & Keller, M. (1994). The time course of nonchronic major depressive disorder: Uniformity across episodes and samples. Archives of General Psychiatry, 51, 405–410.
39. Coryell, W., Endicott, J., & Keller, M. (1992a). Major depression in a nonclinical sample: Demographic and clinical risk factors for first onset. Archives of General Psychiatry, 49, 117–125.
40. Coryell, W., Endicott, J., & Keller, M. (1992b). Rapid cycling affective disorder: Demographics, diagnosis, family history, and course. Archives of General Psychiatry, 49, 126–131.
41. Coryell, W., Endicott, J., Maser, J. D., Keller, M. B., Leon, A. C., & Akiskal, H. S. (1995). Long-term stability of polarity distinctions in the affective disorders. American Journal of Psychiatry, 152, 385–390.
42. Coryell, W., Keller, M., Endicott, J., Andreasen, N., Clayton, P., & Hirschfeld, R. (1989). Bipolar II illness: Course and outcome over a five-year period. Psychological Medicine, 19, 129–141.
43. Coryell, W., Scheftner, W., Keller, M., Endicott, J., Maser, J., & Klerman, G. L. (1993). The enduring psychological consequences of mania and depression. American Journal of Psychiatry, 150, 720–727.
44. Coryell, W., Turvey, C., Endicott, J., Leon, A. C., Mueller, T., Solomon, D., & Keller, M. (1998). Bipolar I affective disorder: Predictors of outcome after 15 years. Journal of Affective Disorders, 50, 109–116.
45. Coyne, J. C., Kessler, R. C., Tal, M., Turnbull, J., Wortman, C. B., & Greden, J. F. (1987). Living with a depressed person. Journal of Consulting and Clinical Psychology, 55, 347–352.
46. Cross-National Collaborative Group. (1992). The changing rate of major depression: Cross-national comparisons. Journal of the American Medical Association, 268, 3098–3105.
47. Cyranowski, J. M., Frank, E., Young, E., & Shear, M. (2000). Adolescent onset of the gender difference in lifetime rates of major depression: Atheoretical model. Archives of General Psychiatry, 57, 21–27.
48. Daley, S., Hammen, C., Burge, D., Davila, J., Paley, B., Lindberg, N., & Herzberg, D. (1997). Predictors of the generation of episodic stress: A longitudinal study of late adolescent women. Journal of Abnormal Psychology, 106, 251–259.
49. Davidson, R. J. (1993). Cerebral asymmetry and emotion: Conceptual and methodological conundrums. Cognition and Emotion, 7, 115–138.
50. Depue, R. A., & Iacono, W. G. (1989). Neurobehavioral aspects of affective disorders. Annual Review of Psychology, 40, 457– 492.
51. Depue, R. A., Krauss, S., Spoont, M. R., & Arbisi, P. (1989). General Behavior Inventory identification of unipolar and bipolar affective conditions in a nonclinical university population. Journal of Abnormal Psychology, 98, 117–126.
52. Dohrenwend, B. P., Shrout, P. E., Link, B., Martin, J., & Skodol, A. (1986). Overview and initial results from a risk-factor study of depression and schizophrenia. In J. E. Barrett (Ed.), Mental disorder in the community: Progress and challenges (pp. 184–215). New York: Guilford Press.
53. Downey, G., & Coyne, J. C. (1990). Children of depressed parents: An integrative review. Psychological Bulletin, 108, 50–76.
54. Dunayevich, E., Strakowski, S. M., Sax, K. W., Sorter, M. T., Keck, P. E., Jr., McElroy, S. L., & McConville, B. J. (1996). Personality disorders in first- and multiple-episode mania. Psychiatry Research, 64, 69–75.
55. Dupont, R. M., Jernigan, T. L., Heindel, W., Butters, N., Shafer, K., Wilson, T., Hesselink, J., & Gillin, C. (1995). Magnetic resonance imagining and mood disorders: Localization of white matter and other subcortical abnormalities. Archives of General Psychiatry, 52, 747–755.
56. Eaton, W. W., Neufeld, K., Chen, L., & Cai, G. (2000). A comparison of self-report and clinical diagnostic interviews for depression. Archives of General Psychiatry, 57, 217–222.
57. Eckblad, M., & Chapman, L. J. (1986). Development and validation of a scale for hypomanic personality. Journal of Abnormal Psychology, 95, 214–222.
58. Egeland, J. A., Gerhard, D. S., Pauls, D. L., Sussex, J. N., Kidd, K. K., Allen, C. R., Hostetter, A. M., & Housman, D. E. (1987). Bipolar affective disorders linked to DNA markers on chromosome 11. Nature, 325, 783–787.
59. Emslie, G. J., Rush, A. J., Weinberg, W. A., Kowatch, R. A., Hughes, C. W., Carmody, T., & Rintelmann, J. (1997). A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Archives of General Psychiatry, 54, 1031–1037.
60. Endicott, J., & Spitzer, R. L. (1978). A diagnostic interview: The schedule for affective disorders and schizophrenia. Archives of General Psychiatry, 35, 837–844.
61. Evans, S., Cloitre, M., Kocsis, J. H., Keitner, G. I., Holzer, C. P., & Gniwesch, L. (1996). Social-vocational adjustment in unipolar mood disorders: Results of the DSM-IV field trial. Journal of Affective Disorders, 38, 73–80.
62. Faedda, G., Baldessarini, R., Suppes, T., Tondo, L., Becker, I., & Lipschitz,D.(1995).Pediatric-onsetbipolardisorder:Aneglected clinicalandpublichealthproblem.HarvardReviewofPsychiatry, 3, 171–195.
63. Faraone, S. V., Biederman, J., Mennin, D., Wozniak, J., & Spencer, T. (1997). Attention-deficit hyperactivity disorder with bipolar disorder: A familial subtype? Journal of the American Academy of Child and Adolescent Psychiatry, 36, 1378–1387.
64. Faraone,S.V., Biederman,J.,Wozniak, J.,Mundy, E., Mennin, D., & O’Donnell, D. (1997). Is comorbidity with ADHD a marker for juvenile-onset mania? Journal of theAmericanAcademy of Child and Adolescent Psychiatry, 36(8), 1046–1055.
65. First, M. B., Spitzer, R. L., Gibbon, M., & Williams, J. B. W. (1995). Structured clinical interview for DSM-IV Axis I disorders. Washington, DC: American Psychiatric Press.
66. Frank, E., Kupfer, D. J., Wagner, E. F., McEachran, A. B., & Cornes, C. (1991). Efficacy of interpersonal psychotherapy as a maintenance treatment of recurrent depression. Archives of General Psychiatry, 48, 1053–1059.
67. Frank, E., Swartz, H., & Kupfer, D. (2000). Interpersonal and social rhythm therapy: Managing the chaos of bipolar disorder. Biological Psychiatry, 48, 593–604.
68. Garber, J., & Flynn, C. (2001). Vulnerability to depression in childhood and adolescence. In R. Ingram & J. Price (Eds.), Vulnerability to psychopathology: Risk across the lifespan (pp. 175– 225). NewYork: Guilford Press.
69. Geller, B., Williams, M., Zimerman, B., Frazier, J., Beringer, L., & Warner, K. L. (1998). Prepubertal and early adolescent bipolarity differentiate from ADHD by manic symptoms, grandiose delusions, ultra-rapid or ultradian cycling. Journal of Affective Disorders, 51, 81–91.
70. Gerlsma, C., Emmelkamp, P. M. G., & Arrindell, W. A. (1990). Anxiety, depression, and perception of early parenting: A metaanalysis. Clinical Psychology Review, 10, 251–277.
71. Gershon, E. S. (1990). Genetics. In F. K. Goodwin & K. R. Jamison (Eds.), Manic depressive illness (pp. 373–401). New York: Oxford University Press.
72. Gitlin, M. J. (2002). Pharmacologic treatment for depression. In I. H. Gotlib & C. Hammen (Eds.), Handbook of depression (pp. 360–382). New York: Guilford Press.
73. Gitlin, M., Swendsen, J., Heller, T., & Hammen, C. (1995). Relapse and impairment in bipolar disorder: A longitudinal study. American Journal of Psychiatry, 152, 1635–1640.
74. Gold, P. W., Goodwin, F. K., & Chrousos, G. P. (1988). Clinical and biochemical manifestations of depression: Relation to the neurobiology of stress. The New England Journal of Medicine, 319, 348–419.
75. Goodman, S., & Gotlib, I. (1999). Risk for psychopathology in the children of depressed mothers: A developmental model for understanding mechanisms of transmission. Psychological Review, 106, 458–490.
76. Goodman, S. H., Schwab-Stone, M., Lahey, B. B., Shaffer, D., & Jensen P. S. (2000). Major depression and dysthymia in children and adolescents: Discriminant validity and differential consequences in a community sample. Journal of the AmericanAcademy of Child and Adolescent Psychiatry, 39, 761– 770.
77. Goodwin, F., & Ghaemi, S. N. (1999). Bipolar disorders: State of the art. Dialogues in Clinical Neuroscience, 1, 41–51.
78. Goodwin, F. K., & Jamison, K. R. (1990). Manic-depressive illness. New York: Oxford University Press.
79. Gotlib, I. H., & Hammen, C. L. (1992). Psychological aspects of depression: Toward a cognitive-interpersonal integration. London: Wiley.
80. Gotlib, I. H., Lewinsohn, P. M., & Seeley, J. R. (1995). Symptoms versus a diagnosis of depression: Differences in psychosocial functioning. Journal of Consulting and Clinical Psychology, 65, 90–100.
81. Gotlib, I., Lewinsohn, P., & Seeley, J. (1998). Consequences of depression during adolescence: Marital status and marital functioning in early adulthood. Journal of Abnormal Psychology, 107, 686–690.
82. Gunnar, M. R. (1998). Quality of early care and buffering of neuroendocrine stress reactions: Potential effects on the developing human brain. Preventive Medicine, 27, 208–211.
83. Hamilton, M. (1960). A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry, 12, 56–62.
84. Hammen, C. L. (1991a). Depression runs in families: The social context of risk and resilience in children of depressed mothers. New York: Springer-Verlag.
85. Hammen, C. L. (1991b). The generation of stress in the course of unipolar depression. Journal of Abnormal Psychology, 100, 555–561.
86. Hammen, C. L. (2000). Vulnerability to depression in adulthood. In R. Ingram & J. Price (Eds.), Handbook of vulnerability to psychopathology: Risk across the lifespan (pp. 226–257). New York: Guilford Press.
87. Hammen, C. L. (2002). The context of stress in families of children with depressed parents. In S. Goodman & I. Gotlib (Eds.), Children of depressed parents: Alternative pathways to risk for psychopathology (pp. 175–179). Washington, DC: American Psychological Association.
88. Hammen, C. L., Burge, D., Daley, S., Davila, J., Paley, B., & Rudolph, K. (1995). Interpersonal attachment cognitions and prediction of symptomatic responses to interpersonal stress. Journal of Abnormal Psychology, 104, 436–443.
89. Hammen, C. L., & Compas, B. (1994). Unmasking unmasked depression: The problem of comorbidity in childhood depression. Clinical Psychology Review, 14, 585–603.
90. Hammen, C. L., & Goodman-Brown, T. (1990). Self-schemas and vulnerability to specific life stress in children at risk for depression. Cognitive Therapy and Research, 14, 215–227.
91. Hammen, C. L., Henry, R., & Daley, S. (2000). Depression and sensitization to stressors among young women as a function of childhood adversity. Journal of Consulting and Clinical Psychology, 68, 782–787.
92. Hammen,C.L.,Marks,T.,Mayol,A.,&deMayo,R.(1985).Depressive self-schemas, life stress, and vulnerability to depression. Journal ofAbnormal Psychology, 94, 308–319.
93. Hammen, C., & Rudolph, K. (1996). Childhood depression. In E. J. Mash & R. A. Barkley (Eds.), Child psychopathology (pp. 153–195). New York: Guilford Press.
94. Harrington, R., Fudge, H., Rutter, M., Pickles, A., & Hill, J. (1990). Adult outcomes of childhood and adolescent depression: Psychiatric status. Archives of General Psychiatry, 47, 465–473.
95. Harrow, M., Goldberg, J. F., Grossman, L. S., & Meltzer, H. Y. (1990). Outcome in manic disorders: A naturalistic follow-up study. Archives of General Psychiatry, 47, 665–671.
96. Heim, C., Ehlert, U., Hanker, J. P., & Hellhammer, D. H. (1998). Abuse-related post-traumatic stress disorder and alterations of the hypothalamic-pituitary-adrenal axis in women with chronic pelvic pain. Psychosomatic Medicine, 60, 309–318.
97. Helzer, J. E., & Pryzbeck, T. R. (1988). The co-occurence of alcoholism with other psychiatric disorders in the general population and its impact on treatment. Journal of Studies on Alcohol, 49, 219–224.
98. Hendrick, V., Altshuler, L. L., & Suri, R. (1998). Hormonal changes in the postpartum and implications for postpartum depression. Psychosomatics, 39, 93–101.
99. Hollon, S. D., Haman, K. L., & Brown, L. L. (2002). Cognitive behavioral treatment of depression. In I. H. Gotlib & C. Hammen (Eds.), Handbook of depression (pp. 383–403). New York: Guilford Press.
100. Horwath, E., Johnson, J., Klerman, G. L., & Weissman, M. M. (1992). Depressive symptoms as relative and attributable risk factors for first-onset major depression. Archives of General Psychiatry, 49, 817–823.
101. Ingram, R. E., Miranda, J., & Segal, Z. V. (1998). Cognitive vulnerability to depression. New York: Guilford Press.
102. Johnson, S., Greenhouse, W., & Bauer, M. (2000). Psychosocial approaches to the treatment of bipolar disorder. Current Opinions in Psychiatry, 13, 69–72.
103. Johnson, S. L., & Roberts, J. R. (1995). Life events and bipolar disorder: Implications from biological theories. Psychological Bulletin, 117, 434–449.
104. Johnson, S. L., Winett, C., Meyer, B., Greenhouse, W., & Miller, I. (1999). Social support and the course of bipolar disorder. Journal of Abnormal Psychology, 108, 558–566.
105. Joiner, T., & Coyne, J. C. (Eds.). (1999). The interactional nature of depression: Advances in interpersonal approaches. Washington, DC: American Psychological Association.
106. Joiner, T. E., Jr., & Metalsky, G. I. (1995). A prospective test of an integrative interpersonal theory of depression: A naturalistic study of college roommates. Journal of Personality and Social Psychology, 69, 778–788.
107. Jones, N. A., Field, T., Fox, N. A., Lundy, B., & Davalos, M. (1997). EEG activation in 1-month-old infants of depressed mothers. Development and Psychopathology, 9, 491–505.
108. Judd, L. L. (1997). The clinical course of unipolar major depressive disorders. Archives of General Psychiatry, 54, 989–991.
109. Judd, L., Akiskal, A., Maser, J. D., Zeller, P. J., Endicott, J., Coryell, W., Paulus, M. P., Kunovac, J. L., Leon, A. C., Mueller, T. I., Rice, J. A., & Keller, M. B. (1998). A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders. Archives of General Psychiatry, 55, 694–700.
110. Judd, L. L., Akiskal, H. S., Zeller, P. J., Paulus, M., Leon, A. C., Maser, J. D., Endicott, J., Coryell, W., Kunovac, J. L., Mueller, T. I., Rice, J. P., & Keller, M. B. (2000). Psychosocial disability during the long-term course of unipolar major depressive disorder. Archives of General Psychiatry, 57, 375– 380.
111. Kashani, J. H., & Carlson, G. A. (1987). Seriously depressed preschoolers. American Journal of Psychiatry, 144, 348–350.
112. Kaslow, N. J., Deering, C. G., & Racusin, G. R. (1994). Depressed children and their families. Clinical Psychology Review, 14, 39–59.
113. Kaslow, N., McClure, E., & Connell, A. (2002). Treatment of depression in children and adolescents. In I. H. Gotlib & C. Hammen (Eds.), Handbook of depression (pp. 441–464). New York: Guilford Press.
114. Keller, M. B., Lavori, P. W., Coryell, M. D., Endicott, J., & Mueller, T. I. (1993). Bipolar I: A five-year prospective follow-up. The Journal of Nervous and Mental Disease, 181, 238–245.
115. Keller, M. B., Lavori, P. W., Endicott, J., Coryell, W., & Klerman, G.L.(1983).“Doubledepression”:Twoyearfollow-up.American Journal of Psychiatry, 140, 689–694.
116. Keller, M., Lavori, P. W., Mueller, T. I., Endicott, J., Coryell, W., Hirschfeld, R. M. A., & Shea, T. (1992). Time to recovery, chronicity, and levels of psychopathology in major depression. Archives of General Psychiatry, 49, 809–816.
117. Kelsoe, J. R. (1997). The genetics of bipolar disorder. Psychiatric Annals, 27, 285–292.
118. Kendler, K. S., Gardner, C. O., & Prescott, C. A. (1999). Clinical characteristics of major depression that predict risk of depression in relatives. Archives of General Psychiatry, 56, 322–327.
119. Kendler, K. S., Neale, M. C., Kessler, R. C., Heath, A. C., & Eaves, L. J. (1992). A population-based twin study of major depression in women. Archives of General Psychiatry, 49, 257–266.
120. Kendler, K. S., & Prescott, C. A. (1999). A population-based twin study of lifetime major depression in men and women. Archives of General Psychiatry, 56, 39–44.
121. Kendler, K. S., Thornton, L. M., & Gardner, C. O. (2000). Stressful life events and previous episodes in the etiology of major depression in women: An evaluation of the “Kindling” hypothesis. American Journal of Psychiatry, 157, 1243–1251.
122. Kennedy, S. H., Javanmard, M., & Vaccarino, F. J. (1997). A review of functional neuroimaging in mood disorders: Positron emission tomography and depression. The Canadian Journal of Psychiatry, 42, 467–475.
123. Kessler, R., & Magee, W. (1993). Childhood adversities and adult depression: Basic patterns of association in a U.S. national survey. Psychological Medicine, 23, 679–690.
124. Kessler, R., McGonagle, K., Zhao, S., Nelson, C., Hughes, M., Eshelman, S.,Wittchen, H., & Kendler, K. (1994). Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: Results from the National Comorbidity Survey. Archives of General Psychiatry, 51, 8–19.
125. Kessler, R. C., Rubinow, D. R., Holmes, C., Abelson, J. M., & Zhao, S. (1997). The epidemiology of DSM-III-R bipolar I disorder in a general population survey. Psychological Medicine, 27, 1079– 1089.
126. Klein, D. N., Taylor, E. B., Harding, K., & Dickstein, S. (1988). Double depression and episodic major depression: Demographic, clinical, familial, personality, and socioenvironmental characteristics and short-term outcomes. American Journal of Psychiatry, 145, 1226–1231.
127. Kobak, R. R., Sudler, N., & Gamble, W. (1991). Attachment and depressive symptoms during adolescence: A developmental pathways analysis. Development and Psychopathology, 3, 461– 474.
128. Kovacs, M. (1996). Presentation and course of major depressive disorder during childhood and later years of the life span. Journal of the American Academy of Child and Adolescent Psychiatry, 35(6), 705–715.
129. Kraepelin, E. (1921). Manic-depressive insanity and paranoia (R. M. Barclay, Trans.). Edinburgh, Scotland: Livingstone.
130. Kutcher, S. P., Robertson, H. A., & Bird, D. (1998). Premorbid functioning in adolescent onset bipolar I disorder: A preliminary report from an ongoing study. Journal of Affective Disorders, 51, 137–144.
131. Lapalme, M., Hodgins, S., & LaRoche, C. (1997). Children of parents with bipolar disorder: A meta-analysis of risk for mental disorders. Canadian Journal of Psychiatry, 42(6), 623– 631.
132. Lewinsohn, P. M., Hoberman, H., & Rosenbaum, M. (1988). A prospective study of risk factors for unipolar depression. Journal of Abnormal Psychology, 97, 251–264.
133. Lewinsohn,P.M.,Hops,H.,Roberts,R.E.,Seeley,J.R.,&Andrews, J. A. (1993). Adolescent psychopathology: I. Prevalence and incidence of depression and other DSM-III-R disorders in high school students. Journal of Abnormal Psychology, 102, 133–144.
134. Lewinsohn, P. M., Klein, D. N., & Seeley, J. R. (1995). Bipolar disorders in a community sample of older adolescents: Prevalence, phenomenology, comorbidity, and course. Journal of the American Academy of Child and Adolescent Psychiatry, 34(4), 454–463.
135. Lewinsohn, P. M., Roberts, R. E., Seeley, J. R., Rohde, P., Gotlib, I. H., & Hops, H. (1994). Adolescent psychopathology: II. Psychosocial risk factors for depression. Journal of Abnormal Psychology, 103, 302–315.
136. Lewinsohn, P. M., Rohde, P., Klein, D. M., & Seeley, J. R. (1999). Natural course of adolescent major depressive disorder: I. Continuity into young adulthood. Journal of the American Academy of Child andAdolescent Psychiatry, 38, 56–63.
137. Lewinsohn, P. M., Rohde, P., Seeley, J. R., & Fischer, S. A. (1993). Age-cohort changes in the lifetime occurrence of depression and other mental disorders. Journal of Abnormal Psychology, 102, 110–120.
138. Lish, J. D., Dime-Meenan, S., Whybrow, P. C., Price, R. A., & Hirschfeld, R. M. A. (1994). The National Depressive and Manic-Depressive Association (DMDA) survey of bipolar members. Journal of Affective Disorders, 31, 281–294.
139. Lyons, M. J., Eisen, S. A., Goldberg, J., True, W., Lin, N., Meyer, M., Toomey, R., Faraone, S. V., Merla-Ramos, M., & Tsuang, M. T . (1998). A registry-based twin study of depression in men. Archives of General Psychiatry, 55, 468–472.
140. Maes,M.,&Meltzer,H.Y.(1995).Theserotoninhypothesisofmajor depression. In F. E. Bloom & D. J. Kupfer (Ed.), Psychopharmacology: The fourth generation of progress (pp. 933–944). New York: Raven Press.
141. McCauley, E., Myers, K., Mitchell, J., Calderon, R., Schloredt, K., & Treder, R. (1993). Depression in young people: Initial presentation and clinical course. Journal of the American Academy of Child and Adolescent Psychiatry, 32, 714–722.
142. McCauley, J., Kern, D., Kolodner, K., Dill, L., Schroeder, A., DeChant, H., Ryden, J., Derogatis, L., & Bass, E. (1997). Clinical characteristics of women with a history of childhood abuse: Unhealed wounds. Journal of the American Medical Association, 277, 1362–1368.
143. McElroy, S. L., Strakowski, S. M., West, S. A., Keck, P. E., Jr., & McConville, B. J. (1997). Phenomenology of adolescent and adult mania in hospitalized patients with bipolar disorder. American Journal of Psychiatry, 154(1), 44–49.
144. McGuffin, P., Katz, R., Watkins, S., & Rutherford, J. (1996). A hospital-based twin register of the heritability of DSM-IV unipolar depression. Archives of General Psychiatry, 53, 129–136.
145. McNeal, E. T., & Cimbolic, P. (1986). Antidepressants and biochemical theories of depression. Psychological Bulletin, 99, 361–374.
146. Merikangas, K., Weissman, M., Prusoff, B., & John, K. (1988). Assortative mating and affective disorders: Psychopathology in offspring. Psychiatry, 51, 48–57.
147. Miklowitz, D. J., Goldstein, M. J., Nuechterlein, K. H., Snyder, K. S., & Mintz, J. (1988). Family factors and the course of bipolar affective disorder. Archives of General Psychiatry, 45, 225–231.
148. Moos, R. H., Cronkite, R. C., & Moos, B. S. (1998). Family and extra family resources and the 10-year course of treated depression. Journal of Abnormal Psychology, 107, 450–460.
149. Murphy, J. M., Laird, N. M., Monson, R. R., Sobol, A. M., & Leighton, A. H. (2000). A 40-year perspective on the prevalence of depression: The Stirling County Study. Journal of the American Medical Association, 57, 209–215.
150. Murray, C. J., & Lopez, A. D. (1996). The global burden of disease. Cambridge, MA: Harvard University Press.
151. Musselman, D., Evans, D., & Nemeroff, C.B. (1998). The relationship of depression to cardiovascular disease: Epidemiology, biology, and treatment. Archives of General Psychiatry, 55, 580– 592.
152. National Institute of Mental Health. (1998). Genetics and mental disorders: Report of the NIMH genetics workgroup (NIMH Publication No. NIH-98-4268). Bethesda, MD: Author.
153. Nezu, A. M., Ronan, G. F., Meadows, E. A., & McClure, K. S. (Eds.). (2000). Practitioner’s guide to empirically based measures of depression. New York: Kluwer Academic/Plenum.
154. Nietzel, M. T., & Harris, M. J. (1990). Relationship of dependency and achievement/autonomy to depression. Clinical Psychology Review, 10, 279–297.
155. Nolen-Hoeksema, S. N. (1990). Sex differences in depression. Stanford, CA: Stanford University Press.
156. Nolen-Hoeksema, S. N., & Girgus, J. S. (1994). The emergence of gender differences in depression during adolescence. Psychological Bulletin, 115, 424–443.
157. Nottelmann, E. D., & Jensen, P. S. (1998). Current issues in childhood bipolarity. Journal of Affective Disorders, 51, 77–80.
158. Papolos, D., & Papolos, J. (1999). The bipolar child: The definitive and reassuring guide to childhood’s most misunderstood disorder. New York: Broadway Books.
159. Peselow, E. D., Sanfilipo, M. P., & Fieve, R. R. (1995). Relationship between hypomania and personality disorders before and after successful treatment. The American Journal of Psychiatry, 152(2), 232–238.
160. Plotsky, P. M., Owens, M. J., & Nemeroff, C. B. (1998). Psychoneuroendocrinology of depression. Psychoneuroendocrinology, 21, 293–307.
161. Post, R. M. (1992). Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. American Journal of Psychiatry, 149, 999–1010.
162. Post, R. M., Rubinow, D. R., & Ballenger, J. C. (1984). Conditioning, sensitization, and kindling: Implications for the course of affective illness. In R. Post & J. Ballenger (Eds.), Neurobiology of mood disorders (pp. 432–466). Baltimore: Williams &
163. Potthoff, G., Holahan, C. J., & Joiner, T. E., Jr. (1995). Reassurance-seeking, stress generation, and depressive symptoms: An integrative model. Journal of Personality and Social Psychology, 68, 664–670.
164. Puig-Antich, J., Kaufman, J., Ryan, N. D., Williamson, D., Dahl, R. E., Lukens, E., Todak, G., Ambrosini, P., Rabinovich, H., & Nelson, B. (1993). The psychosocial functioning and family environment of depressed adolescents. Journal of the American Academy of Child and Adolescent Psychiatry, 32, 244–253.
165. Rao, U., Hammen, C., & Daley, S. (1999). Continuity of depression during the transition to adulthood: A5-year longitudinal study of young women. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 908–915.
166. Regier, D. A., Kaelber, C. T., Rae, D. S., Farmer, M. E., Knauper, B., Kessler, R. C., & Norquist, G. S. (1998). Limitations of diagnostic criteria and assessment instruments for mental disorders. Archives of General Psychiatry, 55, 109–115.
167. Ribeiro, S. C. M., Tandon, R., Grunhaus, L., & Greden, J. F. (1993). The DST as a predictor of outcome in depression: A metaanalysis. American Journal of Psychiatry, 150, 1618–1629.
168. Robins, L. N., Helzer, J. E., Croughan, J., & Ratcliff, K. S. (1981). National Institute of Mental Health Diagnostic Interview Schedule: Its history, characteristics, and validity. Archives of General Psychiatry, 38, 381–389.
169. Rosenfarb, I. S., Becker, J., & Khan, A. (1994). Perceptions of parental and peer attachments with mood disorders. Journal of Abnormal Psychology, 103, 637–644.
170. Rush, A. J., Gullion, C. M., Basco, M. R., Jarrett, R. B., & Trivedi, M. H. (1996). The Inventory of Depression Symptomatology (IDS):Psychometricproperties.PsychologicalMedicine,26,477– 486.
171. Sapolsky, R. M. (2000). Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Archives of General Psychiatry, 57, 925–935.
172. Schildkraut, J. J. (1965). The catecholamine hypothesis of affective disorders: Areview of supporting evidence. American Journal of Psychiatry, 122, 509–522.
173. Schurhoff, F., Bellivier, F., Jouvent, R., Mouren-Simeoni, M. C., Bouvard, M., Allilaire, J. F., & Leboyer, M. (2000). Early and late onset bipolar disorders: Two different forms of manicdepressive illness? Journal of Affective Disorders, 58, 215–221.
174. Segal, Z. V., & Ingram, R. E. (1994). Mood priming and construct activation in tests of cognitive vulnerability to unipolar depression. Clinical Psychology Review, 14, 663–695.
175. Segal, Z. V., Shaw, B. F., Vella, D. D., & Katz, R. (1992). Cognitive and life stress predictors of relapse in remitted unipolar depressed patients: A test of the congruency hypothesis. Journal of Abnormal Psychology, 101, 26–36.
176. Segal, Z. V., Williams, J. M., Teasdale, J. D., & Gemar, M. (1996). A cognitive science perspective on kindling and episode sensitization in recurrent affective disorder. Psychological Medicine, 26, 371–380.
177. Shea, M. T., Widiger, T. A., & Klein, M. H. (1992). Comorbidity of personality disorders and depression: Implications for treatment. Journal of Consulting and Clinical Psychology, 60, 857–868.
178. Shrout, P. E., Link, B. G., Dohrenwend, B. P., Skodol, A. E., Stueve, A., & Mirttznik, J. (1989). Characterizing life events as risk factors for depression: The role of fateful loss events. Journal of Abnormal Psychology, 98, 460–467.
179. Siever, L. J., & Davis, K. L. (1985). Overview: Toward a dysregulation hypothesis of depression. American Journal of Psychiatry, 142, 1017–1031.
180. Smith, A. L., & Weissman, M. M. (1992). Epidemiology. In E. S. Paykel (Ed.), Handbook of affective disorders (pp. 111–129). New York: Guilford Press.
181. Smith, K. A., Fairburn, C. G., & Cowen, P. J. (1997). Relapse of depression after rapid depletion of tryptophan. The Lancet, 349, 915–919.
182. Solomon, D. A., Keller, M. B., Leon, A. C., Mueller, T. I., Lavori, W., Shea, T., Coryell, W., Warshaw, M., Turvey, C., Maser, J. D., & Endicott, J. (2000). Multiple recurrences of major depressive disorder. The American Journal of Psychiatry, 157, 229– 233.
183. Sorenson, S. B., Rutter, C. M., & Aneshensel, C. S. (1991). Depression in the community: An investigation into age of onset. Journal of Consulting Clinical Psychology, 59, 541–546.
184. Strakowski, S. M., DelBello, M. P., Sax, K. W., Zimmerman, M. E., Shear, P, K., Hawkins, J. M., & Larson, E. R. (1999). Brain magnetic resonance imaging of structural abnormalities in bipolar disorder. Archives of General Psychiatry, 56, 254–260.
185. Strakowski, S. M., Keck, P. E., McElroy, S. L., West, S. A., Sax, K. W., Hawkins, J. M., Kmetz, G. F., Upadhyaya, V. H., Tugrul, K. C., & Bourne, M. L. (1998). Twelve-month outcome after a first hospitalization for affective psychosis. Archives of General Psychiatry, 55, 49–55.
186. Strober, M., Schmidt-Lackner, S., Freeman, R., Bower, S., Lampert, C., & DeAntonio, M. (1995). Recovery and relapse in adolescents with bipolar affective illness: A five-year naturalistic, prospective follow-up. Journal of the American Academy of Child and Adolescent Psychiatry, 34(6), 724–731.
187. Thornicroft, G., & Sartorius, N. (1993). The course and outcome of depression in different cultures: 10-year follow-up of the WHO collaborative study on the assessment of depressive disorders. Psychological Medicine, 23, 1023–1032.
188. Tohen, M., Waternaux, C. M., & Tsuang, M. T. (1990). Outcome in mania: A 4-year prospective follow-up of 75 patients utilizing survival analysis. Archives of General Psychiatry, 47, 1106– 1111.
189. Turvey, C. L., Coryell,W. H.,Arndt, S., Solomon, D.A., Leon,A. C., Endicott, J., Mueller, T., Keller, M., &Akiskal, H. (1999). Polarity sequence, depression, and chronicity in bipolar I disorder. Journal of Nervous and Mental Disease, 187, 181–187.
190. Van Gorp, W. G., Altshuler, L., Theberge, D. C., Wilkins, J., & Dixon, W. (1998). Cognitive impairment in euthymic bipolar patients with and without prior alcohol dependence. Archives of General Psychiatry, 55, 41–46.
191. Wallace, J., & O’Hara, M. W. (1992). Increases in depressive symptomatology in the rural elderly: Results from a cross-sectional and longitudinal study. Journal of Abnormal Psychology, 101, 398–404.
192. Warren, W. L. (1994). Revised Hamilton Rating Scale for Depression (RHRSD): Manual. Los Angeles: Western Psychological Services.
193. Wehr, T. A., & Goodwin, F. K. (1983). Biological rhythms in manicdepressive illness. In T. A. Wehr & F. K. Goodwin (Eds.), Circadian rhythms in psychiatry (pp. 129–184). Pacific Grove, CA: Boxwood.
194. Weissman, M. M., Bland, R. C., Canino, G. J., Faravelli, C., Greenwald, S., Hwu, H. G., Joyce, P. R., Karam, E. G., Lee, K., Lellouch, J., Lepine, J. P., Newman, S. C., RubioStipec, M., Wells, J. E., Wickramaratne, P. J., Wittchen, H. U., & Yeh, E. K. (1996). Cross-national epidemiology of major depression and bipolar disorder. Journal of the American Medical Association, 276, 293–299.
195. Weissman, M. M., & Markowitz, J. C. (2002). Interpersonal psychotherapy for depression. In I. H. Gotlib & C. Hammen (Eds.), Handbook of depression (pp. 404–421). New York: Guilford Press.
196. Weissman, M. M., Wolk, S., Goldstein, R. B., Moreau, D., Adams, P., Greenwald, S., Klier, C. M., Ryan, N. D., Dahl, R. E., & Wickramaratne,P.(1999).Depressedadolescentsgrownup.Journal of the American Medical Association, 281(18), 1707–1713.
197. Weissman, M. M., Wolk, S., Wickramaratne, P., Goldstein, R., Adams, P., Greenwald, S., Ryan, N., Dahl, R., & Steinberg, D. (1999). Children with prepubertal-onset major depressive disorder and anxiety grown up. Archives of General Psychiatry, 56, 794–801.
198. Weller, E., Weller, R. A., & Dogin, J. W. (1998). A rose is a rose is a rose. Journal of Affective Disorders, 51, 189–193.
199. Wells, K. B., Stewart, A., Hays, R. D., Burnam, A., Rogers, W., Daniels, M., Berry, S., Greenfield, S., & Ware, J. (1989). The functioning and well-being of depressed patients. Journal of the American Medical Association, 262, 914–919.
200. Winokur, G., Coryell, W., Keller, M., Endicott, J., & Akiskal, H. (1993). A prospective follow-up of patients with bipolar and primary unipolar affective disorder. Archives of General Psychiatry, 50, 457–465.
201. Winokur, G., Coryell, W., Keller, M., Endicott, J., & Leon, A. (1995). Afamily study of manic-depressive (bipolar I) disease: Is it a distinct illness separable from primary unipolar depression? Archives of General Psychiatry, 52, 367–373.
202. World Health Organization. (1992). International statistical classificationofdiseasesandrelatedhealthproblems(10thed.).Geneva, Switzerland:Author.
203. Zlotnick, C., Kohn, R., Keitner, G., & Grotta, S. A. D. (2000). The relationship betweeen quality of interpersonal relationships and major depressive disorder: Findings from the National Comorbidity Survey. Journal of Affective Disorders, 59, 205–215.
204. Zonderman,A.B.,Herbst,J.H.,Schmidt,C.,Costa,P.T.,&McCrae, R. R. (1993). Depressive symptoms as a nonspecific, graded risk for psychiatric diagnoses. Journal of Abnormal Psychology, 102, 544–552.