Disorders of Mood and Anxiety

EMOTIONS ARE TRANSIENT RESPONSES to specific stimuli in the environment (eg, the presence of danger), the body (eg, pain), or, for humans, the mind (eg, a train of thought). When an emotional state is prolonged, it can become one’s dominant emotional state over time, or mood. Mood thus may be independent of immediate personal and environmental circumstances.

Mood and anxiety disorders are the most common serious disorders of the brain. Mood disorders generally involve either depression or elation. Anxiety disorders involve abnormal regulation of a powerful emotion, fear. In both mood and anxiety disorders the core symptoms have a major emotional component and are accompanied by physiological, cognitive, and behavioral abnormalities.

We discuss disorders of mood and anxiety together because both involve negative emotional states and because they appear to involve overlapping neural circuits that include the amygdala and the anterior cingulate cortex. There also is evidence for overlapping risk factors between major depressive disorder and some anxiety disorders. Commonalities of circuitry and genetic risks, as well as the negative effects of long-term anxiety on a person’s mood, may explain the observation that nearly 60% of patients with major depressive disorder also suffer from an anxiety disorder. Anxiety disorder most commonly precedes the onset of depression.

Because emotions are transient responses to stimuli that can be reproduced in the laboratory, they have proven more amenable than moods to neuroscientific study. Objective measurement of moods is difficult, compared with the more stereotypic physiological or behavioral components of emotional responses (see Chapter 48), and experimental approaches to regulating mood have had limited success. Good animal models exist for certain emotions, such as fear and pleasure, and because many features of these states appear to be conserved in evolution, the animal models are relevant to humans (see Chapter 48).

Animal models have allowed detailed investigation of the neural circuitry, physiology, and biochemistry underlying these states. For example, studies of rodent models of instinctive (unlearned) fear and learned fear (in which an animal learns to associate a previously neutral cue with a threat) have elucidated the “fear circuits” centered in the amygdala and the hypothalamus. These circuits activate the sympathetic nervous system to alter heart rate and blood pressure, stimulate secretion of stress hormones, and elicit species-specific defensive behaviors such as motionlessness (“freezing”) in rodents and escape behaviors in other species. Such basic investigations are providing testable hypotheses for studies of fear and anxiety and their disorders in humans.

In contrast, neurobiological investigations of moods are less advanced. Although much evidence suggests that animals do have moods, developing empirical methods of ascertaining what those moods are and how they match human experience has been challenging. Most animal models of depression were not developed to investigate the pathophysiology of the human disease, but as empirical screens for antidepressant drugs. Many of these models are based on chronic stress; although chronic stress and depressed mood have many features in common, they are not identical.

The lack of well-validated animal models of moods and mood disorders has made it difficult to identify the neural circuitry responsible for the regulation and maintenance of moods. Much investigation of mood circuitry has perforce been carried out in humans using noninvasive technologies such as neuroimaging.

The Most Common Disorders of Mood Are Unipolar Depression and Bipolar Disorder

In the 5th century BC moods were thought to depend on the balance of four humors—blood, phlegm, yellow bile, and black bile. An excess of black bile was believed to cause depression. In fact, the ancient Greek term for depression, melancholia, means black bile. Although this explanation of depression seems fanciful today, the underlying view that psychological disorders reflect physical processes is correct.

Only in the past three decades have relatively precise criteria for mood disorders been developed in parallel with those for thought and cognitive disorders (see Chapter 61). Disorders of mood are now classified based on symptoms, natural history (including age of onset, course, and outcome), patterns of familial transmission, and response to treatment. Based on these factors, one can distinguish between two major classes of disorders in people who suffer from depression. Unipolar depression is diagnosed in people who suffer only from depressive episodes; bipolar disorder is diagnosed in individuals in whom depression alternates with episodes of mania (Table 63–1).

Another important distinction is that between primary and secondary mood disorders. Mood disorders caused by drugs (eg, drugs used to treat hypertension) or pathophysiological processes that affect the brain (eg, hypothyroidism) are considered secondary to another condition. The onset of depression late in life also may be secondary to pathophysiological processes such as Parkinson disease or diffuse vascular disease affecting cerebral vessels. Although such cases are important, our discussion here focuses on mood disorders, unipolar and bipolar illnesses, arising as independent pathophysiological processes.

Unipolar Depression Often Begins Early in Life

The key clinical features of unipolar depression can be summarized in Hamlet’s words, “How weary, stale, flat, and unprofitable seem to me all the uses of this world!” Untreated, an episode of depression typically lasts 4 to 12 months. The central feature of depression is an unpleasant (dysphoric) mood present most of the day, day in and day out, often accompanied by intense mental anguish, the inability to experience pleasure (anhedonia), and a generalized loss of interest in the world. Sadness is most typical, but anger, irritability, and loss of interest in usual pursuits can predominate in some patients.

Major depression is distinguished from normal sadness or grief by its severity, pervasiveness, duration, and associated symptoms, including physiological, behavioral, and cognitive symptoms (Table 63–1). Physiological symptoms include sleep disturbance, most often insomnia with early morning awakening, but occasionally excessive sleeping; loss of appetite and weight loss, but occasionally excessive eating; and decreased energy. Behaviorally, some depressed patients exhibit slowed motor movements, described as psychomotor retardation, whereas others can be extremely agitated. Cognitive symptoms are evident in both the content of thoughts (hopelessness, thoughts of worthlessness and of guilt, suicidal thoughts and urges) and in cognitive processes (difficulty concentrating, slow thinking, and poor memory).

Table 63–1 Symptoms of Mood Disorders

In the most severe forms of depression psychotic symptoms can occur, including delusions (unshakable false beliefs that cannot be explained by a person’s culture) and hallucinations. The psychotic symptoms of depression generally reflect the person’s feelings that he or she is worthless or bad. A severely depressed person might, for example, believe that he or she is emitting a potent odor because he or she is rotting from the inside.

The most serious negative outcome from depression is suicide. Suicide is the eighth leading cause of death in the United States, and the third leading cause of death among young people 15 to 24 years of age. More than 90% of suicides are associated with mental illness, with depression being the leading cause.

In the standard classification of psychiatric disorders in the United States—the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) of the American Psychiatric Association—episodic, primary, unipolar depression that lasts for at least two weeks is classified as major depression. Major depression often begins early in life; approximately one-half of cases occur in those younger than 25 years of age, but first episodes are observed across the life span. Those who have had a first episode in childhood or adolescence have a particularly high likelihood of recurrence. Once a second episode has occurred, a pattern of repeated relapse and remission generally sets in. Some people do not recover completely from their first acute episode and have chronic, albeit milder, unremitting depression that can be punctuated by acute exacerbations. Chronic, somewhat milder depressions lasting more than 2 years are called dysthymia. Although the symptoms of dysthymia are less severe than those of a major depressive episode, the long duration of the symptoms makes this a very disabling illness.

Bipolar Disorder Includes Episodes of Mania

Bipolar disorder is named for its chief symptom, swings of mood between mania and depression. Mania is characterized by euphoria or irritability, a marked increase in energy and a decreased need for sleep, impulsiveness, and excessive engagement in goal-directed behaviors, often with poor judgment characterized by extreme optimism. For example, a person might go on spending sprees well beyond his or her means. During manic episodes self-esteem is inflated, often reaching delusional proportions; individuals might consider themselves to be royalty, prophets, or even deities.

Mania also affects cognition. During a manic episode a person often cannot stick to a topic and might jump quickly from idea to idea, making comprehension difficult. Speech is typically rapid and difficult to interrupt. Psychotic symptoms commonly occur during manic episodes and are generally consistent with the person’s elevated mood. For example, people with mania can have delusions that they possess special powers. The symptoms that characterize the depressive episodes in bipolar disorder are indistinguishable from those in unipolar depressions.

Patients who have had at least one manic episode are considered to have bipolar disorder, even if they have not yet experienced a depressive episode. The onset of manic episodes tends to be relatively rapid, occurring over a period of a few days to a few weeks. Bipolar disorder generally begins in young adulthood, uncommonly in childhood. Most episodes lack a clear precipitant, but sleep deprivation can initiate a manic episode, suggesting a relationship between neural systems that regulate circadian rhythms and those that regulate moods. People with bipolar disorder have recurrent episodes of the illness, both manias and depression. However, the rate of cycling between mania, depression, and normal mood (euthymia) varies widely. Between periods of mania or depression some people with bipolar disorder are relatively free of symptoms, but a large fraction have residual symptoms. A few patients have severe, chronic symptoms despite treatment.

Mood Disorders Are Common and Disabling

The lifetime risk of major depressive disorder in the United States is 16.2%. Within any 1 year 6.6% of the population suffers major depression. The prevalence of depression differs in different countries and cultures, but the nature of the symptoms is remarkably similar around the world.

In childhood major depression occurs equally in males and females. After puberty, however, depression occurs more commonly in females independent of culture. In the United States the ratio of females to males with major depression is 1.7:1. Depression is the leading cause of disability worldwide.

In contrast to the high frequency of unipolar depression, bipolar disorder is less common, with a prevalence of 1% that exhibits relatively little variability from country to country. As with major depression, the symptoms are the same across countries and cultures. The risk of bipolar disorder is equivalent in males and females worldwide.

Both Genetic and Nongenetic Risk Factors Play an Important Role in Mood Disorders

As with schizophrenia, both bipolar disorder and major depression run in families with patterns of transmission that are inconsistent with simple Mendelian (single gene) dominant, recessive, or sex chromosome-linked modes of inheritance. One way to estimate the influence of genes on a disease phenotype is to measure the increased risk that results from relatedness to a person who has the disease. This increase in risk can be expressed as a recurrence risk ratio. The recurrence risk ratio provides a rough measure of the aggregate influence of genes on a trait but does not provide insight into how many genes might be involved.

Recurrence risk ratios demonstrate that genes contribute to the risk of unipolar depression but exert a much stronger influence on the risk of bipolar disorder (Table 63–2). As in schizophrenia (see Chapter 62), the concordance rates among monozygotic twin pairs (who are genetically identical) are less than 100%. Thus genes alone do not cause mood disorders but must interact with developmental or environmental factors to produce illness.

Table 63–2 Recurrence Risk Ratios (λ) for Mood Disorders and Schizophrenia

Overall the genetic risk for mood disorders, like that for schizophrenia, is genetically complex. Genetic linkage and association studies suggest there are multiple pathways of genetic risk for mood disorders, and thus no single gene will likely prove to be either necessary or sufficient.

From the point of view of prevention it is important to sort out the relative roles of genes and environmental risk factors because the latter can be modified. Much evidence suggests that stressful and adverse life events increase the risk of major depression; even here, however, genes may play a role in two ways because they shape a person’s temperament. First, temperament plays a role in the kinds of situations into which people place themselves; second, genetic factors can influence the response that people have to adverse life experiences when they do occur. Such interactions between genetic and environmental factors complicate the task of isolating risk factors.

Specific Brain Regions and Circuits Are Involved in Mood Disorders

Because animal models of mood and mood regulation are not fully convincing, investigation of the circuitry involved in mood disorders has relied to a great extent on structural and functional imaging of humans, and to a lesser degree on postmortem analyses of human brains. Neuroimaging studies of major depression and bipolar disorder have identified abnormalities in brain regions thought to be involved in emotion and cognition (Figure 63–1). Despite progress to date, imaging has not yet identified specific abnormalities in a neural system that can be used reliably to diagnose major depressive or bipolar disorder.

Figure 63-1 Brain centers of emotional dysfunction in patients with depression. Each of these interconnected structures plays a role in regulating emotion and physiological and behavioral responses to emotional stimuli. Abnormalities in one or more of these regions or in the interconnections among them are associated with failures of emotion regulation. (Reproduced, with permission, from Davidson, Putnam, and Larson 2000.)

One brain region that has consistently been implicated in both major depressive and bipolar disorders is the gyrus of the anterior cingulate cortex. This structure runs parallel to the corpus callosum, along the medial surface of each cerebral hemisphere (Figure 63–1). It has two functional subdivisions. A rostral and ventral subdivision is thought to be involved in emotional processes and autonomic function; it has extensive connections to the hippocampus, the amygdala, orbital prefrontal cortex, anterior insula, and nucleus accumbens. A caudal subdivision is thought to be involved in cognitive processes and the control of behavior; it connects with the dorsal regions of prefrontal cortex, secondary motor cortex, and posterior cingulate cortex.

Abnormal function in both subdivisions of the anterior cingulate cortex has been documented in people with mood disorders (Figure 63–2). However, abnormal functioning during major depressive episodes and the depression phase of bipolar disorder has been most consistently found in the rostral subdivision, which is concerned with emotion, and especially in the subgenual region (the region ventral to the genu of the corpus callosum). Indeed, a decrease in activity of the subgenual anterior cingulate gyrus following antidepressant treatment correlates with the success of the treatment (Figure 63–3).

Figure 63-2 Involvement of the anterior cingulate cortex in depression. The figure summarizes the findings of several studies using brain imaging. Colored circles show sites of activation or deactivation before or after treatment of patients with depression. Black circles indicate pretreatment hyperactivity among patients who responded to treatment; green circles indicate posttreatment decreased activity in responders; pink circles indicate hypoactivity in depressed subjects; yellow circles indicate increased activity with remission of depression; and the sole brown circle indicates decreased activity with remission of depression. Studies involving emotional tasks (blue circles) and cognitive tasks (purple circles) in nonpsychiatric subjects are also shown. The large red area shows the location of treatment response observed in an electroencephalogram (EEG) study of depression. (Adapted, with permission, from Pizzagalli et al. 2001.)

Figure 63-3 Increased activity in the anterior cingulate cortex predicts responsiveness to treatment with antidepressant drugs. Regional cerebral glucose metabolism was measured by positron emission tomography (PET) as a proxy for brain activity. Depressed patients with elevated metabolism in the rostral anterior cingulate cortex had better responses to antidepressant treatment than those who did not. Cingulate hypermetabolism may represent an adaptive response to depression that predicts antidepressant response. (Reproduced, with permission, from Mayberg et al. 1997).

Neuro-imaging also implicates the amygdala and hippocampus in mood disorders. The involvement of the amygdala is not surprising given the wealth of evidence that this structure is involved in the processing of negative emotions, including fear (see Chapter 48). Enlargement of the amygdala has been found in depression, and increases in the basal level of activity in the amygdala have been observed in depression, bipolar disorder, and anxiety disorders. As in many disorders, the volume of the hippocampus may be reduced in depression. This change correlates with the duration of prior episodes of depression and not with the age of the person, consistent with the idea that protracted major depression might produce hippocampal atrophy. Nonetheless, until longitudinal studies are conducted we cannot be certain whether a small hippocampus is a risk factor for depression or a result of it.

Despite the findings that we have described, the use of neuroimaging to study depression is still in its early stages. Most studies to date have been restricted to anatomical measurement of brain structures or to basal (unstimulated) brain activity in depressed subjects compared with healthy control subjects. Investigators are now beginning to use activation paradigms, in which brain activity is measured in response to specific cognitive or emotional stimuli.

Activation paradigms can be a powerful means of identifying brain circuits associated with specific normal and disordered function. For example, in healthy subjects the anterior cingulate cortex is activated by pain, cognitive conflict, and errors in task performance. Thus the anterior cingulate cortex may ascertain whether behavior is successfully proceeding toward desired goals, and perceived discrepancies between goals and outcomes could contribute to depression.

Depression and Stress Are Interrelated

In some cases depression follows a stressful experience; conversely, the experience of depression is itself stressful. Indeed, depression shares several features with chronic stress, including changes in appetite, sleep, and energy. Major depression and chronic stress may also share biochemical changes, such as persistent activation of the hypothalamic-pituitary-adrenal (HPA) axis (Figure 63–4).

Figure 63-4 The hypothalamic-pituitary-adrenal axis. Neurons in the paraventricular nucleus of the hypothalamus synthesize and release corticotropin-releasing factor (CRF), the key regulatory hormone in this cascade. Secretion of CRF follows a circadian pattern, and the effects of stress are superimposed on this circadian pattern. Excitatory fibers from the amygdala convey information about stress and activate CRF secretion and biosynthesis; inhibitory fibers descend from the hippocampus. CRF enters the hypophyseal portal system and stimulates the corticotrophic cells of the anterior pituitary. These cells synthesize and release adrenocorticotropic hormone (ACTH), which enters the systemic circulation and ultimately stimulates the adrenal cortex to release glucocorticoids. In humans the major glucocorticoid is cortisol; in rodents it is corticosterone. Both cortisol and synthetic glucocorticoids such as dexamethasone act at the level of the pituitary and hypothalamus to inhibit further release of ACTH and CRF respectively. (Adapted, with permission, from Nestler, Hyman, and Malenka 2009.)

In depressed individuals daily production of the glucocorticoid stress hormone cortisol and secretion of corticotrophin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) can all be elevated. A transient increase in cortisol secretion, as occurs with acute stress, suppresses the immune system (saving energy and delaying inflammatory processes that might inhibit the fight-or-flight response), shifts the body to a catabolic state (making energy available to confront the cause of the stress), increases energy levels, sharpens cognition, and may increase confidence. However, a chronic increase may contribute to symptoms of depression. For example, people with Cushing disease (in which pituitary tumors secrete excess ACTH leading to excess cortisol) often experience depression and insomnia.

Feedback mechanisms within the HPA axis normally permit cortisol (or exogenously administered glucocorticoids) to inhibit CRH and ACTH secretion and therefore to suppress additional cortisol synthesis and secretion. In approximately one-half of people with major depression this feedback system is impaired; their HPA axis becomes resistant to suppression even by potent synthetic glucocorticoids such as dexamethasone. Although readily measurable disturbances of the HPA axis are not sensitive or specific enough to be used as a diagnostic test for depression, the observed abnormalities suggest strongly that altered stress responses are an important component of depression in a large proportion of people with the illness.

If recurrent depression causes the decrease in hippocampal volumes described above, it may be that excessive cortisol secretion is the cause. Two theories have been offered to explain how depression might lead to hippocampal atrophy. One is that persistently elevated levels of glucocorticoids can damage mature neurons, perhaps making them more susceptible to glutamate excitotoxicity (see Chapter 43). The other is that elevated cortisol levels or some other aspect of chronic stress suppresses normal neurogenesis (the formation of new neurons), resulting in fewer cells being produced and thus a smaller hippocampus.

In many animals, as well as humans, new granule cells within the dentate gyrus of the hippocampus are produced during adult life. In rodents these new neurons are incorporated into neural circuits. Stressful or aversive experiences as well as glucocorticoids inhibit the proliferation of granule cell precursors and thus suppress normal rates of neurogenesis in the hippocampus. In contrast, antidepressants, including the selective serotonin reuptake inhibitors, increase the rate of neurogenesis. Thus depression might cause hippocampal atrophy by inhibiting neurogenesis and antidepressants might reverse this effect by treating the depression (therefore decreasing stress) and possibly by directly stimulating neurogenesis (by mechanisms that are not yet understood).

These hypothalamic and hippocampal abnormalities may contribute to the symptoms of depression and influence its course. Hypothalamic CRH secretion is under the stimulatory control of pathways from the amygdala and inhibitory pathways from the hippocampus. Damage to the hippocampus could lead to a vicious cycle in which loss of inhibitory control of CRH secretion would lead to greater cortisol release, producing additional hippocampal atrophy. In fact, depression can be accompanied by memory impairments that could be explained by hippocampal dysfunction, either by itself or in conjunction with disturbances in executive function involving the prefrontal cortex, such as failure of attentional mechanisms at the time of memory encoding.