Mood Disorders

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Chapter 111

Mood Disorders


Mood is a subjective emotional state, and fluctuations in mood are expected, especially in response to the joys and sorrows of everyday life. Mood disorders, however, extend beyond these common emotional variations. Patients with mood disorders often present with impairment in functioning, often severe and with threats to life that include suicide, profound self-neglect, and impaired judgment. They are also associated with impaired physical, social, and family functioning as well as with psychological and physical pain and a negative perception of physical health. Patients with mood disorders are most often seen in general medical settings, including the emergency department (ED), often in crisis. One fourth to one third of ED patients screen positive for mood disorders.1

The Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR), divides mood disorders into four broad categories2: (1) depressive disorders, (2) bipolar disorders, (3) mood disorder due to a general medical condition, and (4) substance-induced mood disorder. Because the specific pathophysiologic mechanisms of these disorders are not fully understood, they are categorized by groupings of symptoms that persist for defined lengths of time. As research into the biology, genetics, and treatment of mood disorders advances, we hope to one day be able to more clearly demonstrate the pathophysiologic abnormalities.


Up to 50% of Americans will meet the criteria for a DSM-IV-TR disorder sometime in their life.3 Mental health patients are the fastest growing group of patients presenting to the ED.4 In 2007, 12.5% of the 94 million ED visits in the United States were for psychiatric reasons,5 which was an increase from 5.4% in 2000.6 The lifetime prevalence for mood disorders is estimated to be 20.8%.3

The World Health Organization ranks major depressive disorder as one of the most prevalent and disabling diseases in the world.7 The 12-month prevalence for major depressive disorder is 5.28% and the lifetime prevalence is 13.23%.8 Patients with major depressive disorder frequently have other comorbid mental health issues, including anxiety disorders (36.1% 12-month and 41.4% lifetime prevalence), personality disorders (37.9% 12-month and 30.8% lifetime prevalence), and substance use disorders (4.6% 12-month and 17.2% lifetime prevalence).8

Although it is less prevalent than major depressive disorder, bipolar disorder is a serious and potentially life-threatening illness. Up to 80% of patients with bipolar disorder will exhibit suicidal behavior, and 51% will attempt suicide.9 Suicidal behavior can occur during all phases of bipolar disorder, but patients experiencing a depressed or a mixed episode are at higher risk, especially those with severe depressive symptoms and a sense of hopelessness.10 Bipolar disorder is diagnosed on a spectrum, decreasing in severity from bipolar disorder type I, consisting of both depressive and manic episodes, to bipolar disorder type II, which has depressive and hypomanic episodes, to subthreshold bipolar disorder, such as cyclothymia and bipolar NOS (not otherwise specified). Bipolar disorder type I has a 0.6% 12-month prevalence and a 1.0% lifetime prevalence, bipolar disorder type II has a 0.8% 12-month prevalence and a 1.1% lifetime prevalence, and subthreshold bipolar disorder has a 1.4% 12-month prevalence and a 2.4% lifetime prevalence.11

Most of the disability caused by bipolar disorder occurs during the depressive phase of the illness. On average, patients with bipolar disorder spend 30% of their time in a depressive phase, 10% in a manic phase, and 6% in a mixed phase.12

Principles of Disease

The pathophysiology of the mood disorders is not well established, but quite a bit is known about the neurophysiology, genetics, and psychosocial aspects of the disorders.


The immediate effects of most available antidepressants are to increase the availability and activity of serotonin and norepinephrine in the synapse with subsequent stimulation of the postsynaptic neuron. This is done by direct binding to the presynaptic and postsynaptic receptors, blocking reuptake of the neurotransmitter or inhibiting the enzymatic breakdown of the neurotransmitter. Because norepinephrine and serotonin systems traverse large portions of the brain, one hypothesis is that a monoamine deficiency is a cause of depression. There is a risk in deriving a theory from the mechanism of action of available antidepressants, but there is research to support the monoamine deficiency hypothesis. Positron emission tomography (PET) scans have demonstrated a 30% increase in TPH-2, a brain-specific tryptophan hydroxylase enzyme in some depressed patients.13 Studies demonstrate that depletion of oral tryptophan and tyrosine, amino acids essential for the production of serotonin and norepinephrine, respectively, can induce a depressive episode in subjects with a history of depression but not in healthy controls.14 Numerous studies of monoamine metabolite levels in cerebrospinal fluid, plasma, urine, and postmortem brains of patients with depression did not reliably demonstrate a monoamine deficiency, indicating that there could be downstream effects involving second-messenger systems such as cyclic adenosine monophosphate and phosphatidylinositol.15

Other neurotransmitter systems may play a role in the development of depression. A study using magnetic resonance spectroscopy demonstrated decreased levels of both glutamate and γ-aminobutyric acid in the prefrontal cortex of depressed subjects.16 Intravenous ketamine, an N-methyl-D-aspartate (NMDA) antagonist, induces a rapid antidepressant effect17 and suggests a role for glutamate in the pathophysiologic process of depression. This is important because the excitotoxic effects of glutamate can lead to neuronal loss and atrophy of some brain regions.18 The brain relies on the actions of protective and regenerative cytokines, such as brain-derived neurotrophic factor (BDNF), and all of the known antidepressants and electroconvulsive therapy raise levels of BDNF and subsequently result in neurogenesis of certain brain regions, such as the hippocampus. Sleep deprivation and light therapy both have antidepressant effects, which suggests circadian rhythm abnormalities as a contributing mechanism for depression.15,19,20 A novel antidepressant under investigation suggests a role for the melatonergic system and abnormalities in circadian rhythms.21 Other theories include decreased neurosteroid synthesis, impaired endogenous opioid functioning, monoamine-acetylcholine imbalance, inflammatory effects of cytokines, and dysfunction of specific brain structures and circuits.15

The neurophysiology of bipolar disorder is less understood than that of unipolar depression, in part because of the fluctuating mood states and the heterogeneity of the disorder. Bipolar disorder may in part arise from abnormalities in the connections within and between structures in the brain.22 Specifically implicated are circuits interconnecting the amygdala, hypothalamus, striatum, and subdivisions of the frontal cortex, all of which are involved in both the generation and regulation of emotion.22


Neuroimaging studies of the brain suggest that abnormalities in certain areas and the interconnections between those areas may be involved in the mood disorders. A common magnetic resonance imaging (MRI) finding in patients with mood disorders, especially bipolar disorder, is an increased occurrence of subcortical hyperintensities in areas such as the periventricular areas, basal ganglia, and thalamus.23 High-resolution MRI demonstrates reduced volumes in the hippocampus, orbital cortex, and anterior cingulate. These findings are associated with more severe illness, bipolar disorder, and increased cortisol levels.23 Volume reduction in the hippocampus is associated with high illness chronicity.23

PET scans demonstrate a global reduction of glucose metabolism in the anterior regions of the brain, such as the dorsolateral prefrontal cortex. These findings are mood state dependent and are seen in both unipolar and bipolar depression. Patients in a depressed episode have lower relative functioning on the left side of the brain, and those who are hypomanic or manic have lower relative functioning on the right side of the brain.23

The amygdala is a clustering of nuclei that process emotional stimuli, especially fear, anger, and sadness. Functional neuroimaging suggests that amygdala activity is increased when the subject is exposed to emotionally relevant stimuli.23 It has connections throughout the brain that regulate anticipatory anxiety (bed nucleus of the stria terminalis), cortisol release (hypothalamus), attention and mood (nucleus basalis of Meynert, locus ceruleus, ventral tegmental area), and sympathetic arousal (periaqueductal gray).18 A decreased amygdala volume has been associated with unipolar depression.18 There is decreased amygdala volume in children and adolescents with bipolar disorder and increased volume in adults with bipolar disorder.18

Endocrine System

The perception of stress in the environment by the cerebral cortex and the amygdala activates circuits and structures in the brain to cause physiologic changes such as increased alertness, decreased appetite, increased heart rate, and activation of the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis may play a role in depression, especially in cases of early childhood and chronic stress.

Activation of the HPA axis releases corticotropin-releasing hormone (CRH) from the hypothalamus. This results in a release of corticotropin (ACTH) from the anterior pituitary, which enters the bloodstream and stimulates release of cortisol from the adrenal glands. Cortisol then provides negative feedback to the hypothalamus and the pituitary to decrease the secretion of CRH and corticotropin, respectively.

There is evidence that CRH and cortisol play a role in depression. Although not specific, patients with depression may have increased levels of free cortisol in the plasma, cerebrospinal fluid, and urine.24 Increased CRH has been demonstrated in cerebrospinal fluid, and increased levels of CRH messenger RNA and protein have been demonstrated in limbic brain regions.24 Also, some patients with melancholic or psychotic depression have been shown to have an overactive HPA axis demonstrated by an inability of dosed dexamethasone to suppress cortisol release.25 Although none of these measures is reliable as a diagnostic tool (e.g., the dexamethasone suppression test has been shown to be 90% sensitive for detection of depression but only 30-50% specific), successful treatment to remission has been shown to reverse some of these abnormalities.24,26


Genetic vulnerability to mood disorders has not been traced to a single gene. It is likely to be due to the additive effects of many genes and environmental influences on how these genes are expressed.27

Major depressive disorder has a heritability of 37 to 38%,28 lower than the heritability of bipolar disorder.15 The heritability of major depressive disorder is higher in women than in men28 and may be higher in early-onset, more severe, and recurrent forms of the disorder.15 Genetic linkage studies have identified various chromosomal regions that are of interest in major depressive disorder, but not all of these have been consistently replicated.15 There may also be some environmental factors that could have epigenetic effects.15 One example of this is the region that codes for 5-HTT, a serotonin transporter protein. Individuals with one or more copies of the short allele of the 5-HTT promoter polymorphism have been shown in some but not all studies to be more prone to depression and suicidality when they are faced with an adverse life event compared with those with only the long allele.27

Bipolar disorder is one of the most heritable medical illnesses.29 Bipolar disorder has a heritability of 80 to 85% and a monozygotic twin concordance of 40 to 45%.29 There is also considerable overlap between the heritability of bipolar disorder and other DSM-IV-TR diagnoses. First-degree relatives of patients with bipolar disorder have an increased risk for both bipolar disorder and unipolar depression, but first-degree relatives of patients with unipolar depression do not have increased bipolar risk.29 There is also overlap of genetic risk between bipolar disorder and schizophrenia.29 Several different genes and linkage studies have been investigated, but the results have been inconsistent.29

Psychosocial Factors

The etiology of most psychiatric problems, including the mood disorders, involves complex interactions between both biologic and psychosocial factors.30 The complex neural mechanism that regulates mood responds to and is modified by each person’s experience, including events in early childhood, reward and punishment during growth and development, interpersonal relationships, and various kinds of loss. Psychosocial theories of mood disorder form the basis for psychotherapy.

Stressful Life Events

Environmental stress and adverse life events, such as parental neglect, sexual and physical abuse, and death of a loved one, have been shown to play a role in the onset of a mood episode as well as in the development and course of the mood disorders.30 Neuroanatomic changes, such as decreased hippocampal volume and increased amygdala volume, and the correlation between the mechanisms of depression and molecular mechanisms of neuroplasticity suggest that stress has an adverse effect on the brain.31 This supports the finding that a stressful life event is more likely to precede a first mood episode than subsequent episodes in both major depressive disorder and bipolar disorder.32 Stressful events that patients perceive as reflections on their self-esteem are more likely to trigger mood episodes. Because many who are exposed to severe stressful life events do not develop mood disorders, it is likely that environmental, psychological, and social factors affect brain neurophysiology in susceptible individuals.30 This is supported by models such as the activation of the HPA axis and increased susceptibility in those with a short 5-HTT allele described earlier.

Cognitive-Behavioral Theory

The cognitive model was first described by Aaron Beck and is the basis for cognitive-behavioral therapy. The cognitive theory looks at how individuals organize and interpret their experiences. These are called schemas. Those prone to depression develop depressogenic schemata composed of cognitive distortions, such as a tendency to focus on the negative, and overgeneralization. Beck proposed that those with depression have a negative cognitive triad composed of disparaging views about themselves, views of the world as hostile and demanding, and views that that the future will bring further suffering and failure.32

The concept of “learned helplessness” was developed on the observation that animals subject to repeated noxious stimuli, such as electric shock, and blocked from escape eventually stop trying to escape. They become apathetic, even when escape becomes available.33 This concept was later applied to humans and adapted to construct a behavioral mode of therapy for depression.

Clinical Features

Major Depressive Disorder

Major depressive disorder is characterized by one or more major depressive episodes, as defined by DSM-IV-TR criteria (Boxes 111-1 and 111-2), and a lifelong absence of manic episodes. A major depressive episode is characterized by disturbances in four major areas: mood, psychomotor activity, cognition, and vegetative function.34 The patient must have at least five symptoms for a minimum of 2 weeks.

BOX 111-1

Summary of DSM-IV-TR Criteria for a Major Depressive Episode

Five or more of the following symptoms have been present almost every day during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.

    Note: Do not include symptoms caused by a general medical condition, and do not include mood-incongruent delusions or hallucinations.

Symptoms do not meet criteria for a “mixed episode.”

Symptoms cause clinically significant distress or impairment in social, occupational, or other functioning.

Symptoms are not caused by direct physiologic effects of a substance (e.g., drug of abuse, medication) or a general medical condition (e.g., hypothyroidism).

Symptoms are not better accounted for by bereavement; after the loss of a loved one, the symptoms persist for longer than 2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.

Modified from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, text rev. Washington, DC, American Psychiatric Association, 2000.

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