Mood Disorders
Perspective
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.
Epidemiology
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
Neurophysiology
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
Neuroanatomy
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
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
Genetics
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.
Psychodynamic Theory
The psychodynamic model was first developed by Sigmund Freud and later extended and modified by others, such as Karl Abraham and Melanie Klein. Basic tenets of this theory are that early childhood experiences during key developmental stages can predispose some individuals, depression can be linked to real or imagined loss, introjection of lost objects can be used as a defense against feelings of loss, and feelings of anger can be directed inward toward the self.32
Clinical Features
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.
Mood Disturbances
The patient must exhibit a depressed mood or anhedonia to meet DSM-IV-TR criteria for a diagnosis of a depressive episode.2
Thought Process and Content
Patients with severe depression may have psychotic symptoms. The hallucinations and delusions that accompany depression are usually mood congruent, meaning that the themes of the psychotic content are consistent with the depressed mood. An example could be voices saying extremely unpleasant things or punishing the patient for previous wrongs. The patient may report being “already dead” or feeling like “my insides have rotted away.” Such hallucinations may suggest the Cotard syndrome, in which patients hold the belief that they do not exist or that they are dead.35 Mood-incongruent psychotic symptoms do not reflect the mood as clearly and are less likely to occur in a depressed state. Examples are a fear that one is being followed or having one’s thoughts controlled by external forces.
Special Considerations
Children and Adolescents.: Criteria for depression in children and adolescents are the same as for depression in adults. Depression in these age groups can, however, present differently from that in adults and is often misunderstood, masked in its presentation, or simply overlooked. Adequate treatment maximizes the child’s potential and minimizes the serious negative impact that depression can have on multiple spheres of development.
Prepubertal children are more likely to have somatic complaints, psychomotor agitation, and mood-congruent hallucinations and less likely to have disturbances in sleep and appetite. Some children are misdiagnosed as having attention deficit disorder, especially if symptoms involve poor concentration, listlessness, agitation, and withdrawal from daily activities.36
Adolescents with depression may show increased oppositional behavior and substance abuse and tend to describe more irritability than depressed mood. Other characteristics are social withdrawal, increased rejection sensitivity, and decline in school performance. Some adolescents may be first diagnosed only with depression on receiving treatment for drug and alcohol problems.36
The selective serotonin reuptake inhibitors sertraline, fluoxetine, and citalopram are all effective in treating depression in this population. There is some evidence that treatment of adolescents and young adults may lead to increased suicidal ideation, and this has resulted in a Food and Drug Administration (FDA) “black box” warning. It is important that these patients be treated for depression but that the patients be monitored closely for suicidal thoughts, especially shortly after treatment with a selective serotonin reuptake inhibitor has started.36
Geriatric.: Age is not itself a risk factor for depression. However, depression is more common in older adults because of more frequent occurrences of loss and grief, comorbid health issues, and loss of autonomy. The elderly may have a tendency to report more somatic complaints than younger adults with depression do. They are also more vulnerable to development of melancholic depression, which is characterized by early morning awakening, diurnal variation in mood, low self-esteem, and low mood reactivity.37
Other Depressive Disorders
Seasonal Affective Disorder.: Seasonal affective disorder is not a separate mood disorder but a subclassification of major depressive disorder that is diagnosed when major depression occurs during seasons with less daylight (fall and winter), then either resolves or occasionally changes to manic episodes in seasons with more daylight, for at least 2 consecutive years. Melatonin, a hormone secreted in the brain and produced at high levels in the dark, has been implicated in the etiology of this disorder. Symptoms generally include hypersomnia, anergia, weight gain, and craving for carbohydrates. Phototherapy is an effective and safe treatment of seasonal depression.38 Light exposure to the eyes seems to be essential, but the exact mechanism of action is still unknown.
Postpartum Depression.: Symptoms of depression are common in the postnatal period. Up to 65% of mothers report some depressed mood after childbirth, often called postpartum blues. Symptoms are generally mild and transient, although in 10% of mothers, it may lead to a full-fledged episode of major depression. The signs and symptoms of postpartum depression are similar to those of a major depressive disorder, but the onset is within 4 weeks of delivery.39
Dysthymic Disorder.: Dysthymic disorder is a long-standing, fluctuating, low-grade depression. Some features of a major depressive episode may be present, but marked changes in appetite or psychomotor disturbances are not typically observed. Depressed mood typically begins early in life, and the individual may report having always been depressed. Affected individuals generally are able to carry out their work assignments, but they gain little pleasure from the leisure activities others find enjoyable, such as recreation, time with family, or sexual activity. They typically experience significant impairment in interpersonal functioning.
Bipolar Disorders
Manic Episode
During a manic episode (Box 111-3), the disturbance in mood must be severe enough to include psychosis, the need for hospitalization, or marked impairment in functioning. Bipolar disorders are much less common than major depressive disorder. The overall prevalence of a manic episode is 1.6% in both women and men.40
Mood Disorders Caused by a General Medical Condition
Certain medical illnesses have a well-known association with mood disorder (Box 111-4). In Parkinson’s disease, electrical stimulation to a certain area of the substantia nigra alleviates symptoms of depression. Stimulation of an area only 2 mm away can cause acute reversible symptoms of depression, such as crying, not wanting to live, and hopelessness.41 Parkinson’s disease has a well-known association with depression, with up to 40% of patients demonstrating major depression.42
Certain malignant neoplasms have a well-known association with depression, including pancreatic carcinoma, brain neoplasm, and disseminated malignant disease (e.g., lymphoma).43 Coronary artery disease,44 myocardial infarction, stroke, end-stage renal disease, acquired immunodeficiency syndrome, several endocrine diseases, and connective tissue disease are also associated with major depressive disorder.45 After a myocardial infarction, patients with depression experience a 3.5-fold increase in cardiovascular mortality compared with nondepressed patients.46 The development of stroke, diabetes, and osteoporosis appears to be more likely in patients with depression than in those who are not depressed.47,48
Depression related to medical conditions may be different in some respects from primary depression and responds less favorably than primary depression to antidepressant medication.49 Two significant issues arise in the assessment of patients with depression who have a serious medical illness. First, symptoms of depression must be distinguished from the symptoms and signs associated with serious medical illness (e.g., weight loss, loss of energy, slowing of activity, sleep disturbance, loss of ability to concentrate). Some experts have proposed that alternative criteria for depression caused by a general medical condition be substituted for DSM-IV-TR neurovegetative symptoms in patients with serious medical illness, such as depressed appearance, social withdrawal, pessimism or self-pity, anhedonia, and nonreactive mood. Second, it is important to determine if mood changes associated with terminal, rapidly progressive, or painful illness should be considered appropriate adjustment and grief. Although patients with such diseases may understandably be sad, most do not have major depression. The treatment of major depression in such patients should be considered and can greatly improve their quality of life.
Mood Disorders Caused by Medications or Other Substances
Certain medications are associated with symptoms of mood disorders (Box 111-5). Intoxication with or chronic heavy use of alcohol, sedatives, hypnotics, anxiolytics, narcotics, and other depressants can cause symptoms of a major depressive episode. Stimulants such as cocaine, phencyclidine, hallucinogens, and amphetamines can cause symptoms of a manic episode. Mood disorder symptoms can also develop during withdrawal. To qualify for this diagnosis, the symptoms must not occur exclusively during a course of delirium, must cause significant distress or impairment of functioning, and must develop within a month of either substance intoxication or withdrawal.
Substance abuse is often seen in patients with underlying depressive or bipolar conditions.
Diagnostic Strategies
The initial history and physical examination should focus on the presenting complaints and evaluate the possibility that drug abuse, medications, or a general medical condition may be responsible for the patient’s condition. The diagnosis of a mood disorder is based on history and observation of the patient’s ability to relate to family and medical staff and style in relating to them. The patient’s body language may be helpful. Precipitating events (e.g., loss of job or relationship), accompanying symptoms (e.g., hallucinations, delusions, anxiety disorder, mania), and suicidal ideation or intent should be assessed. The patient’s history should be confirmed through interviews with family, friends, or eyewitnesses to the events that precipitated the ED visit. A tentative diagnosis can be established by use of DSM-IV-TR criteria. Laboratory tests to investigate medical conditions may be necessary (see Box 111-4), but no tests can confirm or exclude mood disorders.
Management
Emergency Department Stabilization
Initiation of treatment for a mood disorder is not typically done in the ED. An exception is the acute manic episode (or possibly a severe depressive episode with psychosis) with behavior so extreme that the patient or others are threatened. Such cases may involve significant hallucinations, delusions, and other features of psychoses. In such cases, intramuscular or oral administration of haloperidol with or without lorazepam can calm such patients. A typical regimen for “rapid tranquilization” is an initial dose of 5 mg haloperidol with 2 mg lorazepam intramuscularly and reassessment in 30 to 45 minutes for resolution of “target” symptoms such as agitation. A second dose is administered after 30 to 60 minutes as needed for improvement in hallucinations, delusions, agitation, or violent behavior.50 Most patients respond after one or two doses. Benztropine (Cogentin), 1 to 2 mg, is often given initially to prevent extrapyramidal symptoms. Despite a black box FDA warning about prolongation of QT intervals and torsades de pointes, droperidol (2.5-5 mg) is a popular antipsychotic drug used effectively for agitation.50
The “atypical” antipsychotic medicines, including ziprasidone, risperidone, olanzapine, aripiprazole, and quetiapine, cause fewer of the side effects associated with conventional antipsychotic agents, such as acute dystonia, other extrapyramidal symptoms, and sedation. Oral doses should be offered first, and several agents, including risperidone, olanzapine, and aripiprazole, are available in rapidly dissolving tablet form. Three are available as an intramuscular injection: ziprasidone (Geodon), olanzapine (Zyprexa), and aripiprazole (Abilify). Ziprasidone 10 to 20 mg is effective; however, its use is limited to 40 mg per 24 hours. Olanzapine 2.5 to 10 mg effective but is associated with postural hypotension, and it is not recommended in combination with benzodiazepines because of the risk of hypoventilation. Aripiprazole is the newest agent and at doses of 9.75 to 15 mg seems to be the least sedating of the atypicals, but it is more likely to cause nausea and vomiting.51–56 Immediate psychiatric consultation should begin during the initiation of rapid tranquilization because patients undergoing rapid tranquilization will generally require hospitalization (Box 111-6).
Long-Term Treatment
Antidepressant Therapy
Many effective antidepressants are available for first-episode uncomplicated major depression. After 4 to 6 weeks of therapy, the response rate is usually 60% or greater for all agents. However, 10 to 15% of patients quit medication trials,57 and many patients in general medical practice are inadequately treated.46
Psychotherapy
Depressed patients benefit most from a combination of somatic therapy (medication or ECT) and psychotherapy. All patients with incomplete therapeutic response, recurrent depression, or comorbid conditions (e.g., anxiety or panic, substance abuse) should receive multimodal treatment.58
References
1. Boudreaux, ED, Clark, S, Camargo, CA, Jr. Mood disorder screening among adult emergency department patients: A multicenter study of prevalence, associations and interest in treatment. Gen Hosp Psychiatry. 2008;30:4–13.
2. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC:The American Psychiatric Association; 2000.
3. Kessler, RC, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593–602.
4. Larkin, GL, et al. Mental health and emergency medicine: A research agenda. Acad Emerg Med. 2009;16:1110–1119.
5. Chang, G, et al. Hospital variability in emergency department length of stay for adult patients receiving psychiatric consultation: A prospective study. Ann Emerg Med. 2011;58:127–136.
6. Hazlett, SB, McCarthy, ML, Londner, MS, Onyike, CU. Epidemiology of adult psychiatric visits to US emergency departments. Acad Emerg Med. 2004;11:193–195.
7. The World Health Report 2002: Reviewing the Risks, Promoting Healthy Life. Geneva, Switzerland: World Health Organization, 2002.
8. Hasin, DS, Goodwin, RD, Stinson, FS, Grant, BF. Epidemiology of major depressive disorder: Results from the National Epidemiologic Survey on Alcoholism and Related Conditions. Arch Gen Psychiatry. 2005;62:1097–1106.
9. Valtonen, H, et al. Suicidal ideation and attempts in bipolar I and II disorders. J Clin Psychiatry. 2005;66:1456–1462.
10. Valtonen, HM, et al. Suicidal behaviour during different phases of bipolar disorder. J Affect Disord. 2007;97:101–107.
11. Merikangas, KR, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry. 2007;64:543–552.
12. Frye, MA. Clinical practice. Bipolar disorder—a focus on depression. N Engl J Med. 2011;364:51–59.
13. Meyer, JH, et al. Elevated monoamine oxidase a levels in the brain: An explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry. 2006;63:1209–1216.
14. Ruhe, HG, Mason, NS, Schene, AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: A meta-analysis of monoamine depletion studies. Mol Psychiatry. 2007;12:331–359.
15. Belmaker, RH, Agam, G. Major depressive disorder. N Engl J Med. 2008;358:55–68.
16. Hasler, G, et al. Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry. 2007;64:193–200.
17. Zarate, CA, Jr., et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–864.
18. Savitz, JB, Drevets, WC, `Brain circuits in major depressive disorder and bipolar disorder, Kaplan and Sadock’s Comprehensive Textbook of Psychiatry. 9th ed. Sadock, BJ, Sadock, VA, Ruiz, P, eds., Kaplan and Sadock’s Comprehensive Textbook of Psychiatry. Philadelphia:Lippincott Williams & Wilkins; 2009;vol 1:1675–1685.
19. Kundermann, B, Hemmeter-Spernal, J, Huber, MT, Krieg, JC, Lautenbacher, S. Effects of total sleep deprivation in major depression: Overnight improvement of mood is accompanied by increased pain sensitivity and augmented pain complaints. Psychosom Med. 2008;70:92–101.
20. Even, C, Schroder, CM, Friedman, S, Rouillon, F. Efficacy of light therapy in nonseasonal depression: A systematic review. J Affect Disord. 2008;108:11–23.
21. Srinivasan, V, et al. Pathophysiology of depression: Role of sleep and the melatonergic system. Psychiatry Res. 2009;165:201–214.
22. Mahon, K, Burdick, KE, Szeszko, PR. A role for white matter abnormalities in the pathophysiology of bipolar disorder. Neurosci Biobehav Rev. 2010;34:533–554.
23. Thase, ME. Mood disorders: Neurobiology. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan and Sadock’s Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:1664–1674.
24. Carroll, BJ, et al. Pathophysiology of hypercortisolism in depression. Acta Psychiatr Scand Suppl. 2007;433:90–103.
25. Nemeroff, CB. Recent findings in the pathophysiology of depression. Focus. 2008;6:3–14.
26. Copolov, DL, et al. Specificity of the salivary cortisol dexamethasone suppression test across psychiatric diagnoses. Biol Psychiatry. 1989;25:879–893.
27. Joska, JA, Stein, DJ. Mood disorders. In: Hales RE, Yudofsky SC, Gabbard GO, eds. The American Psychiatric Publishing Textbook of Psychiatry. 5th ed. Washington, DC: American Psychiatric Publishing; 2008:457–503.
28. Kendler, KS, Gatz, M, Gardner, CO, Pedersen, NL. A Swedish national twin study of lifetime major depression. Am J Psychiatry. 2006;163:109–114.
29. Barnett, JH, Smoller, JW. The genetics of bipolar disorder. Neuroscience. 2009;164:331–343.
30. Mental Health: A Report of the Surgeon General, 1999. www.surgeongeneral.gov/library/mentalhealth/home.html, 2011.
31. Pittenger, C, Duman, RS. Stress, depression, and neuroplasticity: A convergence of mechanisms. Neuropsychopharmacology. 2008;33:88–109.
32. Mood disorders. In: Sadock BJ, Sadock VA, eds. Kaplan and Sadock’s Synopsis of Psychiatry. 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2008:527–562.
33. Suomi, SJ. Early stress and adult emotional reactivity in rhesus monkeys. Ciba Found Symp. 1991;156:171–183.
34. Akiskal, HS. Mood disorders: Clinical features. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan and Sadock’s Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:1679.
35. Pearn, J, Gardner-Thorpe, C. Jules Cotard (1840-1889): His life and the unique syndrome which bears his name. Neurology. 2002;58:1400–1403.
36. Mood disorders and suicide in children and adolescents. In: Sadock BJ, Sadock VA, eds. Kaplan and Sadock’s Synopsis of Psychiatry. 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2008:1258–1269.
37. Geriatric psychiatry. In: Sadock BJ, Sadock VA, eds. Kaplan and Sadock’s Synopsis of Psychiatry. 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2008:1348–1358.
38. Lam, RW, Tam, EM, Shiah, IS, Yatham, LN, Zis, AP. Effects of light therapy on suicidal ideation in patients with winter depression. J Clin Psychiatry. 2000;61:30–32.
39. Kornstein, SG, Sloan, DME. Depression and gender. In: Stein DJ, Kupfer DJ, Shatzberg AF, eds. Textbook of Mood Disorders. Washington, DC: American Psychiatric Publishing; 2006:687.
40. Hendrick, V, Altshuler, LL, Gitlin, MJ, Delrahim, S, Hammen, C. Gender and bipolar illness. J Clin Psychiatry. 2000;61:393–396.
41. Bejjani, BP, et al. Transient acute depression induced by high-frequency deep-brain stimulation. N Engl J Med. 1999;340:1476–1480.
42. Cummings, JL. Depression and Parkinson’s disease: A review. Am J Psychiatry. 1992;149:443–454.
43. McDaniel, JS, Musselman, DL, Porter, MR, Reed, DA, Nemeroff, CB. Depression in patients with cancer. Diagnosis, biology, and treatment. Arch Gen Psychiatry. 1995;52:89–99.
44. Gonzalez, MB, et al. Depression in patients with coronary artery disease. Depression. 1996;4:57–62.
45. Evans, DL, et al. Depression in the medical setting: Biopsychological interactions and treatment considerations. J Clin Psychiatry. 1999;60(Suppl 4):40–55.
46. Gilbody, S, Whitty, P, Grimshaw, J, Thomas, R. Educational and organizational interventions to improve the management of depression in primary care: A systematic review. JAMA. 2003;289:3145–3151.
47. Pignone, MP, et al. Screening for depression in adults: A summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;136:765–776.
48. Insel, TR, Charney, DS. Research on major depression: Strategies and priorities. JAMA. 2003;289:3167–3168.
49. Popin, MK. Consultation-liaison psychiatry. In: Jacobson JL, Jacobson AM, eds. Psychiatric Secrets. 2nd ed. Philadelphia: Hanley & Belfus; 2004:381.
50. Nockwitz, R, Rund, DA. Psychotropic medications. In: Tintinalli JE, ed. Emergency Medicine: A Comprehensive Study Guide. 6th ed. Columbus, OH: McGraw-Hill; 2003:1918.
51. Daniel, DG, Potkin, SG, Reeves, KR, Swift, RH, Harrigan, EP. Intramuscular (IM) ziprasidone 20 mg is effective in reducing acute agitation associated with psychosis: A double-blind, randomized trial. Psychopharmacology (Berl). 2001;155:128–134.
52. Brook, S, Lucey, JV, Gunn, KP. Intramuscular ziprasidone compared with intramuscular haloperidol in the treatment of acute psychosis. Ziprasidone I.M. Study Group. J Clin Psychiatry. 2000;61:933–941.
53. Allen, MH, Currier, GW, Hughes, DH, Reyes-Harde, M, Docherty, JP. The Expert Consensus Guideline Series. Treatment of behavioral emergencies. Postgrad Med. 2001;Spec No:1–88.
54. Currier, GW, Simpson, GM. Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation. J Clin Psychiatry. 2001;62:153–157.
55. Citrome, L. Atypical antipsychotics for acute agitation. New intramuscular options offer advantages. Postgrad Med. 2002;112:85–88.
56. Battaglia, J, Lindborg, SR, Alaka, K, Meehan, K, Wright, P. Calming versus sedative effects of intramuscular olanzapine in agitated patients. Am J Emerg Med. 2003;21:192–198.
57. McIntyre, JS. Practice Guideline for Major Depressive Disorder in Adults, 2nd ed. Washington, DC: The American Psychiatric Association; 2000.
58. Scott, J. Treatment of chronic depression. N Engl J Med. 2000;342:1518–1520.
