Alejandro S. Cazzulino
Maria A. Oquendo
Mood disorders are defined by the presence of a distinct period of persistently altered disposition, specifically, depressed, manic, or hypomanic states. These states are categorized as depressive or bipolar disorders depending on the presenting symptoms and the longitudinal course of the illness. Comorbidity between mood and neurologic disorders occurs frequently. Furthermore, not only may mood, especially depressive, symptoms be part or precede the clinical presentation of some neurologic disorders (e.g., Huntington disease [HD]) but they may also increase the risk for cerebrovascular disorders, and possibly some dementias, and therefore have a considerable impact in the prognosis and quality of life of primary neurologic disorders.
Major depression is one of the leading causes of disability in the United States and worldwide. It ranked 11th in terms of disabilityadjusted life years (DALYs) in a study of 291 diseases and injuries conducted in 21 regions. Moreover, according to the National Mental Health Association, depression affects 1 in every 33 children and 1 in every 8 adolescents. In any given year, about 21 million people in the United States will suffer from major depression (http://www.nimh.nih.gov/health/publications/the-numbers-count-mental-disorders-in-america/index.shtml#MajorDepressive).
The incidence of depression is nearly twice as high in women as it is in men, and suicide attempts are more numerous in women. However, death from suicide is far more common in men. Additionally, postpartum depression occurs after as many as 10% of all deliveries. The 12-month prevalence of depression in the U.S. population is estimated to be around 8.1% for women and 4.6% for men.
Bipolar disorder has a lifetime risk of 0.3% to 1.5%, with equal prevalence among men and women. It is estimated that around 10% of depressed patients may in fact be bipolar but have yet to be diagnosed.
Although the underlying biology of depression has not been fully elucidated, it is clear that several key systems are involved. These include the serotonergic, glutamatergic, noradrenergic, and dopaminergic systems. Other putative pathophysiologic processes include neuroinflammation, hypothalamic-pituitary-adrenal axis dysfunction, and neuroplasticity.
Genetic factors are thought to be relevant due to the high heritability of mood disorders, estimated at about 30% to 40%. The data from twin studies indicates that environmental factors also play an important role in the expression of mood disorders. Nonetheless, the risk of becoming ill increases two- to threefold for first-degree family members of patients with mood disorders. Of note, despite early suggestions that bipolar disorder is more heritable than depressive disorders, the evidence that genetic vulnerability or heritability of mood disorders differs between bipolar and unipolar conditions is mixed and far from definitive.
The serotonergic system plays a key role in depression, with studies demonstrating an overall decrease in serotonin (5-HT) function. Brain imaging studies demonstrate increased 5-HT1A-receptor binding and fewer brain 5-HT reuptake sites. Tryptophan (serotonin’s precursor) depletion has been shown to produce rapid depressive relapses in patients with a history of depression but no change in subjects with no personal or familial history of mood disorders. This suggests that low levels of 5-HT in the brain are not sufficient to cause depression but may act in concert with other factors in vulnerable individuals to cause symptoms. Indeed, many antidepressants exert their action through modulation of serotonin transmission.
Other neurotransmitter systems have been implicated in depression as well. For example, norepinephrine is linked to the pathophysiology of severe depression, as is dopamine, a neurotransmitter involved in incentive behavior and reward. Low cerebrospinal fluid levels of the dopamine metabolite, homovanillic acid, have been documented in depressed patients and exposure to dopamine-depleting drugs such as reserpine is known to precipitate depression. Changes in other neurotransmitters such as glutamate have also been identified. Glutamate, the main excitatory neurotransmitter appears to be increased in major limbic and cortical systems, possibly in response to stress, and may exert pathogenic effects either by limiting neurogenesis or dendritic remodeling directly or in concert with other factors that have similar effects on neuroplasticity.
Stress is implicated in the pathophysiology of depression, not only as mediated through glutamatergic changes in response but also as exemplified by prominent changes to the neuroendocrine system, especially in the hypothalamic-pituitary axis (HPA). Under normal conditions, stress prompts the HPA axis to secrete serum cortisol. In mood disorders, the HPA axis may become unresponsive to normal negative feedback loop, leading to a failure to restore cortisol to normal levels once the stressor is removed. These changes may be accompanied by the loss of normal diurnal variation in cortisol levels. Whether these changes are linked to early life experiences, leading to enduring changes in the HPA axis thereby increasing the probability of developing a mood disorder later in life, is not known.
Another hypothesis about the pathophysiology of depression posits that depression is a neuroinflammatory process, a concept bolstered by the observation that depressive symptoms (fatigue, anhedonia, anorexia, etc.) could be viewed as “sickness behaviors.” Indeed, changes in inflammatory markers, such as increased interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels have been consistently found in patients with depression. Furthermore, administration of therapeutic cytokines has been shown to cause significant depressive symptoms in 50% of exposed individuals, providing further evidence for the role of neuroinflammation.
As noted earlier, neuroplastic changes in the hippocampus have been linked to depression. Chronic stress is associated with decreased hippocampal neurogenesis, a phenomenon often observed in animal models of depression and postmortem tissue. Treatments with antidepressants seem to reverse these hippocampal deficits in neurogenesis. Both stress and antidepressants have been shown to affect levels of brain-derived neurotrophic factor (BDNF), which is normally highly expressed in hippocampus and prefrontal cortex and plays a major role in neuronal growth, survival, and maturation. BDNF also seems to have antidepressant-like actions and can induce molecular transcription in several key pathways.
Most psychosocial models focus on loss as the cause of depression in vulnerable, or less resilient, individuals. Exogenous factors may include social rejection or loss (interpersonal, financial, or health-related). Certainly, loss of income, job, social status, or the failure to achieve a life goal may produce profound mourning. Regardless, clinical manifestations in response to these stressors are ultimately mediated through brain circuitry and neurochemistry.
The pathophysiology of bipolar disorder is still being clarified, but studies have shown both structural and functional changes in those with the condition. Structural evidence from brain imaging studies shows a reduction of neurons and glial cells in areas such as the prefrontal cortex, amygdala and striatal regions, as well as white matter hyperintensities. Positron emission tomography (PET) studies suggest serotonergic abnormalities reflected in fewer serotonin transporters and more serotonin 1a receptors. Other relevant neurotransmitters include dopamine and glutamate. For instance, drugs that increase dopamine release, such as amphetamines, can induce manic-like symptoms. Similarly, decreased dopamine reuptake and reductions in dopamine transporter availability are linked to bipolar disorder. In addition, increased cortical glutamate levels and vesicular glutamate transporter gene expression are also implicated in the neurobiology of bipolar disorder.
As with depression, bipolar disorder can be viewed as a disorder related to synaptic plasticity involving dysfunction of neuroprotective pathways and impaired neuronal resilience. Multiple pathways related to plasticity are implicated including impaired regulation of calcium signaling cascades, associated with oxidative stress, and mitochondrial and endoplasmic reticulum stress response dysfunction.
Several intracellular molecular pathways affected by lithium and pertinent to neuroplasticity have been investigated as potential pathophysiologic contributors. The phosphoinositol pathway, involved in protein kinase C activation, regulates expression of several genes including BDNF. In fact, altered levels of BDNF are posited to contribute to the polarity switch process. Another lithium target, glycogen synthase kinase-3 (GSK3) is a key component of Wnt signaling and has effects on neurotransmission, neuroplasticity, neuronal growth, and metabolism.
A depressive episode is distinct from the normal emotional feelings of sadness or loss or a passing state of these emotions. Functional impairment and significant distress are key criteria and indeed, depression encompasses dysfunction in affective, cognitive, behavioral, and psychomotor domains.
In order to make the diagnosis, at least one of two gateway symptoms must be present for a minimum of 2 weeks: depressed mood and/or substantial decrease in interest or pleasure. Interestingly, depressed mood can manifest in a variety of ways and patients may report feeling down, sad, depressed, anxious, angry, or irritable. Of note, males may be more likely to present with irritability or anger, sometimes making the diagnosis more challenging to identify. Women more often present with “classic” sadness or depression. Anhedonia, or inability to feel pleasure, manifests as a reduction or loss of interest in things, people, or activities. As “gateway symptoms,” the diagnosis of depression cannot be made in the absence of at least one of them.
Cognitively, patients may experience difficulty concentrating or making decisions, a decrease in productivity, forgetfulness, and slowed thoughts. In addition, patients often report distorted thoughts that are negative and pessimistic, including feelings of worthlessness, loss of self-esteem, and unreasonable self-blame or guilt. The future is regarded with a sense of doom or dread and hopelessness. Moreover, negative memories from the past may be preferentially recalled. At times, such cognitive distortions may be of delusional intensity. For example, patients may become convinced they are gravely ill or impoverished and unable to process or “believe” results from medical tests or bank reports. Other delusions typical of depression with psychotic features focus on pessimism or deserved punishment. Auditory hallucinations that are usually simple and mood congruent may be present as well.
The behavioral symptoms of depression include changes in appetite and weight and disruptions of sleep patterns. Sleep disturbances include difficulty falling asleep (early insomnia), waking up in the middle of the night (middle insomnia), and waking up earlier than usual (terminal insomnia). Middle and terminal insomnias are more specific to depression than early insomnia, which is more common in the absence of a mood disorder. However, some patients experience hypersomnia rather than insomnia. Similarly, patients often report poor appetite and weight loss, although increased appetite and weight are sometimes observed, too. Other behavioral symptoms include loss of libido.
Psychomotor activity is usually diminished in depression and low energy and physical fatigue are often present. Patients may experience difficulty completing day-to-day activities and self-care or find that these activities require greater effort. In extreme cases, patients may become virtually immobile and mute, and this condition combined with loss of appetite and overall self-neglect can result in a medical emergency due to dehydration or poor nutrition. In contrast, some patients exhibit psychomotor agitation, which is often accompanied by intense anxiety. Agitation can often be seen in depressed patients but may also result from the side effects of antidepressant medications.
Perhaps, the most worrisome symptom of depression is suicidal thinking or behavior. Suicidal ideation may range from passing thoughts that life is not worth living to well-defined plans with intent to kill oneself. About 15% of patients with depression acknowledge a suicide attempt at some point in their lives and between 2% and 12% of patients with depression commit suicide. This is another way in which depression can lead to morbidity and mortality.
On examination, depressed patients characteristically exhibit a dejected posture, with bent shoulders, frowning, and a downcast gaze. Gestural movements and facial expressions are reduced, and grooming may be neglected. Patients usually take more time to start answering questions and speak slowly and softly.
The distinguishing feature of bipolar disorder is the presence of a manic or hypomanic state that lasts a week or longer (can be less for
hypomania). As with depressive disorders, there are impairments in affective, cognitive, psychomotor, and behavioral domains.
hypomania). As with depressive disorders, there are impairments in affective, cognitive, psychomotor, and behavioral domains.
Mania, lasting a minimum of 1 week, is characterized by abnormally elevated or euphoric feelings. As with depression, there can be significant irritability and anger, especially when the patient is frustrated. Patients often appear exaggeratedly cheerful and happy.
Cognitive abnormalities include rapid or even racing thoughts, which may translate into rapid, pressured speech that can, as the severity of mania progresses, become increasingly disorganized. As thoughts become disorganized, speech can exhibit flight of ideas or loosening of associations. In addition, patients are easily distracted and have difficulty focusing on tasks that require concentration. Patients also frequently exhibit impaired judgment and engage in activities they would normally eschew if well. Patients may go on spending sprees, engage in promiscuous sexual behaviors, or make risky business decisions. Cognitive distortions in mania often include inflated self-esteem and grandiose ideas such as a sense of being special, capable of anything, or possessing special powers. As in depression, the cognitive distortions can cross the line into delusional or psychotic thinking. Grandiose delusions are a common psychotic feature in mania.
Behaviorally, manic patients are usually overactive with increased energy levels and engage in multiple activities. Typically, the number of hours of sleep is reduced, without the sensation of fatigue or sleepiness. In fact, insomnia is often the first recognizable symptom of a manic episode. Appetite is usually reduced and combined with increased activity can lead to significant weight loss. Manic patients classically dress with bright colors, use excess make up, or wear extravagant clothing. Movements are exaggerated or theatrical, and patients may express excessive familiarity toward strangers.
From a psychomotor vantage, manic patients frequently have increased psychomotor activity. They may engage in both goaloriented activities at an accelerated pace or be overactive in a general way, with pacing or fidgeting.
Interviewing can be very difficult, as manic psychopathology tends to block communication. It is usually counterproductive for the physician to spend time arguing with or countering the illogical thinking of the patient. Insight is absent in virtually all cases and, therefore, patients typically object to treatment.
Hypomania has a similar clinical presentation but may be briefer, cause less functional impairment, and has no psychotic symptoms.
Although the presence of manic or hypomanic episodes differentiates bipolar from depressive disorders, depression is prominent in bipolar disorder. In fact, over the course of the disorder, most bipolar patients spend significantly more time depressed than manic or hypomanic. Bipolar depression usually has an earlier onset, greater risk of suicidal behavior, likely linked to the greater time spent depressed, and more episodes of illness.
There is no pathognomonic sign or symptom and, as of yet, no biologic or neuroimaging markers that can establish the diagnosis of a mood disorder. Therefore, mood disorder diagnoses are established according to their clinical features. Each category has specific criteria, which are defined by consensus and described in manuals such as the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). It is likely that these diagnoses will ultimately be understood as a grouping of multiple distinct disorders and more specific entities within the current disorders will be defined using genetics, epigenetics, brain imaging, and other methods.
Major depressive disorder (MDD) is diagnosed by the presence of at least one major depressive episode. Episodes can occur a single time but, more often, they are recurrent.
Persistent depressive disorder is a form of depression that has less than 5 symptoms, as required in MDD, but lasting for at least 2 years, with little or no remission during that time. Typical symptoms include low mood, lack of energy and interest, low self-esteem, and irritability. Chronic forms of depressive disorders are associated with poorer response to treatment, slower rate of improvement over time, younger age of onset, longer episodes, greater disease burden, higher rates of medical and psychiatric comorbidity, and higher rates of suicidal ideation.
Mood and associated physical symptoms may occur in relation to the menstrual cycle. Premenstrual dysphoric disorder is diagnosed if symptoms are present during the last week of the luteal phase, remit within a few days of the follicular phase, and are absent in the week following menses. A prospectively documented cyclical pattern over at least 2 consecutive months must be present to confirm the diagnosis.
Mood disorders in children and adolescents bring specific diagnostic challenges. Behavioral problems are common and include withdrawal, sullenness, truancy, poor grades, and tantrums. Children and adolescents showing persistent irritability, which manifests as frequent temper outbursts and angry, irritable mood in between outbursts, may be eligible for the diagnosis of disruptive mood dysregulation disorder (DMDD).
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