Psychiatry

Limbic System

The limbic system is the only brain area receiving major hypothalamic input and providing interconnection with widespread cortical areas. Major limbic structures include the amygdala, piriform cortex (parahippocampal gyrus, uncus + amygdala) , hippocampus, substantia innominata, and septal area. The limbic system's diverse roles include memory, drive, affect, autonomic tone, endocrine control, and immunoregulation.

The amygdala is connected extensively to the hypothalamus and other limbic structures. It receives input from widespread sensory cortical regions and paralimbic structures (piriform cortex, entorhinal cortex, and parahippocampal cortex on the temporal lobe medial surface and the cingulate cortex just above the corpus callosum). The amygdala is critical for channeling drive and affect. In lesion studies of monkeys, visual information from one eye was restricted to an intact amygdala, while visual information from the other eye was directed toward a lesioned amygdala. The monkey's typical aggressive behavior when visually provoked was intact only when stimulated through the intact visual pathway. When provoked via the lesioned pathway, the monkey remained passive.

This is observed in the Klüver-Bucy syndrome that arises when the amygdala is disconnected from cortical sensory input. The typical features of the Klüver-Bucy syndrome include (1) indiscriminant sexual behavior toward objects in the immediate extrapersonal space, (2) absence of fight-flight reaction toward threat, and (3) inability to visually distinguish edible from inedible objects except by orally inspecting objects.

The amygdala channels appropriate emotional response toward sensory targets while having an important role in the interpretation and display of affective gestures, including vocalization . The right hemisphere is dominant here. The amygdala also plays an integral role in the experience of strong emotions, including fear, rage, and experiences of familiarity . The amygdala imparts the affective coloring of personal experience that reflects a person's history, present internal state, and characteristics of their present mental experience. Certain disease states engender disruptions of this balance. Thus the affective color of a particular mental process may be distorted, amplified, or diminished, thereby changing the very meaning of the entire experience. This is witnessed in panic attacks, dissociative states, depression, and schizophreniform conditions. In humans, the amygdala does not appear to play a direct role in memory formation, although amnesia resulting from hippocampal damage seems more severe if there is additional involvement of the amygdala. This suggests the amygdala may establish an affective link in memorization. Additional amygdala roles include regulation of autonomic, endocrine, and immunologic function.

The piriform cortex is a relay area for cortical and olfactory information, much the way the thalamus is the relay area for every other sensory modality. This area also has numerous connections with hypothalamus and other limbic regions. Animal studies suggest a role in regulation of the direction of drive within extrapersonal space, such as attack or sexual behaviors.

The hippocampus receives almost all of its input from paralimbic areas, which receive their input from cortical sensory areas. Other inputs include hypothalamus, amygdala, and septal area. Its major role is memory and learning . Isolated hippocampal damage is relatively rare, but combined lesions of hippocampal and parahippocampal areas in infarcts lead to severe amnestic states, even when the amygdala is spared. These structures are necessary for the formation of new memories (recording experience) rather than storage of memories. In addition, they rekindle memories during retrieval. The motivational relevance of experience makes it more likely to be memorized and recalled. This is why storage and retrieval are affected with relative preservation of memory banks (long-term memory) in diseases affecting these structures.

The septal nuclei and substantia innominata contain the major cholinergic cells of the brain, located in the medial septal nucleus, the vertical and horizontal limb nuclei of Broca's diagonal band , and the nucleus basalis of Meynert . These areas project to the hippocampus, olfactory region, widespread cortical regions, and the amygdala. The hypothalamus and various limbic and paralimbic structures give rise to the majority of the inputs to these structures. This cholinergic network is essential for intact memory function. Patients with anterior communicating artery aneurysms or with septal tumors may develop amnestic states. In Alzheimer disease , where memory loss is the major clinical feature, there is a profound loss of cholinergic neurons in the nucleus basalis as well as in widespread cortical regions. Septal lesions may also produce exaggerated emotional reactions to novel or threatening stimuli, hyperdipsia, hyperphagia, and altered taste preference. There is evidence suggesting a role in attaching motivational value to extrapersonal objects.

Major Depressive Disorder

Major depressive disorder (MDD) is a mood disorder characterized by the occurrence of one or more major depressive episodes during one's lifetime. To diagnose a major depressive episode, five (or more) of the following nine symptoms must been present every day or almost every day during the same 2-week period and represent a change from a previous level of functioning. At least one symptom must be either (1) depressed mood or (2) anhedonia (markedly diminished interest or pleasure in all, or almost all, activities. The other seven criteria are (3) a significant decrease or increase in appetite or weight , (4) insomnia or hypersomnia , (5) psychomotor retardation or agitation , (6) fatigue or loss of energy , (7) feelings of worthlessness or excessive or inappropriate guilt , (8) poor concentration or difficulty making decisions , and (9) recurrent thoughts of death, suicidal ideation, or a suicide attempt . These symptoms must cause clinically significant distress or impairment in social, occupational, or other important areas of functioning and should not be due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism).

Subtypes of depression may be defined by the presence of psychotic features (delusions, hallucinations), catatonia (motor disturbances, such as immobility or agitation, stereotyped movements, mutism), melancholy (weight loss, insomnia, morning worsening) or atypism (hypersomnia, hyperphagia), or postpartum onset of depression.

In epidemiologic studies, the 12-month and lifetime prevalence of MDD are, respectively, 5% to 7% and 13% to 18%, and the prevalence seems to be largely unrelated to ethnicity or geography (region of the country or urbanicity). In a recent U.S. epidemiologic survey, being female; Native American; widowed, separated, or divorced; being unemployed or disabled or having low income was significantly associated with higher rates of MDD. The mean age at onset for MDD is in the early 30s. The hazard for childhood onset MDD is relatively low, increases sharply between ages 12 and 16 years, and continues to increase, albeit more gradually, up to the early 40s. The diagnosis of MDD is associated with the presence of one or more psychiatric disorders during one's lifetime in nearly 75% of cases, including anxiety disorders (60%), substance use disorders (25%), and impulse control disorders (30%).

The neurobiologic basis and pathophysiology of MDD continue to be enigmatic. This is likely due in part to the heterogeneity of MDD, which may represent a group of disorders with several underlying pathologies, in which both genetic and environmental factors play a role. Studies have investigated disturbances in several neurotransmitters (serotonin [5-HT, i.e., 5-hydroxytryptamine], norepinephrine [NE], and dopamine, and more recently glutamate); in neuroendocrine and neuroimmune mechanisms, in particular, the hypothalamic-pituitary-adrenal axis involved in the response to stress; and in neurotrophic factors regulating plasticity in the brain. It is important to emphasize that neurotransmitters and hormones are integrated in anatomic and functional circuitry interacting at several levels. Imaging and postmortem studies suggest that MDD patients have structural and subtle cellular and molecular alterations within a complex neural network involving the prefrontal cortex, subgenual cingulate cortex, hippocampus, and amygdala.

MDD genetics are complex and multifactorial; this disorder frequently occurs in families, having an estimated heritability of approximately 40%. Through linkage, association, and genome-wide association studies, several candidate genes and regions of the genome are identified that may contribute to MDD; however, these findings are not consistent in variable studies. Each individual gene probably contributes only to a very small proportion of the variance, interacting with environmental factors.

Initial treatment modality choices in MDD are influenced by a number of factors, including symptom severity, co-occurring psychiatric or medical conditions, psychosocial stressors, and the patient's preference. Antidepressant medications include selective serotonin reuptake inhibitors (SSRIs), usually used as a first choice, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and others, including bupropion, nefazodone, trazodone, and mirtazapine. The choice of an antidepressant is based on side-effect profile, tolerability, safety, and history of prior response to treatment.

After an initial phase of pharmacologic treatment of 2 to 3 months, aimed at achieving full remission of symptoms, pharmacotherapy is typically continued for approximately 4 to 9 months to prevent early relapse. Psychotherapy, alone or combined with medications, may also be considered as initial treatment for patients with mild-to-moderate MDD. Electroconvulsive therapy (ECT) is a potentially very successful treatment option for patients who are more severely ill, present psychotic features or catatonia, and for those who are acutely suicidal.

Postpartum Depression

The postpartum period has clearly been defined as a time of increased vulnerability to psychiatric illness in women; up to 85% of women experience some type of mood disturbance after childbirth. Most of these women experience transient and relatively mild mood symptoms (“the blues”); however, about 10% to 15% of women experience a more disabling and persistent form of mood disturbance, either postpartum depression (PPD) or postpartum psychosis. Although postpartum psychiatric illness was initially conceptualized as a group of disorders specifically related to childbirth, more recent evidence suggests that affective illness emerging during the postpartum period is clinically indistinguishable from affective illness occurring at other times during a woman's life. In fact, most women with postpartum illness will also go on to have mood episodes that are not related to either pregnancy or childbirth.

The Diagnostic and Statistical Manual of Mental Disorders (i.e., DSM-IV ) does not list postpartum psychiatric disorders separately but instead uses a specifier, for example, “with postpartum onset” to describe any depressive, manic, or mixed episode (in major depressive disorder, bipolar disorder, or brief psychotic disorder) when the episode occurs within the first 4 weeks after delivery . Although risk of postpartum psychiatric illness is the highest in the first 4 weeks after childbirth, several different studies indicate that women remain at very high risk for affective illness during the first 3 months after delivery. In fact, women remain at heightened risk up to 1 year after childbirth. Thus many experts define postpartum psychiatric illness as any episode occurring within the first year after childbirth.

Bipolar Disorder

Bipolar disorder is a mood disorder characterized by the occurrence of manias or hypomanias, and depressions. Manias consist of elevated, irritable, or expansive mood with at least three of the following symptoms if the mood is elevated (four if irritable): (1) decreased need for sleep, (2) flight of ideas, (3) hypertalkativeness (including pressured or excessive speech), (4) grandiosity, (5) distractibility, (6) increase in goal-directed behavior or agitation, and (7) increase in high-risk pleasurable activities, such as spending sprees, reckless driving, or sexual indiscretions. Manic episodes last at least 1 week but may be of any duration if they lead to hospitalization. Psychotic symptoms may occur in the setting of a mania and sometimes take the form of grandiose delusions, although other psychotic symptoms, including auditory hallucinations, may occur. A hypomania is less severe, does not result in hospitalization, and may last only 4 days; although otherwise, it includes similar but lesser-intensity symptoms than mania.

Depressive episodes consist of either depressed mood or anhedonia with five or more of the following concomitant symptoms: (1) significant decrease or increase in sleep, and/or (2) appetite, (3) low energy, (4) psychomotor retardation or agitation, (5) excessive guilt, (6) feelings of worthlessness, (7) poor concentration, (8) difficulty making decisions, and (9) recurrent thoughts of death, suicidal ideation, or a suicide attempt.

Bipolar disorder is divided into two primary types. Bipolar I disorder is diagnosed when a patient experiences a manic episode. Typically, these patients experience both manias and major depressive episodes; however, the presence of a mania alone is sufficient to make the diagnosis. Bipolar II disorder is diagnosed when a patient experiences at least one hypomania and at least one depressive episode. There are related illnesses that fall within the bipolar spectrum but do not meet the criteria for full bipolar disorder. These include patients who experience medication-induced mania or hypomania, as well as cyclothymia.

The epidemiology of bipolar disorder is relatively consistent throughout the world and does not appear to vary significantly between ethnic groups. Population-based studies demonstrated approximately 0.6% prevalence for bipolar disorder type I, 0.4% for bipolar disorder type II, and 1.4% for subthreshold bipolar disorder. There is not a significant gender difference in predilection for this illness. Of interest, the first episode is more likely to be a mania in men and a depressive event in women. The onset of bipolar disorder symptoms generally occurs in adolescence, particularly in the late teens. Onset of bipolar disorder is usually in the early 20s for both men and women.

Bipolar disorder genetics are complex and indicate an overlapping risk with schizophrenia. Twin studies demonstrate that bipolar disorder is strongly heritable. Estimates suggest that up to 80% of risk for bipolar disorder may be inherited. A subunit of L-type calcium channels is among the first genes consistently associated with bipolar disorder.

Functional neuroimaging studies point to significant effects on the anterior limbic network, with particular activation of the amygdala, striatum, and thalamus in bipolar disorder patients when compared with healthy control subjects. However, these studies are limited by small sample size, lack of control for medication, and a mix of mood states at the time patients were scanned. The understanding of bipolar disorder at a cellular and molecular level has advanced from a focus primarily on neurotransmitters, where there are important abnormalities, to an increased focus on signaling pathways and cellular plasticity and resilience.

Lithium preparations were the first effective therapy for bipolar disorder. Several additional classes of medications subsequently demonstrated efficacy. Current pharmacologic preferences include lithium, still considered to be one of the most effective treatments, as well as certain anticonvulsants, that is, valproic acid, lamotrigine, and carbamazepine, and second-generation antipsychotic medications. The treatment of bipolar depression remains a particular challenge, with relatively few medications demonstrating clear efficacy. However, there are some very valuable nonmedication treatment modalities available. Electroconvulsive therapy (ECT) is typically used during severe episodes or when other treatments are not effective. Structured psychosocial interventions, such as cognitive-behavioral therapy, are also useful in illness management.

Generalized Anxiety Disorder

Generalized anxiety disorder (GAD) is characterized by excessive, uncontrollable, and often irrational worry, about everyday things that is disproportionate to the actual source of worry. To diagnose GAD, excessive worry must be present for at least 6 months, the person finds it difficult to control the worry, and the anxiety and worry are associated with three (or more) out of six symptoms. These include (1) restlessness or feeling keyed up or on edge, (2) being easily fatigued, (3 ) difficulty concentrating or mind going blank, (4) irritability, (5) muscle tension, and (6) sleep disturbance (difficulty falling or staying asleep, or restless unsatisfying sleep). As with other axis I diagnoses, the symptoms must cause clinically significant distress or impairment in social, occupational, or other important areas of functioning and are not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hyperthyroidism), and do not occur exclusively during a mood disorder, psychotic disorder, or a pervasive developmental disorder.

The prevalence of GAD in the National Comorbidity Survey (NCS) was 1.6% for current GAD (defined as a 6-month period of anxiety that continued in the 30 days before the interview), 3.1% within the previous 12-month period, and 5.1% for lifetime diagnosis. In most epidemiologic studies, the lifetime prevalence of GAD is reported between 3% and 6%, with a higher prevalence in women (2 : 1 female/male ratio). The usual age at onset is variable—from childhood to late adulthood, with the median age at onset being approximately 31 years. There is significant comorbidity associated with other psychiatric disorders (up to 90% of patients meet criteria for another disorder), the most frequent being major depression (up to 60%), dysthymia (40%) alcohol abuse/dependence (38%), and other anxiety disorders (social phobia, agoraphobia, and panic). The presence of comorbid psychiatric disorders has significant negative effects on prognosis. Finally, GAD patients often have multiple medical comorbidities, including migraine, chronic pain, gastrointestinal problems, cardiac, and/or respiratory disorders further complicating assessment and treatment.

GAD may occur in families. Twin studies also suggest that genes are at least partly responsible for the disorder; however, the heritability is modest. The genetic correlation between major depression and GAD is very high. GAD usually begins at an earlier age, and symptoms may manifest themselves more slowly than in most other anxiety disorders. Some people with GAD report onset in early adulthood, usually in response to a life stressor. The clinical course of GAD is often chronic, with 40% of patients reporting an illness lasting more than 5 years. GAD is associated with pronounced functional impairment, resulting in decreased vocational function and reduced quality of life. Moreover, GAD patients are often high users of outpatient medical care, contributing significantly to health-care costs.

Anxiety disorders are thought to result from abnormal processing of threat-related stimuli, as well as functional deficits in brain pathways underlying fear learning and memory. Neuroimaging studies in GAD suggest increased activity in the fear circuitry involving the amygdala, anterior cingulate cortex, and insula, as well as increased activity in the prefrontal cortex, which appears to have a compensatory role in reducing GAD symptoms. Serotonergic, noradrenergic, and gamma-aminobutyric acid (GABA) inhibitory systems dysfunction may relate to expression of GAD. The adrenal system and chronic stress response is also implicated in GAD pathophysiology, with the amygdala mediating arousal and fear by activating the hypothalamic-pituitary-adrenal (HPA) axis. Other putative neuroendocrine mechanisms are currently under investigation.

Different classes of antidepressants are efficacious in GAD. Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) are usually used as first choice, with tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and others, including buspirone and mirtazapine, as other therapeutic options. Benzodiazepines also provide effective therapies for GAD, having the advantages of a short latency of therapeutic onset and a generally favorable side-effect profile. Major drawbacks include sedation, cognitive impairment, and the possibility of long-term adverse effects (i.e., development of tolerance), physical dependence, and a withdrawal syndrome. Other drugs used in GAD management include pregabalin and sympatholytic agents (propranolol, prazosin, clonidine), and atypical antipsychotics that may have an adjunctive role to antidepressants in cases of treatment resistance. Psychotherapy, in particular cognitive-behavioral therapy, as monotherapy or combined with medications, may also be considered as initial treatment for patients with mild-to-moderate symptoms.

Social Anxiety Disorder

Introduction and Clinical Presentation. Social anxiety disorder (SAD), or social phobia, is characterized by persistent fear of social or performance situations in which an individual will face exposure to unfamiliar people or scrutiny by others. The individual typically fears behaving in an embarrassing or humiliating fashion, or revealing symptoms of anxiety. Exposure to these situations provokes anxiety or panic symptoms, leading the individual to avoid such situations whenever possible. Physical symptoms may include diaphoresis, tachycardia, trembling, nausea, flushing, and difficulty speaking, for example.

DSM-IV criteria stipulate that this condition contributes to significant functional impairment (for example, in work or relationships) or distress. Of note, the individual recognizes that the fear is excessive or unreasonable. Although the diagnosis has been criticized for ascribing a medical diagnosis to a normal population trait, shyness, the persistence and severity of these symptoms—and in particular their impact on functioning—argues otherwise.

Diagnostic criteria distinguish a generalized form, that is, occurring in most social situations, or a specific form, that is, one which occurs only in particular circumstances, such as public speaking or public performance, or writing or eating in front of others. However, these are not necessarily distinct subtypes, although the generalized form may be more disabling overall.

Epidemiology. The lifetime prevalence of SAD is ≈12%, with 12-month prevalence of ≈7%. SAD often has early onset, with about half of cases presenting by age 11 years; on the other hand, later onset in many patients provides further support for SAD being something other than the trait of shyness. As with major depressive disorder, SAD is seen more commonly in females. As with other psychiatric disorders, rates of comorbidity are high, having overlap with major depression and substance use disorder, for example.

Treatment of SAD relies on either cognitive-behavioral therapy, delivered individually or in a group setting, or pharmacotherapy. Standard medication treatments use selective serotonin reuptake inhibitors, although other antidepressants, including monoamine-oxidase inhibitors and serotonin-norepinephrine reuptake inhibitors have also demonstrated efficacy. Anxiolytic medications, such as benzodiazepines, are sometimes used as well. Scales such as the Liebowitz Social Anxiety Scale may be used to quantify severity over time.

Pathophysiology. SAD has been noted to be familial, and often coaggregates with major depression, panic disorder, and agoraphobia. Twin studies suggest that about 40% of liability is inherited. Although candidate gene studies have implicated multiple genes, no single association has been convincingly demonstrated, and genome-wide studies have not been reported. The potential role of neuropeptides involved in social cognition, such as oxytocin and arginine vasopressin, is also under active investigation. For example, rodent models illustrate the capacity of oxytocin to diminish social avoidance, which may inform future treatment development in SAD.

Functional magnetic resonance imaging (fMRI) implicates the amygdala and insula activation in SAD, for example, on tasks requiring processing of emotional faces. fMRI also suggests there may be abnormal connectivity evident in the resting state, involving frontal and occipital structures. Other studies also suggest basal ganglia dysfunction in SAD; of interest, SAD is seen more commonly in individuals with Parkinson disease, which may provide convergent evidence for the role of basal ganglia in these symptoms.