Ch 19 Neurobiology of Schizophrenia, Mood Disorders & Anxiety PDF

CHAPTER 19- Neurobiology of Schizophrenia, Mood Disorders & Anxiety Disorders What is schizophrenia? What part of the brain is associated with the S/S of this disorder? Schizophrenia is the term coined by Eugen Bleuler in 1911 to describe a collection of illnesses characterized by thoug...

CHAPTER 19- Neurobiology of Schizophrenia, Mood Disorders & Anxiety Disorders What is schizophrenia? What part of the brain is associated with the S/S of this disorder? Schizophrenia is the term coined by Eugen Bleuler in 1911 to describe a collection of illnesses characterized by thought disorders, which reflect a break in reality or splitting of the cognitive from the emotional side of one’s personality. It is a heritable disorder, though not a simple genetic disorder in which inherited disease alleles will always lead to illness – it likely involves several genes located on different chromosomes and thus differs from mendelian disorders. Affects 1% of the world’s population. Related to genetic predisposition and prenatal/perinatal vulnerability factors. Brain abnormalities in schizophrenia are believed to originate in the prenatal period of cell proliferation and migration o Maternal illnesses such as having viral infections results from neurodevelopmental defects that occur in fetal life Neurochemical and neuroanatomic alterations of patients with schizophrenia: o Under activation of glutamate receptors also contributes to schizophrenia ▪ Level of glutamic acid decarboxylase a major enzyme in GABA biosynthesis, is reduced, which likely impairs normal cognitive/emotional functions. o Negative symptoms and cognitive alterations in schizophrenia are proposed to result from reduced dopaminergic neurotransmission in the mesocortical dopamine pathway. o Another neurotransmitter system that may underlie the pathogenesis is the excitatory neurotransmitter glutamate and its actions on the NMDA (N-methyl-D-aspartate). o Enlargement of the lateral and third ventricles and widening of the frontocortical fissures and sulci. Individuals with cerebral ventricle enlargement often exhibit cognitive impairments and negative symptom and respond poorly to treatment. o Reduction in the thalamus and temporal lobe areas (amygdala, hippocampus, and parahippocampal gyrus). ▪ Reduction in thalamus size may disrupt neurotransmission between the cortex and primary sensory and motor areas. ▪ Temporal lobe alterations may contribute to positive symptom. o Brain studies in adolescents with early onset reveal progressive loss of cortical gray matter in temporal lobes, somatosensory and motor cortices, and the dorsolateral cortex. o The progressive loss in frontal lobe volume is accompanied by increased severity of negative symptom and further reduction in cognitive functioning. o Functional alterations in the dorsolateral prefrontal cortex (reduced blood flow and metabolism) compromise abilities to engage in goal-directed and cognitive problem-solving behavior. o Reelin, an extracellular matrix protein involved in neuronal migration during development and in synaptic function during adulthood, is reduced Structural Brain Abnormalities PRESENTATION  Cerebral ventricular changes Cognitive impairments and negative symptoms; also respond poorly to treatment. Temporal lobe alteration Positive symptoms present Dorsal prefrontal cortex Negative symptoms are present; impaired initiation and maintenance of changes (especially DLPFC) goal-oriented activities and cognitive problem-solving in relation to working memory Disorganized thought in schizophrenia is characterized by positive and negative symptoms, including auditory hallucinations, paranoid delusions, and cognitive deficits. Positive symptoms: linked to excess dopamine o Delusions o Hallucinations o Disturbances in thought o Bizarre behavior Negative symptoms: linked to prefrontal pathologies o Loss of affect (flattened affect) o Lack of speech (alogia) o Absence of pleasure (anhedonia) o Attention deficits o Apathy o Catatonia o Immobility Define depression and its types Mood disorders: when emotional states, such as sadness (or mania), become chronic and uncontrollable. o Alterations in hypothalamic-pituitary-adrenal (HPA) system, serotonin (decrease), norepinephrine, and dopamine are related to depression symptoms. o Two major classifications of mood disorders: ▪ Unipolar, or major or clinical depression. ▪ Bipolar disorder. o Genetic, environmental, neurochemical dysregulation, and neuroendocrine dysregulation have been found to play a role in the pathogenesis and/or etiology of depression. Major depression: unremitting feelings of sadness and despair, dysphoric mood accompanied by frequent insomnia, loss of appetite and loss of body weight, and reduced interest in pleasurable activities and interpersonal relationships. o Most common mood disorder and the leading cause of disability in the U.S. and throughout the world. o Diagnosed by the presence of five or more of the following symptoms in a two weeks period, with at least one symptom being either depressed mood or loss of interest of pleasure: ▪ Depressed or irritable mood ▪ Loss of interests or pleasure ▪ Significant (>5%) weight gain or loss in a month ▪ Insomnia or hypersomnia ▪ Psychomotor agitation or retardation ▪ Fatigue or loss of energy  ▪ Feelings of worthlessness or excessive guilt ▪ Poor concentration or indecisiveness ▪ Recent thoughts of death or suicide Theories of Etiology: o Genetic predisposition and environmental influences: current view of mood disorders is that the illness stems from a complex interplay between susceptible genes and environmental influences, such as the interplay between life stressors and a potentially dysfunctional serotonin system, which appears to elevate the risk of depression. o Neurochemical dysregulation: monoamine hypothesis of depression found that a deficit in the concentration of brain norepinephrine, dopamine, and/or serotonin = underlying cause of depression; also found a reduction of monoamine metabolites in the CSF in depressed clients. o Neuroanatomic and functional abnormalities ▪ Norepinephrine receptor alterations have been found in the frontal cortex of some suicide victims. ▪ In depressed individuals, there is a widespread decrease in serotonin 5-HT1A receptor subtype binding in the frontal, temporal, and limbic cortex, as well as serotonin transporter binding in the cerebral cortex and hippocampus. There are also reports of reduced frontal lobe volume in depressed individuals and decreased or asymmetric temporal lobe volume with bipolar illness and depression. o Neurochemical dysregulation: ▪ Chronic activation of the HPA system and elevated glucocorticoid secretion are found in major depression. Antidepressant drugs effective in normalizing the mechanisms responsible for increased HPA hormone secretion are associated with a good clinical response. ▪ Psychosocial stress-induced activation of the immune system increases secretion of proinflammatory cytokines, such as interleukin-1α (IL-1α) and IL-β, tumor necrosis factor– alpha (TNF-α), and IL-6, which modulates signaling pathways throughout the periphery and brain and augments further secretion of HPA hormones and monoamine metabolism. This may lead to chronic elevations in cortisol levels. ▪ A reduction in the development of new hippocampal neurons (neurogenesis), and a deficit in hippocampal brain-derived-neurotrophic factor (BDNF) levels have been identified in animal models of stress-induced depression. ▪ There is also an altered hypothalamic-pituitary-thyroid (HPT) system in approximately 20% to 30% of persons with MDD. Individuals exhibit increased CSF levels of thyrotropin- releasing hormone, blunted thyroid-stimulating hormone response to TRH challenge, and decreased nocturnal rise in TSH level that normally occurs between midnight and early morning. Not to be confused with bipolar disorder, which is accompanied by manic episodes. o Bipolar I: features manic episodes and at least one major depressive episode. o Bipolar II: characterized by recurrent major depressive episodes with one or more episodes of hypomania. o Symptoms of a manic episode include: ▪ Elevated mood ▪ Irritable mood ▪ Inflated self-esteem  ▪ Decreased need for sleep ▪ Excessive talking ▪ Racing/crowded thoughts ▪ Distractibility ▪ Increase in goal-directed activity ▪ Excessive risky activities Depression Bipolar (Mania) Reduction in brain monoamine neurotransmission Elevated brain monoamine neurotransmission (monoamine hypothesis of depression) Deficit of norepinephrine, dopamine, and/or Loci on chromosomes 18 & 22 serotonin Increased cortisol, which stay elevated throughout evening and early morning Abnormal thyroid hormones Life stressors and potential dysfunction of serotonin elevates risk Persons with copies of two s alleles more likely to develop MDD and have suicidal thought in response to stress Alterations in blood flow to prefrontal and limbic brain regions (amygdala = emotional behavior) Structural brain alterations: reduced frontal lobe and limbic system volumes Etiology and link to cortisol and depression Persistent elevations in cortisol may induce immunosuppression that compromises the body’s immune systems to contain inflammation which may trigger depression Psychosocial stress-induced activation of the immune system increases secretion of proinflammatory cytokines, such as interleukin-1α (IL-1α) and IL-β, tumor necrosis factor–alpha (TNF-α), and IL-6 o Modulates signaling pathways throughout the periphery and brain and augments further secretion of HPA hormones and monoamine metabolism. o This may lead to chronic elevations in cortisol levels. Side effects of MAOIs. Commonly reported side effects of MAOIs include sedation or agitation, insomnia, dry mouth, impotence, and weight gain. MAOIs also may induce acute and heightened elevations in blood pressure (e.g., hypertensive crisis) after intake of tyramine-rich foods, such as aged cheeses, sour cream, pods of broad beans, pickled herring, liver, canned figs, raisins, and avocados. MAOI interactions with TCAs, SSRIs, stimulants, and over-the-counter flu medications are dangerous and should be avoided. Because of these adverse side effect issues, MAOIs are used less often than other antidepressants. How Does ECT (electroconvulsive therapy) treat depression? The mechanism of action of ECT is not clear, though the procedure is known to produce alterations in monoamine systems.  ECT effectively alleviates depressive symptom in about 50% to 80% of people. Used when patients fail on antidepressants, or they are severely depressed, pregnant, psychotic, or suicidal. Recent work suggests that ECT increases the volume of the hippocampus and amygdala, brain structures linked to emotion, mood, and cognitive functions. Depressed people with small hippocampal volumes were most likely to show hippocampal volume increases and improved clinical responses after ECT. Neurotrophic processes activated by ECT, including neurogenesis (growth/development of nervous tissue), may underlie these structural changes and clinical benefits. CT effectively alleviates depressive symptom in about 50% to 80% of people, who may then begin to respond to antidepressant medications. Used when patients fail on antidepressants, or they are severely depressed, pregnant, psychotic, or suicidal. Define generalized anxiety disorder. What is the underlying defect? Definition: hallmark s/s are excessive and persistent worrying – the individual worries about life events such as marital relationships, job performance, health, money, or social status. Underlying defects include abnormalities in norepinephrine and serotonin systems: o Reduction in the α2-adrenergic receptor binding. o Decrease in the serotonin levels in CSF. o Reduced platelet binding of paroxetine (an SSRI). o Reduction of benzodiazepine binding in the left temporal hemisphere. o Anticipatory anxiety was associated with elevated cingulate cortex activity and both the heightened anxiety and cingulate cortex activation were reduced after 8 weeks of treatment. o A decrease in pathophysiologic cingulate cortex activity is a predictor of GAD treatment efficacy. o In children and adolescents, heightened right amygdala activation corresponds positively with severity of anxiety. Treatment: o 1st line (relieve GAD s/s in 1 week/ helps with depression too)- ▪ Norepinephrine reuptake inhibitors (venlafaxine) ▪ SSRIs (e.g. paroxetine, sertraline and escitalopram)-side effects include: dry mouth, sleep disturbances, & nausea o 2nd line: Buspirone (efficacy takes 2 weeks). s/e: dizzy, headaches, nausea, mild nervousness o 3rd line: BZ- limited to cases of GAD that does not accompany depression or other anxiety disorders. Characteristics of GAD GAD is diagnosed when person spends at least 6 months worrying excessively and engages in at least 3 of the 6 major symptoms Six major s/s of GAD are:  o Restlessness o Muscle tension o Irritability o Being easily fatigued o Difficulty concentrating o Difficulty sleeping Other characteristics include startling easily, and frequent suffering from depression and/or panic attacks. Complications: substance abuse which may lead to self-medication with alcohol or drugs to relieve anxiety symptoms. Substance abuse is common due to self-medicating. Although GAD tends to be chronic, the symptoms may lessen with age. The severity of symptoms fluctuates over time and may be linked to the changing nature of stress Define panic disorder. What are the complications? Definition: consists of multiple disabling panic attacks and is characterized by intense autonomic arousal involving a wide variety of symptoms: o Lightheadedness o Rapid heart rate (tachycardia) o Difficulty breathing o Chest discomfort o Generalized sweating o General weakness o Trembling o Abdominal distress o Chills or hot flashes *Between panic attacks the person often worries about future panic attacks and fear of losing control and dying. Symptoms occur spontaneously and can last from several minutes to an hour. Etiology: o Heightened pH sensitivity in the amygdala may play a key role in generating fearful perceptions and activating the cerebral cortex and neural circuits in the temporal lobe and brainstem, which further facilitate the production of panic symptoms. o A reduction in GABA-benzodiazepine receptor binding in brain regions, including the hippocampus, insular, and prefrontal cortex, also may contribute to the pathophysiology of this disorder. Complications: o Development of agoraphobia or phobic avoidance of places or situations where escape or help is not readily available, hyperventilation, elevated heart and respiration rates, tachycardia, and a possible addiction to overuse of anxiolytics. Treatment: CBT, antidepressants, benzodiazepines