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Depression module

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McMaster University
Peter Helli

Depression - Mood disorders are disorders of emotion, including mania and depression - Highly under diagnosed and under treated - The prevalence in women is doubled that in men, because women are more apt to recognize mental health issues and see a doctor - Depression often becomes masked in men, comes out in somatic ways: migraines, irritable bowels syndrome, back ache etc, and therefore not recognized as depression - Women may have depression more due to hormonal responses, stress response systems, sexual differences in brain areas (however is still unknown) DSM-IV-TR Criteria for depression Major depression disorder: • Is characterized by a persistent unpleasant mood • Dysthymia which is characterized by chronic mild depressive symptoms, symptoms are the same as depression just a milder form • Depressed mood • Anhedonia (inability to experience pleasure) • Feelings of worthlessness or excessive guilt • Decreased concentration • Psychomotor agitation or retardation, insomnia or hypersomnia, decreased libido • Change in weight or appetite • Thoughts of death or suicidal ideation Sub classifications of depression: • Melancholic features, atypical depression • Depression with psychotic features • Depression with catatonic features • Postpartum specifier • Dysthymia Risk factors for depression: - Childhood emotional, physical and sexual abuses - Prior episode of depression - Family history of depressive disorder - Lack of social support - Stressful life event - Current substance abuse - Economic difficulties Etiology of depression: o Multi-factorial o Dynamic interplay amongst:  Genetic disposition  Environment  Life history  Development  Biological challenges o Deficits in neurotransmitters in the brain, it is believed that major depressive disorders arise from this complex interaction of genes and environmental factors The brain: - About 100 billion neurons, and 10-50 trillion neuroglia which support the nerve cells in the brain - The brain had a mass of about 1300g, 3lbs in adults - Each neuron forms a thousand synapses - 1000 trillion=total number of synapses in the brain (larger than the number of stars in the galaxy) Genetic-environment interaction: - More common among first degree relatives then the general population - Family, twin and adoption studies, adjust the hereditary component to the etiology of mood disorders - The cause is partly genetics and the environment - Scientists have not discovered a gene that cause depression, rather certain variations in genes called polymorphisms may increase the risk for depression - Genes control the metabolism of neurotransmitters and their receptors, number of particular types of neurons and their synaptic connections, intracellular transduction of neuronal signals, and the speed in which all these can change during environmental stressors - The serotonin transporter gene is the most studied in depressive disorders, it contains a polymorphism that gives rise to two different alleles (long and short) - People usually have two copies of each gene in their DNA - The short allele slows down the synthesis for the serotonin transporter gene, which is thought to reduce the speed in which serotonin neurons can adapt changes in their stimulation, deregulation of serotonin Genetic Predisposition: Brain Derived Nerotropic Factor (BDNF) - BDNF is a growth factor that plays a major role in birth, survival and maturation of brain cells during development - BDNF is a protein found in high concentrations in the brain - It is important in neuronal cell growth, as well as the synaptic changes that occur throughout a person’s life - It contributes to these processes by activating the DNAbinding factors that stimulate gene transcription of genes involves in serotonin function - Activation of the serotonin receptors stimulates expression of BDNF factor gene - During brain development this cyclic process promotes outgrowth, synapse formation and survival of serotonin neurons, and the innervations of the multiple brain regions - The ability of the serotonin system to adapt and change in response to various stimuli continues to be influenced by BDNF throughout life - It is believed that BDNF may be the link between stress, neurogenesis and hippocampal atrophy in depression - People diagnosed with major depressive disorder have lower levels of BDNF - BDNF may be related to depression and multiple psychiatric disorders BDNF: val/met genotype • Val and met alleles in gene that codes for BDNF • This polymorphism affects the intracellular transport and secretion of BDNF • People with the met allele seem to have a very small hippocampus at birth, hippocampal hypoactivity at rest, hippocampal hyperactivity while learning and poor hippocampus dependent memory function • The hippocampus is significant to depression because it’s believed to modulate the cognitive aspect of depression such as memory impairments, thoughts and feelings of hopelessness, guilt, doom, and suicidality • People with met allele increases a person’s vulnerability to depression • Studies have shown low levels of BDNF in the hippocampus and prefrontal cortex of systematic depressed patients • Serum studies have shown that serum levels of BDNF are abnormally low in patients with the major depressive disorder • Doctors do not diagnose the patient as having depression if the BDNF is low, however it is important to know so that doctors can try to figure out the best way to increase these levels while treating these patients for depression Neurobiological theory: - Suggests that major depression is caused by a deficiency or disregulation in the CNS concentrations or neural transmitters - The noradrenergic and seroternergic systems which originate deep in the brain and span out over almost the entire brain and modulate many areas of feeling, thinking and behaving, are implicated in depression - Norepinephrine and epi, and serotonin are thought to be involved in the development of depression Neurotransmission - Nerve cells communicate with one another by a process called neurotransmission - They communicate using electrochemical communication which cross the synapse - Neural transmitters are released, either causing an excitatory or inhibitory reaction o 1. The synthesis of a transmitter substance:  Synthesized in the presynaptic neuron and then stored in vesicles  Nerve impulse stimulates the presynaptic neuron, movement of the synaptic vesicle to the cell membrane o 2. The storage and release of the neurotransmitter o 3. Binding of the transmitter to receptors on the postsynaptic membrane:  Once released from the presynaptic neuron, the neurotransmitter moves across the synaptic cleft and binds to receptors on the postsynaptic neuron  The action is dependent on the type of reaction, excitatory or inhibitory  Excitatory: binding of it opens sodium ion channels o 4. Removal of the transmitter from the synaptic cleft  Precise control of synaptic function relies on the rapid removal of the neurotransmitter from the receptor site  The NT can be taken back up to the neuron known as reuptake or diffuse out of the synaptic cleft or be broken down by enzymes into inactive substances or metabolites - Neurotransmitters are typically stored in the vesicles in the presynaptic axonal terminal and released by the process of exocytosis Biogenic Amine Hypothesis: - Suggests that decrease levels of neurotransmitters serotonin and norepinephrine in the synaptic cleft do either to decrease synaptic release or decreased post-synaptic sensitivity is the underlying pathological process in depression - Believed that a reduction in serotonin synthesis may result in depression, but also that depression may result in the reduction of serotonin synthesis (chicken and egg theory going on here) - When serotonin levels are depleted in humans by decreasing levels of tryptophan (the precursor to serotonin), healthy individuals without a personal or family history of MD tend to not show any mood changes while people who have been successfully treated with serotonin reuptake inhibitors will relapse into depression - This research has shown that lowering serotonin factors do not induce depression in all people - Therefore it must be genetic and environmental factors - Dopamine activity has also been implicated in mood disorders, with decreased activity in depression and increased activity in mania - Studies show that the frequency of depression is higher in patients with Parkinson’s disease which is caused by lower rates of dopamine production in the substantia nigra Neurophysiology of symptoms: Prefrontal cortex - Research into brain anatomy has shown that the effects of genetics, environment and deficiencies or dysregulation in the central nervous system concentrations of neurotransmitters causes anatomic changes in many areas of the brain - The prefrontal portion of the cortex is the most evolved portion of the brain - It is described as the chief administer of the brain and is used for planning, problem-solving, intellectual insight, judgement and expression of emotion, regulates thinking and mood - PET and MRI have seen a reduction of the volume of gray matter in the frontal cortex with an associated decrease of activity - The prefrontal cortex is reduced and less active because of the decrease in the neurotransmission of serotonin and norepinephrine and alterations in the neurotransmission of dopamine in this area - Also found to be a decrease in BDNF in the prefrontal cortex - This decrease in neural transmitter activity leads to the decrease of neuronal volume because pathways are not being used so density of these pathways decreases and there is a pruning of these pathways Prefrontal cortex: thought, voluntary motor and sensory functions, speech, and memory patterns and has extensive connections with deeper parts of the brain PET (positron emission tomography) scan: the variable brain tissue uptake of an infused radioactive substance. Drugs can be infused to study neurotransmitter receptor activity of concentration in the brain MRI (magnetic resonance imaging): helps to diagnose structural abnormalities of the brain and can distinguish between grey and white matter Gray matter: white matter is composed of myelinated axons which are axons surrounded by a multilayered lipid and protein covering which electrically insulates the axon of a neuron and increases the speed of nerve impulse conduction, as compared to gray matter which contains neuronal cell bodies, dendrites, unmyelinated axons, axon terminals and neuroglia Temporal lobe: there is decreased functioning in the frontal and temporal lobe due to serotonin, norepinephrine and dopamine is the reason. It is not known if it’s a cause or effect of depression Amygdala: - Located deep in the medial temporal lobe in the primitive part of our brain - Receives neuronal signals from the temporal and occipital lobes of the cortex and communicates with the hypothalamus and other parts of the limbic system - It helps the person relate to the surrounding environment and pattern appropriate behaviour - It is important in emotional function and regulation, sexual arousal, aggression, and fear responses - The amygdala gets increased blood flow and oxygen consumption during depression, it is important in emotional memory and believed to mediate the anhedonia or dec
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