University:
Carleton University
Course:
NEUR 1202 | Neuroscience of Mental Health and Psychiatric Disease
Academic year:

2022
Views:

46

Pages:

29
Author:

T Akintoye

Depressive Disorders Depression vs. depression What is Major Depression Disorder? Mood disorder = when your general emotional state or mood is distorted or inconsistent with your circumstances & interferes with your ability to function o Different types (i.e., SAD, Bipolar Disorder, premenstrual dysphoric disorder) Major Depressive Disorder (MDD) Depression is the most common mood disorder affecting 1 in 6 individuals o Most common most disorder o Individuals experience persistent feeling of sadness & hopelessness & lose interest in activities they once enjoyed o May also show physical symptoms like chronic pain or digestive issues Depression DSM-5 Diagnostic Criteria Persistent feelings of sadness Loss of interests in activities Diminished ability to think or concentrate, or indecisiveness Appetite or weight changes (more than 5% in. month) Depression DSM-5 Diagnostic Criteria Fatigue or decreased energy Slowing down of thoughts & physical movement Feelings of worthlessness or excessive inappropriate guilt Recurrent thoughts of death or suicide Depression DSM-5 Diagnostic Criteria To be diagnosed- must show ≥ 5 symptoms for period of 2 weeks & one must be depressed mood or loss of interest or pleasure Symptoms must not be due to direct physiological effects of a substance or medical condition o i.e, drug abuse, prescribed medication, hypothyroidism Symptoms of MDD cause clinically significant distress or impairment in social, occupational or other important areas of functioning Major depressive episode (MDE) is not better explained by schizophrenia or other psychiatric disorders Note: twice as many females diagnosed relative to males Sex/Gender Differences in Depression: Explained • May reflect patterns of helpseeking • May have a psychosocial explanation, such as social discrimination • May have to do with sex differences in endocrine physiology • Remember, HPA axis! • Estrogens influenced by cortisol (more on this later) What Causes Depression? Genetics • There is extensive evidence for a genetic link to depression. • First-degree relatives (parents, siblings, offspring) of individuals with depression have 2-3 times greater rates of depression than the general population. • The concordance rate between identical twins is 45.6%. • This means that if one twin has depression, the other has a 45.6% chance of also having it. Concordance rate of depression (blue bars) and mood disorders as a whole (orange bars) between identical and fraternal twins. • The concordance rate between fraternal (non-identical twins) is 20.2%. • This shows that depression has a very large genetic component, but the non-genetic, environmental component is still larger. The neurobiological basis of depression Part 1: serotonin Brain Alterations in Depression: The Monoamine Hypothesis Traditionally depression thought to be strictly due to a deficit in monoamine signaling Monoamine- neurotransmitters that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-) Dopamine (DA) Norepinephrine (NE) Serotonin (5-HT) Deficit in signaling = limited release of NTs, deficits in ability to clear NTs in the synapse, limited receptors to bind to, low affinity, etc. The monoamine hypothesis: focus on serotonin Serotonin circuits form one of the ‘ascending’ forebrain systems Plays a major role in sleep, sexual behavior, eating, and mood/cognition Found in great quantities in the gut! Derived from the amino acid tryptophan (serotonin also known as 5-HT or, 5-hydroxytryptophan) Evidence for the monamine hypothesis • Based primarily on evidence that drugs that are effective in treating depression target these systems: • MAO inhibitors are effective antidepressants • Monoamine oxidase (MAO) is an enzyme that inactivates monoamines • Selective serotonin reuptake inhibitors (SSRIs) are antidepressants that block the reuptake of serotonin at synapses • Selective noradrenergic reuptake inhibitors (SNRIs) are antidepressants that block the reuptake of noradrenaline at synapses SSRIs at the synapse The serotonin synapse works much like the other synapses we’ve covered this year. Following release, excess serotonin is broken down by the enzyme monoamine oxidase (MAO), and is also cleared by serotonin reuptake transporters. SSRI drugs like fluoxetine (Prozac) work primarily by blocking serotonin reuptake transporters. This leads to an increase in serotonin in the synapse. Serotonin reuptake transporter SSRI drug Evidence Against the Monoamine Hypothesis • There is little evidence that low levels of these neurotransmitters cause depression • Lowering levels of these neurotransmitters in normal people does not produce depression • Long lag time between treatment and reduction of symptoms • Antidepressant medications alter the levels of these neurotransmitters within days, but it takes weeks for the drugs to start relieving depression • Not everyone is cured, or even helped • SSRIs increase risk of suicide in children and adolescents The Glucocorticoid Hypothesis of Depression • Stressful life events play a role in the etiology of depression • Stressors and genetics may interact to make things even worse. • If stress plays a role in depression, we should start thinking about the HPA axis and how it might be involved in depression. • Recall that cortisol, the main stress hormone of the HPA axis, is part of the glucocorticoid family of hormones. • The glucocorticoid hypothesis suggests that dysfunctional regulation of the HPA axis stress response contributes to depression. HPA axis dysregulation in depression • Abnormal regulation of the HPA axis is one of the most common clinical findings in depression. These include: • Hypercortisolemia • Elevated levels of cortisol in the blood, even during non-stressful times. • Chronic stress can lead to oversecretion of cortisol, associated with depression in adulthood • 45% of adults with depression lasting more than 2 years experienced abuse, neglect, or parental loss as children • Impaired negative feedback of HPA axis • The brain is not able to response to elevated blood cortisol by shutting down CRH, ACTH, and cortisol secretion. HPA axis negative feedback • Normally, cortisol binds to glucocorticoid receptors in the hippocampus to activate the negative feedback system and shut down the stress response. • This means that people with depression cannot shut down their stress response as easily. • Continued exposure to high levels of cortisol further damages the hippocampus. • This means that the longer one is exposed to stress (or depression), the worse things tend to get. - Hypothalamus - Hippocampus CRH (reduced) Ant. Pituitary - Cortisol ACTH (reduced) Reminder of the negative feedback loop that shuts down the stress response (see stress lecture) Depression and the hippocampus • Healthy human hippocampus. Note the cell density (each small dot is a cell). • Close-up view of healthy hippocampal neurons. • Hippocampus from a depressed human. Note the reduced density of cells. • Close-up view of depressed hippocampal neurons. Note the shrunken shape compared to the healthy ones. • Several lines of evidence suggest that the hippocampus is damaged by chronic major depression. Depression and the hippocampus • Neuroimaging studies have shown reductions in hippocampal volume in patients with depression. • Interestingly, successful antidepressant treatment appears to prevent this effect, leading to healthier hippocampal volumes. • So how do antidepressants reverse damage to the hippocampus? Graph showing a negative correlation between hippocampal volume and the number of days of untreated depression in humans. This suggests that the more time someone spends with untreated depression, the smaller the hippocampus becomes. Depression and the hippocampus • It seems that antidepressants help by increasing the rate of neurogenesis in the hippocampus. • Neurogenesis is a process that creates new neurons, and this process is blocked by cortisol and certain cytokines (like IL-1). • A long-term decrease in hippocampal neurogenesis could explain the hippocampal shrinkage seen in depression. • This could also help explain some of the cognitive problems that accompany depression. Hippocampus from control rat (no drugs). Hippocampus from antidepressant treated rat. Note the increased number of newborn neurons (visible as black dots). Links between estrogen and the HPA axis • Since estrogen levels vary over the human menstrual cycle, it’s only possible to understand the stress response in females by studying them at different points in their cycles. • Estrogen itself seems protective against stress and depression. • The negative feedback system is more efficient during the follicular phase, when estrogen is high. • Women show lower cortisol levels in response to social stress during the follicular phase. • SSRI antidepressants work better when combined with estrogen. • Mood tends to drop during the luteal phase (in its extreme form, this is called pre-menstrual dysphoric disorder). Follicular phase. Luteal phase. The human menstrual cycle. The follicular phase is characterized by high estrogen and low progesterone. The luteal phase is characterized by high progesterone and low estrogen. What is psilocybin? • Compound found in various species of fungi (mushrooms) • Inactive, but when ingested / absorbed, immediately converted to psilocin, which has hallucinogenic effects • Psilocin is an agonist to several serotonergic receptors, especially 5HT2A; structurally similar to serotonin • Emerging evidence suggests this compound (alongside other psychedelics) may reduce symptoms of depression So what does cause depression?

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