Pathophysiology: Depression

Increased dopamine activity is also linked with depression.

False! Decreased dopamine is linked. 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.

Prevalence of major depression among men is double than in women.

False! It is more prevalent among women.

What gene is the most studied in major depressive disorder?

The serotonin transporter gene.

Which allele (short or long) in the serotonin transporter gene gives rise to the slowing down of the synthesis of the serotonin?

The short allele in the serotonin transporter gene slows down the synthesis of serotonin (the process implicated in depression). The serotonin transporter gene contains a polymorphism that gives rise to 2 different alleles (long and short). People have two copies of each gene in their DNA, therefore a person can be homozygous for the long allele, homozygous for the short or heterozygous.

Which alleles are produced from a common polymorphism in the gene that codes for BDNF?

"val" and "met". This polymorphism affects the intracellular transport and secretion of BDNF.

ECT is a procedure that electrically stimulates a generalized seizure, and has a 70-90% effective treatment rate for depression. It is given under a general anesthetic with complete muscle relaxation because the motor component of the seizure does not contribute to the therapeutic effects of the treatment. A brief electrical current is passed through the brain to produce a generalized seizure lasting 25 to 150 seconds. On average 6-8 treatments are given at 2 day intervals over a period of 2 to 4 weeks. After symptoms have improved, antidepressant medications are used to prevent relapse. The exact mechanisms of the antidepressant action of ECT remains unclear. It is known to down regulate B-adrenergic receptors in much the same way as antidepressant medications, therefore lowering the stress response. Down regulation occurs when there are excess chemical messengers and the number of active receptors decreases. ECT produces an up-regulation in serotonin. Up-regulation occurs when there is a deficiency in the messenger, so in this cause there is less serotonin so the number of active receptors for serotonin increase. ECT increases the influx of calcium in the brain and has effects on second messenger systems. The first messengers in depression are the neurotransmitters. Second messengers are involved in converting the chemical single into a physiological one that move the nerve impulse across the nerve cell and onto the next nerve cell. ECT has also been show to up-regulate levels of BDNF. After symptoms have improved. Antidepressant medications are used to prevent relapse. The use of ECT is limited by its invasive nature, namely the requirement of the general anesthetic and risk of retrograde amnesia which may be irreversible in some patients. Because of its invasive nature ECT is currently only indicated for patients whose depression is resistant to conventional treatment.

... okey dokey

Psychoneuroimmunology is a recent area of research into a diverse group of proteins known as chemical messengers between immune cells. These messengers called cytokines signal the brain and serve as mediators between immune and nerve cells. Dysregulation of cytokines can result in adverse effects and may manifest as symptoms of major depression and related disorders. Research shows that depression is common in infectious and autoimmune disease. Research has also shown that exposure to cytokines induces depression symptoms and cytokines secretion is increased in major depression. We also know that antidepressants have anti-inflammatory effects and have been use to treat chronic pain. As was previously mentioned, depression often is masked as physical illness and it is believed that there can actually be physical pain associated with depression. This is thought to be because serotonin is a pain-modulating neurotransmitter, and the release of endorphins is centrally mediated by serotonin. It makes sense then that decreases in the availability and action of serotonin at the nerve synapse may be manifested as increased subjective experiences of pain and complaints of physically symptoms of which may be indicative of a depressive illness.

....whoah... yeah...

Psychotherapy helps to reduce the stressors that trigger episodes. It is through that by reducing stressors and negative thinking, the abnormal activity of the neurotransmitters indicated in depression and the stress response can be reduced, aiding in a more normal function of BDNF, neurotransmission, neuroendocrine abnormalities, and reduction and/or prevention of the neuroanatomical changes of depression. Specifically cognitive behaviour therapy is psychotherapy focuses on identifying, analyzing and ultimately changing the habitually inflexible and negative cognition about oneself, others, and the world that occur with depression. The use of cognitive therapy in the acute phase of treatment, combined with medication, has grown in the past few years and may be considered first line treatment for mildly to moderately depressed outpatients. A psychotherapeutic approach may be especially helpful for patients with a history of a childhood adversity or recent stress.

...cool

What are the 7 risk factors associated with depression?

1. childhood emotional, physical and sexual abuse 2. prior episodes of depression 3. family history of depressive disorder 4. lack of social support 5. stressful life event 6. current substance abuse 7. economic difficulties

What were the findings of people with the Met allele?

A relatively small hippocampus at birth, hippocampal hypo activity at rest, hippocampal hyper activation during learning and relatively poor hippocampus dependent memory function. The hippocampus is significant to depression because it is believed to modulate the cognitive aspects of depression such as memory impairments and feelings of hopelessness, guilt, doom, and suicidality.

Antidepressant medications are used to treat depression. Their clinical antidepressant effects occur only after chronic administration of days to weeks. In general these drugs normalize levels of serotonin, dopamine, and norepinephrine in the brain and thus their neurotransmission at the synapse. Antidepressants also increase levels of BDNF and affect synaptic plasticity by increasing the activity of neurotransmitters in the synapse and nerve cell volume. Why does it take days to weeks for an effect?

Antidepressant response takes days to weeks because it requires sufficient time for the levels of BDNF to gradually rise and exert synaptic and nerve cell sprouting.

________ is implicated in depression. It is a growth factor that plays a major role in the birth, survival and maturation of brain cells during development.

BDNF (brain derived neurotropic factor). It is a protein found in high concentrations in the brain. It is important for neuronal cell growth as well as the synaptic changes that occur throughout a person's life. It contributes to these processes by activating DNA-binding factors that stimulate the genes involved in serotonin function, such as the serotonin transporter and trytophan hydrolase, the serotonin synthesizing enzyme. Activation of serotonin receptors in turn stimulates expression of the BDNF factor gene. During brain development, this cyclic process promotes outgrowth, synapse formation and survival of serotonin neurons, and the eventual innervations of 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.

The prefrontal cortex is part of the cerebral cortex, which covers the outermost part of the brain, is the most evolved portion of our brain. Its is described as the "chief administrator of the brain and is responsible for planning, problem solving, intellectual insight, judgement, and expression of emotion. So basically it regulates thinking and mood. What was found in PET and MRI scans with regards to the prefrontal cortex in relation to depression and bipolar disorder?

In some cases of familial major depressive disorder and bipolar disorder it showed a reduction in the volume of grey matter in the prefrontal cortex, with associated decrease in activity in that region. This is because of the decrease in neurotransmission of serotonin and norepinephrine, and alterations in the neurotransmission of dopamine. There is also a decrease in BDNF in this area (basically the neuronal volume is decreased because these pathways are not being used resulting in pruning).

How do tricyclics work?

Inhibit the uptake of norepinephrine and serotonin into the presynaptic terminal allowing them to accumulate in the synapse and thus enhance their action.

What is the function of the temporal lobe and what is found with regards to depression?

Integrates and interprets somatic or bodily, visual and auditory information that is critical for recognition of the familiar, as well as appropriate interpretation of and response to social contexts (accurate interpretation of emotions and ability to respond with socially appropriate levels of emotionality and language). It is also responsible for the modulation and fine-tuning of emotion appropriate to the level of intensity. Also for planning, problem solving, intellectual insight, judgement, and expression of emotion. Physiologically, PET and MRI studies show evidence of decreased functioning in the frontal and temporal lobes. Once again, dysregulation in serotonin, norepinephrine and dopamine are the culprits (not known if these anatomical changes are a cause or effect because the activity returns to normal with the resolution of symptoms)!

Describe transcranial magnetic stimulation.

Involves stimulation of the dorsolateral prefrontal cortex by using weak electric currents which are induced in the tissue by rapidly changing magnetic fields or electromagnetic induction. In this way, brain activity can be triggered in the prefrontal cortex which has decreased volume and activity in depression.

Describe deep brain stimulation.

Involves the implantation of electrodes which are connected to a surgically implanted impulse generator that delivers electrical stimulation to the ventral striatum which has been found to have functional dysregulation in depression. The ventral striatum is connectionally associated with the limbic structures.

The amygdala is located deep in the medial temporal lobe in the primitive part of our brain. It receives neuronal signals from the temporal and occipital lobes of the cortex and communicates with the hypothalamus and other parts of the limbic system. What is its function and what do you find during depression?

It helps a person relate to the surrounding environment and pattern appropriate behaviour. Important in emotional function and regulation, the modulation of affective responses in social settings, as well as sexual arousal, aggression and fear responses. It tends to have increased blood flow and oxygen consumption during depression. The striatum and amygdala and related brain areas are important in emotional memory, and are believed to mediate the anhedonia, anxiety and reduced motivation symptoms of depression.

_________ produced by the pineal gland is thought to help regulate the sleep-wake cycle. The pineal gland synthesizes and releases _________ at night. The rhythm of the cycle is regulated by the _________ ________.

Melatonin, melatonin, circadian clock. Circadian rhythms are cyclic patterns of sleep and wakefulness which are integrated into the 24-hour light-dark solar day and related to the monthly rhythms of the moon. Circadian rhythms function is to provide a temporal organization for physiologic processes and behaviours to promote effective adaptation to our environment. This involves regular cycles of sleep and waking and body functions such as temperature regulation and hormone secretion based on changes in the 24-hour light-dark solar day.

Future direction for research currently involve new drugs that target corticotrophin releasing factor, that dopamine system and the glutamate system which normally stimulates the growth of BDNF and neuroplasticity but if too much glutamate is released in the stress response this can cause neurotoxicity. Other further studies of significance involved research into other polymorphism with effects on patient's response to antidepressants resulting from allelic variations in other genes with roles in the serotonin system, genes involved in the HPA axis, genes involved in corticotrophin releasing factor and the norepinephrine system and genes involved in liver enzymes involved in drug metabolism. Current and future research also needs to focus on looking at the impact of an individual's psychosocial environment on brain chemistry, activity, anatomy and vice versa.

OH DEAR

The variable brain tissue uptake of an infused radioactive substance. Drugs can be infused to study neurotransmitter receptor activity or concentration in the brain. Helps to diagnose structural abnormalities of the brain and can distinguish between grey and white matter. Which one is PET scan and which one defines an MRI?

PET scan is the first and MRI the second.

Major depressive disorder is also associated with multiple endocrine alterations particularly in the: Hypothalamic-pituitary-adrenal or HPA axis. Stress is perceived by the cortex of the brain and transmitted to the deep regions of the hypothalamus, where corticotrophin-releasing factor, or CRF, is released onto pituitary receptors. This stimulus results in the secretion of corticotrophin into plasma, stimulation of corticotrophin receptors in the adrenal cortex, release of cortisol into the blood. What are the findings with cortisol and CRF with regards to depression?

Patients with depression may have elevated cortisol in plasma and cerebrospinal fluid and increased levels of CRF messenger RNA and protein in limbic brain regions. Sensitivity of the hypothalamus to feedback signals for the shutdown of CRF release is about half in severely depressed patients. Disturbances in the function of the HPA axis in depression cause cortisol levels to spike erratically throughout the day.

When serotonin levels are depleted experimentally in humans by oral treatment by decreasing the level of tryptophan (a precursor of serotonin) what happened with regards to healthy individuals without personal or family history of depression and individuals who have been successfully treated with SSRIs?

The healthy individuals without any history showed no mood changes but people who had previously been treated successfully with SSRIs relapsed into depression. This shows lowering serotonin does not induce depression in all people and thus supports the genetic and environmental factors.

How do MAOS's work?

They block the degradation of norepinephrine and serotonin. When norepinephrine is released into the synapse and binds with the postsynaptic receptor the action is terminated by the enzymes monamine oxidase and catecholamine O-methyl transferase. BUTTT monamine oxidase is inhibited by this drug and therefore it is not broken down as quickly and the action is prolonged.

How do SSRIs work?

They inhibit the reuptake of serotonin. Serotonin is released into the synapse and then binds to the postsynaptic receptor. Then binds to the presynaptic receptor because of the reuptake. This causes less to be released and more will be available in the synaptic cleft.

It is also believed that a reduction in serotonin synthesis may result in depression, but also that depression may result in a reduction of serotonin synthesis.

This is true! eeeek! "chicken and egg theory"?

The limbic system includes the hippocampus, parahippocampal gyrus, cingulate gyrus, amygdala, and a bridge like structure called the fornix which connects the hippocampus with the hypothalamus. Higher and lower brain centers communicate with the limbic system to link thoughts and autonomic nervous system responses to emotions. Neurological disorders of the limbic system and basal ganglia are also involved in the development of mood disorders.

True dat!

It is believed that antidepressant treatments may increase synaptic sprouting or rewiring of connections which are dysregulated at the synapse. If you think about the phrase "if you don't' use it you lose it" this can also apply to what happens at the synapse without treatment for depression. Synaptic pruning means that when connections between nerve cells are not used, nerve cells atrophy and volume decreases. With treatment, connections are once again used and formed and brain volume in the areas implicated in depression increase.

True dat...

10% of Canadians are affected by mood disorders.

True!

Certain variations in genes called polymorphisms may increase the risk for depression.

True!

It is believed that the way a person interprets their environment and thinks about themselves can induce and perpetuate depressive symptoms.

True! Psychodynamic factors involve distorted negative beliefs and thought about the self, the environment, and the future that can induce and perpetuate depressive symptoms.

Describe phototherapy (light therapy).

Uses artificial light to influence the production of melatonin and the function of the catecholamine systems (melatonin is a hormone that is produce by the pineal gland and thought to regulate the sleep-wake cycle and possible circadian rhythm to an earlier time). Expose to this light source has produced improvement and relief of depressive symptoms of significant numbers of seasonally depressed individual. It produces no change for individual who are not seasonally depressed

Describe vagal nerve stimulation.

Vagal nerve stimulation or VNS involves using an implanted stimulator that sends electric impulses to the left vagus nerve in the neck via a lead wire implanted under the skin. It is believe that VNS has antidepressant properties via its effects on the locus coeruleus, an area in the brain steam which norepinephrine neurons originate.

Remember from A&P that white matter is composed primarily 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. Compared to grey matter which contains neuronal cell bodies, dendrites, unmyelinated axons, axon terminals and neuroglia.

YEP!

Alteration in the sleep-wake cycle is common in many mental illnesses including depression, and often is one of the prodromal or early warning signs of relapse. Research into the sleep-wake cycle of people with depression has shown that the normal sleep cycle is often reversed in depressed individuals where the person reaches deep sleep earlier in the cycle.

YES MAM

Nerve cells communicate with one another by a process called neurotransmission. Nerve cells communicate by electrochemical signals which cross the point at which two neurons meet called the synapse. Chemical substances called neurotransmitters are released from the axonal terminal of one neuron which is called the presynaptic cell, the neurotransmitter then crosses the synapse and binds to receptors of the postsynaptic cells and causes an excitatory or inhibitory action.

Yesssir!

Social factors:

are adverse or traumatic life events especially that involve the loss an important human relationship or role in life that is followed by a depression

Dual medications like SNRI's work by...

blocking the reuptake of serotonin and norepinephrine.

The biogenic amine hypothesis suggests that ________ levels of the neurotransmitter _________ and __________ in the synaptic cleft due to either __________ presynaptic release or __________ post synaptic sensitivity is the underlying pathologic process in depression.

decreased, serotonin and norepinephrine, decreased, decreased

Depression has an effect on thyroid function and 5-10% of person with depression when tested have a ________ thyroid function.

decreased... Depressed patients with decreased thyroid function are given thyroid replacement therapy in order to reserve this process and speed up with their ability to metabolize and respond to treatment with antidepressant medication.

DSM 5 Criteria: mood disorders of emotion including mania and depression. Depression is commonly divided into 2 categories: major depressive disorder which is characterized by persistent unpleasant mood and dysthymia which is chronic mild depressive symptoms. The DSM criteria for major depressive disorder include the simultaneous presence of 5 or more of the following symptoms during a 2 week period and these must represent a change from previous functioning:... (what are the symptoms?)

depressed mood, anhedonia, feelings of worthlessness or excessive guilt, decreased concentration, psychomotor agitation or retardation, insomnia or hyper-insomnia, decreased libido, change in weight or appetite, and thoughts of death or suicidal ideation.

Studies have shown that having the Met allele in addition to having the short allele of the serotonin transporter and psychosocial stress, _________ vulnerability to depression. Further evidence from postmortem studies have found low levels of ______ in the hippocampus and prefrontal cortex of symptomatic depressed patients.

increases, BDNF. Serum levels are also low in BDNF in patients with major depressive disorder.

Neurotransmitters are typically stored in the vesicles in the presynaptic axonal terminals and released by the process of ________. The 1st step in synaptic transmission is synthesis and release. Neurotransmitters are synthesized in the presynaptic neuron and then stored in synaptic vesicles. Communication between the two neurons begins with a _______ _______ that stimulates the presynaptic neuron, followed by movement of the synaptic vesicle to the cell membrane and release of the neurotransmitter into the synaptic cleft. The 2nd step of synaptic transmission is Receptor Binding. Once released from the presynaptic neuron, the neurotransmitter moves across the synaptic cleft and binds to receptors on the __________ neuron. The action of a neurotransmitter is determined by the type of receptor (excite or inhibit) to which it binds. Binding of a neurotransmitter to a receptor with an excitatory function often results in the opening of an ion channel, such as the sodium channel. Many presynaptic neurons also have receptors to which a neurotransmitter binds. The presynaptic receptors function in a negative feedback manner to inhibit further release of the neurotransmitter. The 3rd step in synaptic transmission is Neurotransmitter Removal. Precise control of synaptic function relies on the rapid removal of the neurotransmitter from the receptor site. A released neurotransmitter can (1) be taken back up into the neuron in a process called ________, (2) diffuse out of the synaptic cleft, or (3) be broken down by enzymes into inactive substances or metabolites.

exocytosis, nerve impulse, postsynaptic, re-uptake

Etiology of depression is multifactorial. It is a dynamic interplay amongst ________, _________, ______ ________, _________, and __________ changes.

genetics, environment, life history, development and biological changes.

Deregulation and neuroanatomical changes in the __________ are believed to be responsible for the neurovegetative symptoms of depression including too much or too little sleep, appetite and energy, as well as loss of interest in sex and other pleasurable activities.

hypothalamus

Behavioural factors:

involve a severe reduction in rewarding activities or an increase in unpleasant events in one's life that result in depression and a further restriction of activity, decreasing the likelihood of experiencing pleasurable activities and intensifying a mood disturbance

Developmental factors:

involve loss of a parent of lack of emotion adequate parenting that may delay or prohibit the realization of appropriate developmental milestones.

Family distress:

involves a disruption in family dynamics involving maladaptive circular patterns in family interactions that contribute to the onset of depression in family members

In research cited in the Rot review, in the non-depressed person, serum BDNF levels do not lower with exposure to stress. In research with people with major depressive disorder, stress activated the amygdala and norepinephrine systems causing symptoms of increased vigilance and fear, and people had an exaggerated stress response and increased levels of CRF and norepinephrine in the plasma. Also people exposed to childhood stress has an exaggerated stress response as adults. In the depressed person cortisol levels return to the normal pattern as depression resolves.

mhm...

Research has shown that some patients with depression have circadian abnormalities of _______, _______, __________, and __________ _________. The sleep cycle usually reverts to normal after the resolution of depression, although this may take ______ to months. It is important that a person with depression attempts to normalize the sleep-wake cycle. Initially in treatment sedative medication may be used, and patients are taught sleep hygiene techniques such as decreased use of alcohol and other stimulants before bedtime.

mood, sleep, temperature, and neuroendocrine secretion. weeks.

The _______ and _________ are thought to mediate cognitive aspects of depression, such as memory impairments and feelings of worthlessness, hopelessness, guilt, doom and sucifidality.

neocortex and hippocampus

The ___________ and ___________ systems which originate deep in the brain and fan out over almost the entire brain, and modulate many areas of feeling, thinking and behaving are implicated in depression.

noradrenergic and serotonergic

It is believed that BDNF may be the link between _____, _________, and _____________ atrophy in depression (BDNF may be related to multiple psychiatric disorders... not only depression).

stress, neurogenesis and hippocampal atrophy

Vagal nerve and transcranial magnetic stimulation have been approved in Canada for the treatment of major depressive disorder and deep brain stimulation is still under experimental investigation. And all of these are only done if ETC isn't effective.

true datttttt