When does major depression appear?
- -may appear at any age, but it first starts to become common at puberty.
- -Typical age of onset is between 20-30 years of age.
- -Depression can appear in older people as well, 10% of those diagnosed with major depression are 55 or older when they have their first episode
What is the prevalence of major depression among younger generations?
- -The prevalence of major depression among younger age groups appears to be increasing
- -15- to 24-year-olds had the highest rates of mood and anxiety disorders of all age groups (about 7% in last 12 months, compared to 5% of 25-64 year olds).
How long does depression normally last?
- -The length of a depressive episode can vary, with some as quick as two weeks, and others lasting several years.
- -The typical duration of the first episode (if untreated) is 4-9 months
- -Depressive episodes often go away on their own, but residual symptoms strongly predict later relapse
What are the diagnostic features of depression?
1) A mood that is depressed, sad, or otherwise gloomy is the primary feature of major depression.
- —>Individuals (particularly males) often show irritability, anger, or crankiness as well
2) These feelings are usually accompanied by anhedonia – the loss of interest in activities that used to bring enjoyment (“without pleasure”)
3) Psychomotor retardation: Individuals may find that even everyday tasks take up an enormous amount of time and energy – it can be hard to even get out of bed (slow movement, slow thinking)
4) Decreased cognitive abilities: Individuals may find it hard to concentrate or make decisions.
- —>When these symptoms appear in the elderly, they are often mistaken for dementia (pseudodementia)
5) Change in appetite: Appetite may either increase or decrease. Those who eat more tend to favor carbohydrate based foods (breads, cakes, sweets, etc.,)
6) Sleep disturbances: Like appetite, sleep can either decrease or increase (insomnia and hypersomnia respectively).
- —>Patients often first visit the doctor with complaints of sleep problem, only to be diagnosed with depression.
7) Feelings of worthlessness or guilt: Individuals may misinterpret everyday occurrences as evidence of personal defects
8) Thoughts of death, suicidal ideation, or suicide attempts: Individuals may be preoccupied with death, may have transient thoughts of suicide with or without a specific plan, or may simply passively wish not to wake up in the morning
What symptoms do you have in atypical depression?
?–reduction in apetite
–psychomotor agitation (people feel keyed up/anxious so it is often mistaken for anxiety)
Why do some people with depression who over-eat prefer carbs?
- -Carbohydrates boosts reward circuit
- -Carbohydrates elevate levels of tryptophan (5HT or 5-Hydroxytryptophan) which is serotonin
What is the genetic etiology of 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%.
- -The concordance rate between fraternal (non-identical twins) is 20.2%.
- -Depression has a large genetic component, but the non-genetic component is even larger (40 percent of depression is due to genetics but 60 percent is due to environmental events)
- -however, there’s more than one way to get depression. There’s lots of different circuits that can get dysregulated through lots of different mechanisms where the output is depressed mood
What is the monoamine hypothesis of depression?
- -The monoamine hypothesis suggests depression is caused by reduced synaptic activity of the monoamines norepinephrine and serotonin
- -MAO (monoamine oxidase) is the main enzyme breaks down serotonin and norepinephrine in the synaptic cleft so MAO inhibitors inhibit this enzyme and we get more of the serotonin and norepinephrine
- —>they are not prescribed anymore because you cant have red wine or cheese, etc cause you get get serotonin syndrome
- -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
- -however, there is no one antidepressant that fixes depression because there are so many different circuits involved. We need to target the circuit that got dysregulated in that individual and target the symptom as opposed to the disorder
How do SSRIs work?
- -Populations of serotonergic neurons in the midbrain and hindbrain (dorsal raphe nuclei) and they project to diverse areas of the forebrain including the cortex, the hippocampus, parts of the limbic system and they have retrograde connections to their own neurons (control their own release)
- -Serotonin binds to serotonergic receptors (about 30 different kinds in the brain)
- -Serotonin –sleep, eating, attention, mood regulation
- -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
What is the evidence against the monoamine hypothesis?
- -Professor at McGill had people drink a milkshake that depletes brain levels of tryptophan so it causes a reduction in serotonin in the brain which you can measure by looking at the metabolites. The prediction is that if low serotonin triggers low mood, then you should be triggering low mood in these people, but it doesn’t do that in people. However, you can in people who have a history of depression and you give them this milkshake
- -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 (this is because it boosts your energy before it boosts your mood so you if you are already suicidal it gives you the motivation to do it)
- -Only 55% of people are successfully treated with antidepressants
What is the glucocorticoid hypothesis of depression?
- -The glucocorticoid hypothesis suggests that dysfunctional regulation of the HPA axis stress response contributes to depression.
- -Stressful life events play a role in the etiology of depression
- —>Stressors and genetics may interact to make things even worse
What is the HPA axis dysregulation?
- -Abnormal regulation of the HPA axis is one of the most common clinical findings in depression
- -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 respond to elevated blood cortisol by shutting down CRH, ACTH, and cortisol secretion
- -Normally, cortisol binds to glucocorticoid receptors in the hippocampus to activate the negative feedback system and shut down the stress response
- -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
What do the hippocampal cells in people with depression look like?
- -in healthy people, the hippocampal cells are more dense compared to shrunken shape and reduced cell density in people with depression
- -there’s a negative correlation between hippocampal volume and the number of days someone has untreated depression
- -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.
Why are women 2x as likely to be diagnosed with depression?
- -Women are much more stress-reactive than men. Even at rest, female cortisol levels are higher than males. Women’s stress also fluctuates during their menstrual cycle
- -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).
What is ketamine?
- -Dissociative anesthetic; used as a tranquilizer (mostly veterinary)
- -At low doses, subjects feel detached from their body, sensation of floating, dreamlike and euphoric state (dissociative anesthetic)
- -At higher doses, produces a dissociative state (subjects lose all mental contact with their environment, despite eyes open!)
How does ketamine work in the brain?
- -Principal target is the NMDA receptor
- -when glutamate binds to these NMDA (n-methyl d-aspartate) receptors it promotes the influx of positively charged ions like calcium and sodium, and is responsible for learning and memory.
- -Ketamine is an antagonist so it occupies the NMDA receptor so glutamate cannot work on it. Glutamate promotes learning and memory, but when you take ketamine it prevents glutamate from working so less likely to have memories/memory consolidation
How does low-dose ketamine help with depression?
–Clinical trials have shown a rapid (within hours) reduction in depression symptoms for 65 to 70 percent of treatment-resistant patients.
–Effects last one to three weeks
–Long-term reduction in suicidal ideation!
–Clinical trials have shown a rapid (within hours) reduction in depression symptoms for 65 to 70 percent of treatment-resistant patients.
Effects last one to three weeks
Long-term reduction in suicidal ideation!
–However, drugs that have been developed to block the NMDA receptor have not proved effective
Could there be another mechanism that would explain these effects?
—->Active metabolite of ketamine
–Glutamate and GABA control the monoamines (serotonin for example) so by acting on the glutamate it can act on the serotonergic receptor
Do antidepressants cure depression?
Antidepressents don’t cure depression. They promote neurogenesis and brain plasticity. The brain circuits are ready to be reshaped and remodeled but if you keep thinking negatively the circuits will still be that way so you need psychotherapy to learn how you can think positively and remodel those circuits
