Affective Disorders and Suicide Flashcards
What is the impact of depression?
- Can’t contribute to life in the way one normally can.
- High rates of depression and mood disorders across all income countries.
- Huge impact of mood disorders on the global burden of disease.
Is depression more likely in females or males?
2x more likely in females than males.
What age is depression most prevalent in?
- Highest prevalence in 15-24 year-olds (partly due to puberty)
- Shift during puberty increases depression rates - still higher in females.
What is the difference between normal sadness and depressive disorders?
- Normal Sadness
- Respond to life events (e.g., loss, stress)
- Transient - does not last long.
- Appropriate emotional response.
- Not disabling
- Focal
- Reactive - Depressive Disorders.
- Persistent and prolonged sadness.
- Requires clinical diagnosis and treatment.
- Intense/extreme
- Disabling
- Pervasive
- Unreactive
DMS Diagnostic Criteria (Depression)
- Symptoms can present in opposite ways:
Weight loss or weight gain
Insomnia or excessive sleep - Heterogenous presentation makes treatment difficult. (also it is multi-factorial - hard to treat)
- Suicidal ideation does not need to be daily to meet the criteria — if present once or twice in two weeks, it qualifies.
Atypical Depression
- Most females present with atypical depression.
- Key feature: Mood reactivity (mood improves with positive events).
- Treated with different antidepressants.
Somatic illness
Depression caused by a medical condition
Substance-induced depression
Depression caused by drug use
Adjustment disorder with depressed mood
After a loss of major life change
What is the difference between Bipolar 1 and Bipolar 2?
- Classic form.
- Periods of depression and mania.
- Manic episode = Huge shift in personality (e.g., introverted → extroverted).
- Extreme enough to cause hospitalization.
- Less severe.
- Still causes noticeable behavioral shifts (e.g., pressured speech).
- Not disruptive enough to require hospitalization.
What factors are associated with depression?
- Predisposing Factors
- Familial/genetic factors.
- Early-life experiences. - Developmental Factors
- Psychological traits
- Cognitive styles - Precipitating Factors
- Life events (e.g., loss, trauma)
- Habits & lifestyle (e.g., poor sleep, substance use)
What are the genetic components of depression?
- Strong genetic component
- Heritability
- Explains how much variance in depression risk is due to genes.
- Depression is highly polygenic → Many small genetic effects.
- Even with large sample sizes (~15,000 people), no significant genetic markers found → Small effect size.
- Genetic influence = modulatory effect rather than direct cause.
- Twin and family studies show relatively high heritability.
- Common variants explain only 6–10% of total phenotypic variance.
- Finding significant associations is difficult due to:
- Polygenic nature of MDD (many small effects).
- Phenotypic heterogeneity of MDD (varied symptoms).
- Requires very large sample sizes to detect meaningful genetic links.
What systems are involved in depression?
- Depression is multi-factorial, not just the brain.
- Peripheral system influences brain function.
- Inflammatory system involvement.
- Multiple systems are integrated in depression pathology.
What are some challenges of treating depression?
- Psychiatrists/therapists diagnose, but different doctors prescribe medication.
- Antidepressants take 6–8 weeks to work (sometimes as fast as 14 days).
- Side effects and delayed action reduce compliance.
What are some treatments for depression?
- Exercise (Any type of exercise → 2x improvement in mental health).
- ECT
- Done under anesthesia + muscle relaxants.
- Goal = Induce seizure → “Reset” neural activity.
- Improves dendritic outgrowth.
- Causes short-term memory loss → Not first-line treatment. - Ketamine
(not first-line) - SSRIs (Selective Serotonin Reuptake Inhibitors) / First-line treatment.
What is the biogenic amine hypothesis?
- Based on clinical observations.
- Found when patients taking reserpine for heart issues experienced low mood.
- In other cases, the same drug improved mood when used for other diseases.
- Suggested that neurotransmitters affect mood regulation.
- Reserpine depletes biogenic amines (like noradrenaline) → linked to depression.
- Hydrazide (used for tuberculosis) increased biogenic amines → linked to elevated mood.
- Proposed:
- Depression = deficiency of catecholamines (especially noradrenaline).
- Mania = excess of catecholamines.
What is the Mechanism of TCAs? (Tricyclic Antidepressants)
- Block the reuptake of serotonin → increases serotonin levels.
- Also blocks:
1. Noradrenaline → affects blood pressure and energy levels.
2. Histamine → causes sedation.
3. Adrenergic receptors → causes side effects like: - Postural hypotension (dizziness when standing).
- Dry mouth.
- Constipation.
Numerous side effects → reduces compliance (patients stop taking the drug).
Mechanism of SSRIs (Selective Serotonin Reuptake Inhibitors)
- Cleaner mechanism → blocks only 5-HT (serotonin) reuptake.
- Fewer side effects than TCAs → better patient tolerance.
The goal was to reduce side effects and increase effectiveness of drugs, SSRIs are cleaner but not very effective for many patients.
The Serotonergic Neuron
- Early-generation antidepressants had many side effects.
- All antidepressants take a long time (weeks) to become effective.
- New generations of antidepressants → still working on improving speed and efficacy.
What are the characteristics of Depressive Disorders?
- MDD is the DSM-5 diagnosis of clinical
depression - Complex, heterogeneous, multifactorial, and
often chronic - Affects ~350 million people worldwide (WHO,
2016) - High rates of relapse (20-80%) within 5 years
even after successful treatment. - 30-40% of cases are related to genetics, but no single gene has been identified.
What are the symptoms of depressive disorders?
- Depressed Mood
- Feeling of worthlessness and/or guilt
- Loss of interest in activities which used
to be pleasurable - Significant weight loss or gain
- Insomnia
- The most severe consequence of
MDD is suicide
What are the symptoms of Major Depressive Episode? What MUST happen for a clinical diagnosis of depression.
- 5 of the symptoms must be present for at least 2 weeks. #1 MUST be present.
- Depressed mood or marked diminished interest or pleasure
- Significant weight loss or gain (more than 5% of body weight in a month
- Insomnia or hypersomnia
- Psychomotor agitation or retardation
- Fatigue or loss of energy
- Feelings of worthlessness or inappropriate guilt
- Diminished ability to think or concentrate
- Recurrent thought of death or suicidal ideation
What is the difference between Typical and Atypical Depression? (which is more likely for females to have)
Females are more likely to have Atypical depression.
- Typical:
- Mood is low
- Decreased appetite and Weight Loss.
- Insomnia, early waking.
- Psychomotor slowing or agitation.
- Not sensitive to rejection.
- Best treatment is TCAs, SSRIs. - ATypical
- Mood temporarily improves with positive events.
- Increased appetite, weight gain.
- Hypersomina, excessive sleep
- Leaden paralysis (heavy limbs)
- Strong emotional sensitivity to rejection
- Best treatment is MAOIs, sometimes SSRIs or buropropion.
What are the categories of depressive disorders and the associated relayed diagnoses?
(1) Depressive Disorders
- Major Depressive Disorder (single episode or
recurrent)
- Persistent Depressive Disorder (Dysthymia)
- Depressive Disorder NOS
(2) Related Diagnoses
- Depressive Personality Disorder (proposed)
- Adjustment Disorder with Depressed Mood
How do certain Mood Disorders Present? What are they?
- Persistent Depressive Disorder = Dysthymia
-> A chronic form of mild depression; the symptoms are similar to depressive episode but tend to be less intense and last longer.
-> Mood decrease. - Major Depression.
-> A depressive episode can be categorized as mild, moderate, or severe.
-> Mood decrease. - Bipolar.
-> Consists of both manic and depressive
episodes separated by periods of normal
mood. Manic episodes involve elevated
mood and increased energy, resulting in
over-activity, pressure of speech and
decreased need for sleep.
-> Mood can increase OR decrease.
What criteria do patients need to have for Bipolar disorder: manic episode?
- A distinct period of abnormality and persistently elevated, expansive or
irritated mood, lasting at least 1 week or any duration if hospitalization.
4 of the following:
- inflated self esteem or grandiosity
- decreased need for sleep
- more talkative than usual or pressure of speech
- flight of ideas or thought racing
- distractibility
- increase in goal directed activities or psychomotor agitation
- excessive involvement in pleasurable activities that have a high
potential for painful consequences
In terms of the neurobiology of mood disorders, what are the main lines of investigation?
- Neurochemistry (neurotransmitters,
neuroendocrinology, signal transduction, …) - Genetics/epigenetics
- Neuroimaging (functional and structural studies)
- Biological rhythms
- Neuroimmunology
What is traditional depression treatment based on?
- biopsychosocial approach.
- pharmacological treatment.
- psychoteraphy.
- psychosocial support.
what are some alternative treatments for depression that differ from the traditional ways?
- Exercise
- Acupuncture (Laser acupuncture)
- Brain stimulation (ECT)
- Deep brain stimulation (typically used for movement disorders)
- Psychedelics
What are the different classifications of Antidepressants?
- Tricyclic antidepressants and related
compounds
-Monoamine oxidase inhibitors
-Selective Serotonin Reuptake inhibitors
-5HT2 antagonists
-Selective Norepinephrine Reuptake inhibitors
-Dual action (SSRI + SNRI)
-Stimulants
How is Serotonin (5-HT) connected to Major Depression?
- Low 5-HT metabolism (decreased in cerebrospinal fluid)
- Decreased activity in 5-HT receptor
- Decrease binding in the prefrontal cortex of 5-HTT (serotonin transporter or SERT)
There was increased binding of a 5-HT receptor that was linked to altered serotonin signalling.
1) Historically, serotonin has been linked to depression based on early findings:
- Drugs affecting serotonin also influenced mood.
-Differences in serotonin metabolites and receptor binding have been observed.
- Antidepressants that target serotonin (like SSRIs) have shown mood improvements.
2) Genetic link:
- Genes related to the serotonin/monoamine system were early candidates in depression research.
- However, large-scale studies have not consistently shown a strong genetic association with depression.
3) Current understanding:
- A recent systematic review suggests no solid evidence that changes in serotonin levels directly cause mood changes in humans.
What is the epidemiology of Suice?
- 1M deaths/yr worldwide.
- suicide ranks among the top 10 causes of death for individuals of all ages.
- over 1 in every 100 deaths in 2019 was the result of suicide.
- leading cause of death for males aged 15-34 years.
- nearly 90% of individual who die by
suicide lived with a
psychopathology.
What are the known risk factors associated with SBD (suicidal behaviour disorder)?
- Previous suicide attempts
- Psychiatric disorders
- Hopelessness
- Impulsivity
- Aggression
- Childhood trauma
In SBD, what are the:
1. predisposing factors
2. mediating factors
3. precipitating factors
- family history and genetics -> stable gene function regulation
- early life adversity -> epigenetic regulation
- developmental regulation of behavioural and emotional traits
-> increased anxiety, impulsive aggression (way more rate of completing suicide), chronic substance use, genetic and epigenetic factors also contribute to this.
- developmental regulation of behavioural and emotional traits
- -genetic and epigenetic factors
- acute substance use
- behavioural disposition
- life events
- depressive psychopathology
- hopelessness and cognitive distortions
- suicidal ideation
- increased suicide risk
Neurochemistry of Suicide.
- 5-HT
- Polyamines
- Neurotrophins
- Cytokines
- Lipids (cholesterol) (less cholesterol -> depression with violent suicide)
What are the long-term consequences of early life adversity?
Child abuse (increased prevalence in suicide)
- typically by parents or caregivers
- affects children of all ages, race, economic and cultural backgrounds
- prevalence around 4-16% of children
- strongly predicts long-term socio-economic and health outcomes -> poor educational achievement, unemployment, crime
+ obesity, cardio-vascular disease, chronic pain
depression, PTSD, suicide
MDD & the HPA axis
- HPA axis changes in depression:
1. Increased plasma cortisol.
2. Dexamethasone test failure (cortisol levels do not decrease after dexamethasone - it usually suppresses cortisol) - when suppressed, 2% completed suicide.
- when nonsupressed, 27% completed suicide.
3. Increased CSF CRH levels.
4. More CRH-producing neurons - higher CRH mRNA levels in depressed patients.
Suicide & the HPA axis (normal development vs Early-life adversity)
- Normal development
- normal levels of glucocorticoid receptor in hippocampus
- inhibits stress -> hypothalamus (CRH/AVP) -> Anterior pituitary (ACTH) -> adrenal cortex (cortisol).
- homeostatic respond -> appropriate behavioural response to stress. - Early life adversity.
- low levels of GR.
- overactive HPA axis (not enough inhibition from the hippocampus on stress)
- development of anxiety traits
- suicide crisis
child abuse = hyperactive HPA axis.
How are suicide and depression related?
They share overlapping clinical and molecular characteristics, but Suicidal Behavioral Disorder (SBD) is hard to classify and is only included as an appendix in the DSM.
What genetic factors are involved in depression and SBD?
Both follow the common gene/common variant hypothesis — no single gene is highly penetrant; it’s caused by a combination of genes and environmental influences.
What is the primary treatment for depression?
Drug interventions targeting the serotonergic system (receptors and transporters).
Are there sex differences in depression and SBD?
Yes, noticeable sex differences exist in both Major Depressive Disorder (MDD) and SBD.
What are the causal biological factors in MDD?
- Monoamine hypothesis
- Inflammatory hypothesis
- Genetic and epigenetic anomaly hypothesis
- Structural and functional brain remodelling hypothesis
- Social psychological hypothesis
- HPA axis dysfunction hypothesis
What is the effect of depressive episodes on hippocampal volume?
- first episode - HC volume not significantly different than controls.
- multiple episodes -> HC volumes 10% smaller than FE depression & controls.
What evidence implicated BDNF in depression?
- stress decreases BDNF signalling in the hippocampus
- chronic antidepressant treatment increases BDNF-mediated signaling
- Direct injection of BDNF in hippocampus has
antidepressant effects. - decrease hippocampal BDNF signaling in rodents leads to depression-related behaviors and impairs the
actions of antidepressants - decrease hippocampal BDNF and TrkB alterations in postmortem studies of depression
What is BDNF?
- brain-derived neurotrophic factor.
- protein important for brain development, neuron growth, and maintenance.
-affects learning, memory, and mental health.
What is the difference between serotonin vs. glutamate in depression? (treatment targets)
- Serotonin
- slow-acting - increases BDNF transcription and release over time.
- explains why antidepressants take time to work. - Glutamate
- fast-acting - increases BDNF quickly.
- seen as a new target for faster depression treatment.
What drug targets glutamate to produce a fast antidepressant effect?
- ketamine.
- low doses can produce the desired effect.
- ketamine increases glutamatergic receptors even thought its an antagonist.
- works well but it is not comparable to typical treatments (requires supervision and IV administration).
what are the downsides of using ketamine as a treatment?
- side effects:
poor verbal memory performance
some cognitive benefits seen in certain tasks - hormonal differences:
ketamine is metabolized differently in males and females.
current administration does not account for these differences despite evidence saying it should.
ketamine has an active metabolite.
The Synapse
- Ketamine: glutamate burst, activity dependent BDNF release, increased GABA and glutamate synapse formation ->
nonstressed control, balanced GABA and glutamate; ketamine, reverses stress/depression deficits.
- Chronic stress or depression, decreased BDNF, genetic vulnerability.
Decreased GABA & Glutamate.
What is the mechanism of action of ketamine? (rapid acting antidepressants)
- Ketamine binds open-state NMDA
receptors on GABAergic interneurons,
which inhibits their firing. - Silencing of the inter- neurons results in
disinhibition of excitatory glutamatergic
neurons and a burst-release of glutamate. - Glutamate binds AMPA receptors on the
post-synaptic membrane, leading to
calcium influx through L-type voltagegated calcium channels (VDCC). - This influx causes Bdnf release into the
synaptic cleft, which binds TrkB, its receptor,
on the post-synaptic membrane. - Bdnf binding TrkB activates the Mek and
PI3K pathways in the post-synaptic neuron,
which lead to Gsk3 inhibition, mTOR
activation, and protein translation. - Ketamine’s antidepressant effect is driven
by the resulting synaptogenesis and
serotonergic neurotransmission via
increased translation of Bdnf, PSD-95,
synapsin-1, and GluR1.
Sex-Influenced Symptomology and Prevalence in MDD
- noticeable sex differences in the symptoms and prevalence of MDD.
- Females tend to experience more severe symptoms;
Increased weight gain
Increased fatigue
Comorbid anxiety
Comorbid substance use disorder (SUD)
HPA axis dysfunction
Aggression and impulsivity - treatment response also varies, with sex influencing how patients respond to drugs like tricyclic antidepressants (ADT) and SSRIs.
What are the limitations of sex-specific information in MDD?
- Lack of Female Subjects in Preclinical Studies.
- primarily used male rodents -> gap in knowledge about how MDD affects females.
- misconception that female variability is too high due to hormonal fluctuations, leading to a lack of female representation in studies.
- Biological sex differences in brain function are often ignored. - Sex Differences in Animal Models.
- Aggressive male rodents may become depressed after defeating non-aggressive males, but when paired with a female, aggression may not occur and mating may take place instead.
- Difficult to replicate depression models in females in same way as males.
Steroid hormones & Their impact
Steroid hormones significantly affect how our body and brain respond to various stimuli. While the exact details of these responses may not be critical to understand at a high level, their impact is substantial.
Steroid hormones have a major effect on brain function, including:
-> Influencing individual cells
-> Altering the morphology (structure) of brain regions
These effects are key to understanding the role of steroid hormones in brain activity and behavior.
Prefrontal Cortex Development During Puberty
- Puberty is a critical period for the development of the prefrontal cortex, which is involved in decision-making, emotional regulation, and higher cognitive functions.
- During puberty, the brain shows the largest number of sex-biased genes, meaning that gene expression differs significantly between males and females at this stage.
Correlated Changes Between Brain Regions (Male vs Female)
- Differential Gene Expression by Sex.
- This highlights that males and females are experiencing different biological processes, even in the context of depression. - Starting from Different Points.
- Males and females might start from different biological or developmental starting points.
- Despite these differences, both may end up with similar phenotypes (observable traits or conditions), leading to the same final pathology (e.g., depression).
-This suggests that different pathways or mechanisms may lead to similar outcomes in both sexes.
What are the effects of steroid hormones in the brain? What mechanisms do these effect?
- Effects:
- Neurodevelopment
- Morphological structure & function
(sexually different)
- Behaviour & mood
- Cognition
- Learning & memory - Mechanism:
- Gene expression regulation
- Epigenetic mechanisms (chromatin
remodeling & DNA methylation)
- Programmed neuronal death
- Neuroplasticity
- Synaptic wiring
- Immune factors
- Allosteric modulation of
neurotransmitter receptors
During stress, what differences does the fMRI show?
- Men: higher PFC
responses - Women: higher
limbic-striatal
responses
Why be “cell type specific”? (high-resolution molecular studies in MDD)
- Brain tissue has highly
heterogeneous cell type
composition - Gene expression and DNA
methylation patterns are very
specific to cell types - Bulk tissue (homogenate)
experiments can mask changes
specific to one cell type - Bulk tissue results may be biased
by cell type composition effects
What cell-type contributions are linked to depression?
- Changes in glutamatergic and GABAergic neurons.
- Astrocytic dysfunction (problems with star-shaped brain cells).
- Impaired myelination (damage to the protective layer of nerve fibers).
- Changes in the inflammatory response in the brain.
How can the different roles of brain cells in depression be better understood?
- Using high-throughput single-nucleus RNA sequencing (snRNA-seq) via 10X Genomics Chromium technology.
- In this method, each individual nucleus is encapsulated in a droplet with a barcoded bead, allowing for efficient analysis.
What makes the prefrontal cortex sensitive to stress?
- The protracted (slow) development of the prefrontal cortex makes it more vulnerable to stress during critical windows.
- Stress can alter white matter development, contributing to depression.
What could mediate changes in brain region volume in depression?
- White matter depletion (loss of connections between neurons).
- Loss of neuropil (synaptic connections).
- Altered BDNF levels, which affect brain plasticity and function.
Is there a shared mechanism of action between ketamine and psychedelics?
Yes, both ketamine and psychedelics appear to converge on excitatory cells in the brain, potentially explaining their therapeutic effects.
What new insights are provided by single-cell studies in MDD?
Single-cell studies are revealing new molecular changes that occur in depression, helping to uncover precise mechanisms and potential therapeutic targets.
How might extracellular vesicles help in understanding depression?
Extracellular vesicles can cross the blood-brain barrier and carry biomarkers that reflect the cells from which they originated, potentially offering a window into brain activity and helping identify molecular changes in depression.
