Bipolar Disorder Flashcards
Does Bipolar Disorder have Gender Preference?
No
Causes of Bipolar Disorder?
- Genetic, developmental, societal, cultural, environmental events.
What is the peak age onset of Bipolar?
15-19 years old.
How does bipolar disorder typically present?
Can have acute manic episode with psychotic symptoms. The acute manic episode can rapidly shift to acute pure bipolar depression, or psychotic bipolar depression. Other symptoms usually add complexity.
Bipolar episodes can occur every 2 years (cycling) or every 2 moths (rapid cycling).
What is the most common medication that triggers psychosis?
Cortisol.
What is a common comorbidity with bipolar disorder?
Substance use.
What are common physical and mental signs of both mania and hypomania?
- Decreased need for sleep.
- Increased energy and or motor agitation.
- Racing thoughts.
- Irritability, often more common than, classic euphoria or elation.
How does hypomania differ from mania?
- Hypomania:
Mild, less severe
Little to mild dysfunction
Little to mild lapses of judgment
Commonly responds to outpatient management
Sleep regulation and or benzos can sometimes terminate episode - Mania:
Severe
Severe dysfunction
Major lapses of judgment
Psychotic symptoms
Often requires inpatient treatment
Need for acute mood stabilizer and or neuroleptic treatment
What symptom means it’s no longer hypomania but mania?
Presence of psychotic symptoms or hospitalization.
What are some myths and misconceptions that led to the term “Manic-depressive disease” being changed to “Bipolar Disorder”?
- Term “manic” was associated with violence and dangerous behaviours, which led to the term being changed to “bipolar disorder” to highlight the polarity of the episodes.
- However, we are going back to the concept of reinforcing the recurrent nature of the episodes, independently of their polarity.
3.. The concept of “spectrum” recognizes that individuals can have a range of experiences, and there are multiple components that differentiate one from another.
What is the Genetic Source of Phenotype Heterogeneity for Bipolar Disorder?
- Genes are not specific, multiple genes are responsible -> no answer has come from genetics so far.
- SNPS -> associated to MDD, find them in bipolar as well as SCZ).
- In the old days, SCZ and mood disorders were clear cut, now thats not the case, they all share common SNPS. (example; SCZ are depressed as well)
- Genetics in bipolar disorder, yes useful for some extent, yes, we know some genetic abnormalities linked to disorder, but we cannot do gene disorder and fix the disorder, and he does not think we will ever be there.
What are the sources of phenotype heterogeneity in Bipolar Disorder?
- Genetic
- Biotype/Biomarkers -> Driven Classification - RDoc.
- Disease pattern/ Cycling / Comorbidity and functional consequences.
- Staging? Are we ready?
- Psychosocial factors: a big part of the equation.
What is Research Domain Criteria? What findings did they find from the collected data?
- Research Domain Criteria:
- Study patients based on their functional domains, rather than diagnoses.
- Investigate potential abnormalities at the cellular level (enzymes, genes, etc.)
- Record this data and develop clusters of patients based on functionality.
- Focus on assembling data from billions of patients to identify clusters that respond to specific treatments. - Collected data from around 900 patients with Schizophrenia (SCZ) and Bipolar Disorder.
- Identified 3 biotypes of patients.
- Classified patients according to their functionality level.
- Found that the red and yellow zones have decreased volume compared to normal brains. Old studies would classify the columns with decreased volume as SCZ, but it was associated with Bipolar Disorder.
- Bipolar patients showed the least brain function.
- These findings suggest that the traditional diagnostic categories need to be rethought.
What is the cognitive outcome of Bipolar Disorder?
- The outcome is not as good as once thought. (close to SCZ & rapidly declining)
- Does not take many manic episodes to get cognitive deficits.
(takes about 1 year to get back to normal level of controls after manic episode, if they keep using substances, they never get back to normal control, substance use will worsen the disorder - negative impact of SUD).
What is Cortisol & How is it controlled?
- Cortisol is a stress hormone released by adrenal glands. Its release is controlled by the HPA axis: hypothalamus, pituitary gland, adrenal glands (releases cortisol in response to signals from the hypothalamus)
- CRF neurons in the hypothalamus play a crucial role in regulating stress hormone. They signal the pituitary gland to release ACTH, which then stimulates the adrenal glands to produce cortisol. In depression, there may be overactive CRF system, leading to higher cortisol levels and poor regulation of the stress level.
- The paraventricular nucleus (PVN) in the hypothalamus controls the release of CRF, and it’s involved in stress response regulation.
- Hippocampus: Involved in regulating the stress response by inhibiting the release of CRF.
- Amygdala: Involved in processing emotions, particularly fear and stress, and can activate the HPA axis during stress.
- 5HT (Serotonin): A neurotransmitter that helps regulate mood and is involved in the HPA axis. Low levels of serotonin can lead to increased stress sensitivity and mood disorders like depression.
- ACTH (Adrenocorticotropic Hormone): A hormone released from the pituitary gland that stimulates the adrenal glands to release cortisol. ACTH is controlled by CRF neurons in the hypothalamus.
What is the Dexamethasone Suppression Test (DST)?
- This test measures how well the body’s stress system (HPA axis) responds.
- Dexamethasone is a synthetic steroid that should suppress cortisol production, but in some individuals (non-suppressors), it doesn’t.
What is the difference in patients with non-suppressors and suppressors in terms of suicide risk?
- Non-Supressors:
- Not show suppression of cortisol levels in response to DST.
- Greater risk of serious suicide attempts & developing bipolar disorder later on. - Suppressors:
- Showed suppression of cortisol levels in response to DST.
- Way smaller chance of completing suicide & developing bipolar.
What is the effect of DESPIRAMINE when given for 2 weeks?
- It is an antidepressant.
- After treatment, mice became more responsive to stress.
- Behavior became bi-polar like.
- When it was given to healthy-humans, they hypo-reactive response to stimuli, they did not react as strongly compared to nromal controls.
- This may be linked to GR receptors (receptor for cortisol, the stress hormone).
- Could also involve the Amygdala.
When shown faces expressing fear or happiness, how do bipolar patients react?
- tend to overreact, particularly in the amygdala. Even when not depressed, bipolar patients show heightened emotional reactions.
- In healthy individuals, their brain’s emotion regulation system allows them to calm down and feel reassured.
- In bipolar patients, their emotion regulation system does not work properly, and they remain hyperreactive to all stimuli. (tend to be more fearful)
What areas of the brain control regulation, mood and appraisal?
- Regulation:
- Dorsomedial PFC
- Dorsal ACG
- Ventromedial PFC - Mood
- Ventrolateral PFC
- Ventromedial PFC
- Ventral ACG - Appraisal
- Amygdala
- Insula
- Thalamus
- Ventral striatum
In healthy humans, there is proper regulation for mood and appraisal, in bipolar individuals, there is not, this is the neural basis for affective instability in these patients.
Is there a genetic component to the Amygdala Hyperreactivity that bipolar patients present with?
Yes. Healthy relatives are at higher risk - they are also hyper-reactive, makes patients more prone to anxiety.
What idea was had to bypass the amygdala as a treatment for bipolar?
- Insula Hypometabolism (decreased gre matter) - patients have this - and it is a brain region involved in emotional processing and self-awarness.
- Mindfullness, helps improve neural activation and can help patients manage their emotions better, especially in response to sad mood challenges.
- Idea was to use medidation to help reduce anxiety in BD.
- Idea got rejected.
- Small study done - patients reported feeling better and sleeping better after practicing meditation. Improved sleep is especially important for BD patients, as sleep disturbances are common issue for them.
Bipolar Episodes and Allostatic Load
- Allostatic Load: This refers to the wear and tear on the body caused by repeated stress and episodes. Over time, this leads to disruption in the body’s ability to maintain homeostasis (a stable internal state).
- Bipolar disorder marked by repeated episodes of depression and mania, can become more frequent as disease progresses.
- Other disorders, such as anxiety, often accompany BD, which can cause patients to use substances (e.g., alcohol, cocaine, cannabis) to relieve their symptoms.
As BD progresses, frequency of episodes increases, leading to a decrease in BDNF (Brain-Derived Neurotrophic Factor), important for health and function.
Impact of Stress, Episodes, and Substance Abuse In BD
- Stressors
- Decreased BDNF (brain more vulnerable to damage) - Episodes of Depression and Mania
- Decreased BDNF
- Increase oxidative stress (further damages brain cells) - Substance Abuse
- Cocaine, alcohol, cannabis -> increases allostatic load by adding extra stress on body.
- Worsened symptoms and contributes to long-term damage.
Neuronal Plasticity and Regeneration
- Neurons don’t actually die permanently; they protect the overall network.
- In response to stress or damage, neurons may shrink and retrieve their dendrites.
- Treatment with antidepressants increases neurotransmitter levels, which helps re-establish neuronal connections.
- Both neurons and glial cells can be regenerated from stem cells.
What is the impact of Manic Phases on BDNF?
- During a manic phase, levels of BDNF (Brain-Derived Neurotrophic Factor) in the blood decrease.
- Lower BDNF is associated with a reduction in neuronal connections, which is harmful to brain health.
Stress and Neuronal Degeneration
- Stress increases glucocorticoids (stress hormones) and decreases BDNF.
- This combination can lead to neuronal atrophy or death, increasing the brain’s vulnerability.
- Genetic factors may also contribute to this vulnerability.
What are the effects of anti-depressants on neurons/CA3 region?
- The CA3 region of the brain can show improved survival and growth when treated with antidepressants.
- Antidepressants boost levels of serotonin (5-HT) and norepinephrine (NE), which in turn increase BDNF and support neuronal health.
What are the intracellular pathways that contribute to the actions of stress?
- Stress causes an increase in glutamate, NMDA receptor is activated, CA2+ levels increase - hyper-activation of Ca2+-dependent enzymes, increase in oxygen free radials -> leading to Atrophy, endangerment, and death of neurons.
- Stress causes increase in Glucocorticoid, GR receptor, decrease in glucose transporter and glucose uptake, decrease in energy capacity -> leading to Atrophy, endangerment, and death of neurons.
- Stress causes decrease in BDNF, decrease in trophic support -> leading to Atrophy, endangerment, and death of neurons.
What drug can modulate the AMPA receptor?
Ketamine
Does inflammation and glutamate dysfunction contribute to the pathophysiology of depression?
- Multiple lines of evidence suggests this; inflammation, Glia, and Glutamate in Depression.
- Immunologic abnormalities, especially indices of excess inflammation, are common finding in patients with depression.
- Ratio is in favour of pro and inflammatory cytokines/ IL-4 during state of mania (had a lot of hope with these results - but did not follow through)
IL6/IL-4
TNF-a/IL-4
IL-2/IL-4
IFN-y/IL-4
Increase ratios.
VNTR Polymorphism of the PER3 gene and Age of Onset of Bipolar Disorder (Sleep)
- Sleep is a critical factor in managing BD. Patients are trained to monitor their sleep patterns. A significant change (especially decrease) in sleep should prompt immediate contact with a doctor.
- PER3 Gene: a gene involved in regulating circadian rhythms (body’s internal clock).
- VNTR Polymorphism: Variations in the number of repeats (Variable Number Tandem Repeats) within the PER3 gene.
-> these genetic differences can influence the age of onset of bipolar disorder. Patients with one variant may experience symptoms earlier or later compared to those with another variant. - CLOCK gene - first identified gene that regulates circadian rhythms.
What does research with Clock mutant mice show?
- Behavioural Patterns in Mice:
Disrupted circadian rhythms.
Hyperactivity.
Decreased sleep.
Increased preference for cocaine.
Greater risk for substance use disorders (SUD). - Common Symptoms in Manic Bipolar Patients:
Disrupted circadian rhythms.
Hyperactivity.
Decreased sleep.
Extreme euphoria.
Increased risk-taking.
Propensity toward drug abuse.
Similarities suggest that studying these mutations can provide insights into the manic state of bipolar disorder.
What are some Mitochondrial Abnormalities in BD?
- Phosphorylation Chain Abnormalities.
- leads to increased generation of oxidative compounds.
- Altered production of ATP. - Mitochondrial disorders are linked to multiple medical conditions, not just mental disorders.
- making robust findings related to cortisol.
What is the connection between Low-Self Esteem and Hippocampal Volume?
- Low SE, more likely to develop cognitive deficits than someone who is old but has had high SE all their life.
Are we ready for Staging in Psychiatry?
- In lung cancer, patients are staged on tumour size, spread, etc., which guides treatment decisions.
- In Psychiatry, lacks a formal staging system, making treatment decisions for disorders like bipolar disorder more challenging.
- Many current challenges.
- Diagnosis Fuzziness (even differentiating between BDI and BDII can be hard)
- Treatment resistance (some bipolar patients are more resistent and difficult to treat; a staging system could help identify these patients)
What is the concept behind staging in Bipolar Disorder? What are the research efforts toward a Staging System?
- Stage 4 Bipolar Disorder: Defined as patients experiencing multiple episodes, frequent relapses and treatment resistance.
- Cluster Analysis being Done -> goal to develop staging system over next 4 years, which will incorporate evidence on sleep disruptions and other factors in BD.
What is the connection between Sleep Disturbances and Suicide?
- Common in bipolar disorder and linked to higher suicidality.
- Examples include insomnia, early start of daily activities, and disturbed circadian rhythms.
- These sleep issues are notably more significant in female patients.
- Abnormal circadian cycles in bipolar patients may be triggered by clock genes (such as those involved in regulating sleep patterns).
