Let 17

Question 1

What is the historical background of bipolar disorder?

Answer 1

–Ancient Greeks used terms “mania” and “melancholia” to describe mania and depression
—->Even wrote about lithium salts used in a bath to calm people
–1851, French psychiatrist Jean-Pierre Falret published an article describing what he called “la folie circulaire”
which translates to circular insanity
—->The article details people switching through severe depression and manic excitement, and is considered to be the first documented diagnosis of bipolar disorder
–Early 1900s: Emil Kraepelin was studying individuals who had an episodic course of periods of mania and depression: coined term “manic depressive psychosis”
–At this time, they thought it was related to schizophrenia because they thought the manic phases were psychotic states. When people are significantly manic, it can present as psychosis
–Included in early editions of the DSM as “Manic Depression”
–DSM 5: Bipolar Disorder

Question 2

What are the diagnostic features of bipolar 1?

Answer 2

–A manic episode characterized by the following:
—->Distinct period of abnormally elevated, expansive, or irritable mood; abnormally and persistently increased goal-directed activity or energy lasting at least 1 week and present most of the day, nearly every day
—->Three or more of the following
Inflated self-esteem or grandiosity
Decreased need for sleep
More talkative
Flight of ideas/racing thoughts
Distractibility
Increase in goal-directed activity (socially, work, school, or sexually) or psychomotor agitation (purposeless, non-goal directed activity)
Excessive involvement in activities that have high potential for painful consequences (e.g., foolish business investments, buying sprees)
–Causes marked impairment in social / occupational functioning
–A major depressive episode

Question 3

What are the diagnostic features of bipolar 2?

Answer 3

• -A hypomanic episode characterized by the following:
• —>Distinct period of abnormally elevated, expansive, or irritable mood; abnormally and persistently increased goal-directed activity or energy lasting at least 4 consecutive days and present most of the day, nearly every day
• —>Three or more of the same criteria as Bipolar I
• —>Episode is associated with an unequivocal change in functioning
• —>Disturbance in mood and change in functioning is observable by others
• —>The episode is not severe enough to impair social/occupational functioning or result in hospitalization
• -A major depressive episode

Question 4

What parts of the brain are implicated in bipolar disorder?

Answer 4

The limbic system (emotional), cortex (cognitive), striatum (motor)

Question 5

what is the prevalence/development of bipolar disorder?

Answer 5

• -12-month prevalence estimate is approximately 0.6% –for bipolar I; about 0.3% for bipolar II
• -Male:female ratio is approximately 1:1
• —>Slightly more females for bipolar II tho this may represent treatment –seeking bias
• -Bipolar I: mean age of onset is 18
• —>More than 90% go on to have further mood episodes
• —>Four or more mood cycles / year = rapid cycling
• -Bipolar II: average age of onset is mid 20s
• —>Often begins with a depressive episode; becomes more disabling over time
• —>Can be triggered by childbirth

Question 6

What is the rate of cycling for bipolar disorder?

Answer 6

Rate of cycling varies

• -Rapid cycling consists of four or more cycles in one year
• -Some individuals may cycle several times in one day
• -Rapid shifts in mood referred to as “lability”

Question 7

How is a genome-wide association study done?

Answer 7

We take whatever phenotype we’re interested in (asthma, bipolar disorder, etc), and we take a whole population or group of people with that phenotype we are interested in and we classify them by those clinical manifestations, and we compare them with a control sample of people we know don’t have that disorder or have it running in their family. We then take a sample of DNA and we read the genetic code using SNP-arrays (single-nucleotide polymorphism –a single nucleotide that is different. Ex. CGATGC changed to CTGATGC). The meaning of the gene isn’t changed. For example, we could have it still produce a dopamine transporter protein but with the SNP it could mean the dopamine transporter protein functioning slower or faster than the regular polymorphism. “Poly” means many and “morph” means form: Different forms of the gene (long or short form). We take all this genetic information, put it through computers that can read and pick out where the differences are. We’re looking to see if there is systematic difference between people with bipolar 1 and not.

Question 8

What do genome-wide association studies reveal?

Answer 8

GWA studies for bipolar disorder reveal association of risk for BPD with SYNE1, a gene which encodes nesprin-1
part of the complex that links the nucleoskeleton to the cytoskeleton

Question 9

What is the dopamine theory of bipolar disorder?

Answer 9

–Based on observation that mania can be provoked in individuals who consume moderate to high doses of amphetamines (which primarily work to elevate synaptic levels of dopamine)
—->If hyperdopaminergia underlies the mania, might hypodopaminergia underlie depression?
–Receptors are not permanently fixed on the cell membrane, they can be brought back into the cell
Mania = increased D2/D3 receptor availability so you get increased post-synaptic firing
The brain compensates for this by upregulating dopamine transporter proteins that bring up the dopamine to the presynaptic neuron and inactivate it so we have decreased post-synaptic firing
Depression = increased dopamine reupake
The brain then upregulates d2/d3 receptors to account for the reduction in the d2 signalling
This is the cyclical nature so the brain can return to homeostasis
–The dopamine theory suggests that bipolar disorder is due to a failure of dopamine receptor and transporter homeostasis

Question 10

What drugs are used to treat bipolar disorder?

Answer 10

• -Traditional drugs used to treat BPD (i.e., Lithium, Valproate) do have some action on the D2/3 receptor (they have a more indirect action, they are not ligands)
• -Newer drugs (quetiapine) also has action on this receptor, among others. (treat schizophrenia, bipolar disorder, psychotic disorders)

Question 11

What is the BDNF theory of bipolar disorder?

Answer 11

• -BDNF: one of the proteins involved in regulating the plasticity of the nervous system. When these proteins are very high, you can get lots of circuit remodeling (elevated spine density, proliferation of post-synaptic density, etc)
• -People with bipolar disorder have lower levels of BDNF: During manic AND depressive phases
  a) Lower BDNF is a consequence of the mania/depression
  b) lower BDNF occurs slightly before the mania/depression
  c) occurring in tandem with the mania/depression
• -Lower levels of BDNF not only implicated in the mania or depressive state, but also with the specific symptoms associated

Question 12

What is the mitochondrial theory of bipolar disorder?

Answer 12

• -Mitochondria also regulate reactive oxygen species (ROS)
• -Dysregulation in mitochondria can increase generation of ROS
• -ROS have a free electron which contributes to cell death. Antioxidants can help mitigate the effects of these ROS
• -In BPD a wealth of evidence suggests defective mitochondrial metabolism, morphology, and function
• -May contribute to oxidative stress and inflammation
• -May also lead to cell death (apopotosis)
• —>Could explain loss of cells in brain in bipolar patients
• -Lithium is protective of cell death so it may be preventing cell death, and preventing the BDNF dysfunction, and potentially the dopamine receptor dysfunction

Question 13

What is seasonal affective disorder?

Answer 13

• -Seasonal affective disorder (SAD) is a type of depression brought on by the shorter days of fall/winter
• -Spontaneous remission in the spring/summer
• -Many adults experience similar but milder vegetative symptoms in the fall/winter months

Question 14

Who are typical patients of seasonal affective disorder?

Answer 14

Typical patient: premenopausal woman who experiences carbohydrate craving, hypersomnia, and prominent fatigue during winter depressive episode

Question 15

what are the diagnostic features of SAD?

Answer 15

• -There has been a regular temporal relationship between the onset of major depressive episodes and time of year (e.g., Fall or Winter)
• -Full remissions (or change from depression - mania or hypomania) also occurs at characteristic time of year (e.g., spring)
• -Has been observed over the last 2 years (no non-seasonal depressive episodes)
• -Seasonal episodes > non-seasonal episodes (which may have occurred over the person’s lifespan)

Question 16

What is the neurobiology of SAD?

Answer 16

Complex disorder that results from the interaction of several vulnerability factors acting at different levels, and the various genetic mechanisms that underline them
–biological rhythms, mood regulation, increased eating, light sensitivity

Question 17

How does latitude affect SAD?

Answer 17

• -Latitude” or “photoperiodic” hypothesis: Based on the marked similarity between the core symptoms of SAD and energy-conserving strategies implemented by various species at northern latitudes
• -Hypothesize a clear association between the prevalence of SAD and increasing latitude
• —>Would support the notion that biological adaptations tied to the short days of winter are the primary factor that distinguishes SAD from other mood disorders
• —>Evidence is mixed: could be some individuals genetically protected from SAD

–Evolutionarily, we didn’t want to spend energy during the winter months. The brain that was designed for the paleolithic time is no longer adaptive in some people to this modern world

Question 18

How does melatonin affect SAD?

Answer 18

Melatonin (synthesized from tryptophan) detected by pineal gland. Pineal gland in the midbrain –there is a weakness in the blood-brain barrier around the pineal gland. This is where larger hormones can pass from the bloodstream and into the pineal gland. It detects circulating tryptophan and converts it to melatonin and serotonin

High carbohydrate foods elevate tryptophan so you’re promoting sleepiness because tryptophan gets converted to melatonin which makes you sleepy
Levels of tryptophan increase in response to darkness. Photoreceptors in the retina signal length of day right to pineal gland so we get an upregulation of tryptophan in response to darkness so we will want to sleep more

Thyroid gland regulates energy levels so higher levels of melatonin signal to thyroid gland to release less hormones, so you get decreased metabolism, and thus decreased energy (metabolism is slower so food is not being converted to energy)

Thus, SAD may result from inadequate illumination during fall and winter  excessive signalling in melatonin  less thyroid hormone

Question 19

What is the treatment for SAD?

Answer 19

• -Bright Light Therapy: BLT
• -Recommended “dose”: 5000 lux hours per day
• —>E.g., 10 000 lux for half an hour each morning looking right at it so it stimulates photoreceptors
• —>Early morning treatment (before 8AM) optimal
• -Symptoms such as carb cravings and hypersomnia predict a robust response
• -Insomnia, weight loss = less responsive

Question 20

What do people with bipolar disorder in their mania phase do?

Answer 20

–Mood in a manic episode often described as euphoric, excessively cheerful, high or “feeling on top of the word”
E.g., may spontaneously start extensive conversations with strangers in public
–There have been people who have experienced mania or hypomania in the absence of depressive disorder (unipolar mania which hasn’t been included in the DSM-5)
–Very rarely do people with mania tell their doctor they’re feeling too high/good. Often when people experience extreme mania, someone else has admitted them to the hospital to get help. Or someone during their depressive phase will seek help. No one during a manic episode will think they need help or are ill
–People in their manic episode, particularly women, will engage in highly promiscuous behaviour
–May experience sharper sense of smell, hearing or vision