8 - bipolar disorder Flashcards
what is bipolar disorder?
- bipolar disorders are a group of brain disorders that cause extreme fluctuation in a person’s mood, energy, and ability to function (DSM-5)
- causes extreme mood swings that include emotional highs (mania and hypomania) and lows (depression) that affect thought, perception, emotion, and social behaviour
- significantly reduces average life expectancy
- formally called ‘manic depression’
what are the 2 clinical subtypes of bipolar disorder?
Bipolar I Disorder
Bipolar II Disorder
describe bipolar 1 disorder
- classical bipolar disorder
- manic episodes typically alternate with depressive episodes during the course of illness (vast majority)
- there is a recurrent mania subtype (rare) (dont have depressive episodes)
describe bipolar II disorder
- NOT a milder form of BD1
- lifetime experience of at least one major depressive and one hypomanic (but not manic) episode
- often depressive episodes become predominant over time and are very functionally impairing
- hypomanic episodes do not usually cause impairment, often improve productivity at home/work, and sometimes are not disclosed because they are not seen as a problem by the patient
- usually cause of presentation is depression or unpredictability of mood
- BPII can be mistaken for recurrent MDD if you don’t look for a past history of hypomania
what is a manic episode (DSM-5)?
a distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy, lasting at least 1 week and present most of the day, nearly every day (or any duration if hospitalisation is necessary)
in a manic episode, what has to be present to a significant degree and represent a noticeable change from usual behaviour?
3 or more of the following (4 if mood only irritable):
- inflated self esteem/grandiosity
- decreased need for sleep
- pressure of speech (more talkative than usually or pressure to keep talking)
- flight of ideas or subjective experience that thoughts are racing
- distractibility (ie. attention too easily drawn to unimportant or irrelevant external stimuli)
- increase in goal-directed activity (socially, work or school, sexually) or psychomotor agitation
- excessive involvement in pleasurable activities that have high potential for painful consequences (eg. unrestrained spending, sexual indiscretions, foolish business investments)
the symptoms of mania must be sufficiently severe to cause marked impairment in ____ or _____ functioning or to necessitate ______, or there are ______ features, and must not attribute to the physiological effects of a substance or to another medial condition
- social or occupational functioning
- necessitate hospitalisation
- psychotic features
what is hypomania?
- a distinct period of abnormally and persistently elevated, expansive or irritable mood and abnormally and persistently increased activity or energy, lasting at least 4 consecutive days, and present most of the day, nearly every day
- at least 3 of the features that are seen in mania (or 4 if mood only irritable) must have persistent, represent a noticeable change from usual behaviour, and have been present to a significant degree
- not attributable to the physiological effects of a substance or to another medical condition
what are some difference of hypomania from mania?
- last at least 4 consecutive days unlike at least a week in mania
- hypomanic episode is associated with an unequivocal change in functioning that is uncharacteristic of the individual when not symptomatic
- the disturbance in mood and the change in functioning are observable by others
- the episode is not severe enough to cause marked impairment in social or occupational functioning or to necessitate hospitalisation. if there are psychotic features present, the episode, is by definition, manic
what proportion of the population has a bipolar diagnosis at any point during a 1 year period?
0.5-1%
what proportion of the population has a MDD diagnosis at any point during a 1 year period?
4-5% (5-10x higher than BD)
mean age of 1st mood episode for BP1 and BP2
BP 1 = 18 yo
BP 2 = mid 20s (a little earlier than MDD)
onset of BP in mid-late life requires what?
investigation for medical conditions such as frontal-temporal dementia, and substance ingestion or withdrawal
how much is average life expectancy reduced in BP?
reduced by 9-20 years (similar to SCZ)
what % of BP patients die by suicide? how many attempt? what is the lifetime suicide risk compared to that of the general population?
10-15%. roughly 35% will make at least one attempt
risk at least 15x higher
list some comorbid disorders common in BD?
- anxiety disorders (about 75%)
- ADHD
- impulse-control and conduct problems
- drug or alcohol abuse (roughly 60%)
- eating disorder
- metabolic syndrome
- migraine
are eating disorders more common in BP1 or 2?
BPII
name some environmental risk factors for BD
- more common in high-income countries
- adverse childhood experiences
- stress and loss eg. more common in separated, divorced, widowed individuals
- seasonal effects — mania more common in spring/summer, depression in autumn/winter
- medications
- medical disorders
what medications can increase risk of BP?
- corticosteroids
- L-DOPA
- thyroid hormones
- antidepressants can precipitate mania, esp MAOI/TCAs/SNRI
therefore antidepressants not recommended for bipolar depression, esp BP1. not as effective as in MDD
what medical conditions can increase risk of BD?
- substance misuse
- hypothyroidism ( thyroid hormone is pivotal to the creation and regulation of neurotransmitters like serotonin)
- MS
- cushing’s
- SLE (type of lupus)
- epilepsy
- CVD
- tumours
- neurosyphilis
- AIDS
- head injury
genes and BD?
- heritability >70%
- cumulative small effects of multiple risk genes
- 30 genetic risk loci now identified
> voltage-gated Ca++ and Na+ channels
GluN2A subunit of NDMA receptors
synaptic components
regulation of insulin secretion
endocannabinoid signalling
what are BPI and BPII strongly correlated with?
BPI — schizophrenia
BPII — MDD
on a manhattan plot, what does each dot represent?
a genetic variant, usually a SNP
in the loci identified, they contain genes vital for what?
- normal neuronal and synaptic function, inc for voltage gated Ca++ and Na+ channels
- subunit of the Glu NMDA receptor
- components of the synapse
In statistics you will be used to considering an association significant only if the p-value is less than _____. This is done to lower the likelihood that the association is by chance down to one in twenty. However, in GWA studies, because of the huge number of variants and individuals involved there is a very high chance that any particular association will be a _______. Because of this the significance threshold is typically elevated from ‘p is less than 0.05 or 5x10-2’ to a whopping ‘p is less than _______’. And that is the horizontal red line across the middle of the plot. Associations between particular genetic loci and the disorder or disease of interest that are above this threshold are considered _______
In statistics you will be used to considering an association significant only if the p-value is less than 0.05. This is done to lower the likelihood that the association is by chance down to one in twenty. However, in GWA studies, because of the huge number of variants and individuals involved there is a very high chance that any particular association will be a false positive. Because of this the significance threshold is typically elevated from ‘p is less than 0.05 or 5x10-2’ to a whopping ‘p is less than 5x10-8’. And that is the horizontal red line across the middle of the plot. Associations between particular genetic loci and the disorder or disease of interest that are above this threshold are considered significant
GWAS in schizophrenia — includes loci for what?
D2 receptor, glutamate neuro-transmission, synaptic plasticity, voltage-gated Ca++ channels
8 (27%) of the 30 risk loci in BP are also associated with what?
schizophrenia
do environmental factors or genetic factors contribute more to MDD?
environmental
what kind of drugs do manic episodes in BP respond to?
antipsychotic drugs (D2 receptor antagonists)
what % of patients with BP develop psychosis during their lifetime and mainly in which phase?
50%
manic phase — ie. BPI patients
some in severe depressive episodes
DA, no psychosis and BP?
dopamine synthesis is unaltered in BP without psychosis, therefore an increase in DA doesnt seem to be driving mania
DA, psychosis and BP?
DA synthesis is elevated in striatum in bipolar psychosis
- similar in first-episode SCHZ patients with psychosis
what is an increase in DA in BP psychosis correlated with?
correlated with positive psychotic symptoms
striatal subdivisions BP vs SCZ
BP — all striatal subdivisions (limbic, sensorimotor and associative)
SCZ — only associative striatum
theory behind increased motor activity and involvement in pleasurable and rewarding activities seen in BP but not usual in SCZ?
increased DA in sensorimotor and ventral (limbic, reward) striatum subdivisions instead of just associative
what are the 3 phases of bipolar disorder that need to be treated? how does treatment differ in each phase?
- acute (hypo)manic
- acute major depressive
- maintenance phase — prophylaxis against future (hypo)manic and depressive episodes
- effectiveness of drugs differs across the 3 phases
- antipsychotics good for acute anti manic but few protect against depressive recurrence
what is the only drug with fairly similar effectiveness in all 3 BP phases?
lithium
what drugs are effective in acute manic episodes?
- antipsychotics (ALL) = D2 receptor antagonists, whether psychosis present or not
- lithium (a mood stabiliser)
- valproate (an anti epileptic)
- carbamazepine (an anti epileptic)
what drugs are most effective as anti antics?
antipsychotics and lithium
what 5 antipsychotics are as effective as lithium and are generally more tolerable?
- haloperidol
- quetiapine
- risperidone
- olanzapine
- aripiprazole
what 2 drugs aren’t as effective for mania as lithium or antipsychotics but are a bit more tolerable than lithium and still moderately effective?
valproate and carbamazepine
what is usually used first in clinical practise during an acute manic? what is then often started after?
- antipsychotics — good balance of effectiveness and tolerability and can be introduced quickly
- lithium is often started when the patient is starting to recover as it adds to the anti manic effectiveness and is kept on into the prophylactic phase
However, for patients who cannot tolerate antipsychotic drugs, ______ can be used first-line as an antimanic drug and is effective. It just takes a bit longer as the dose needs to be titrated upwards and requires _______.
- lithium
- blood tests
how are acute depressive episodes treated?
- quetiapine in relatively low dose (a 2nd generation antipsychotic) — has most evidence for effectiveness, usually at lower doses than are use for psychosis
- lamotrigine (an anti epileptic)
- lithium
- antidepressants are usually NOT helpful 1st line
antidepressants in bipolar depression?
- avoid 1st line in BP depression — increase risk of switch to mania or rapid cycling in BP1. usually not effective in BPII
- may sometimes be helpful, but used 2nd or 3rd line and must be used with an effective anti manic drug (eg. AP or lithium)
eg. evidence for effectiveness and safety of fluxetine (AD) + olanzapine (AP) or SSRI + Li combinations - appropriate 1st line in unipolar depressive episodes
treatment in maintenance phase? (prophylaxis)
- lithium = gold standard — superior evidence for prevention of new episodes (both mania and depression); greater evidence base documenting the risks of prolonged exposure; efficacy in reducing the risk of suicide
- quetiapine — better against depression unless higher doses used
- valproate — mainly against mania
apart from ____ and ______, other antipsychotics only protective against mania so are not good for maintenance
quetiapine and olanzapine
describe lithium
- an alkali metal usually administered as a salt (carbonate/citrate)
- not bound to plasma proteins, is not metabolised and is excreted unchanged almost solely by the kidney
- abridged quick by the body
- narrow therapeutic window
lithium : caution and lower the dose in what?
renal impairment
what drugs should be avoided when taking lithium? why?
drugs that reduce renal elimination of lithium eg. ACE inhibitors, thiazide diuretics, NSAIs
otherwise can lead to toxic levels of Li
what is Li entirely reliant on for elimination?
kidney function
what is the narrow therapeutic window of lithium?
0.6-0.8 mmol/L (12 hours post-dose)
what happens when Li is not in its therapeutic window?
- below 0.6 — decreased or absent effectiveness
- above 0.8 — decreased tolerability
- above 1.2 — high risk of toxicity
what do you need when taking Li?
regular blood tests — renal, thyroid, parathyroid function
what are clinical indications for lithium?
- moderate to severe mania
- maintenance/prophylaxis in BP — Li is 1st line mood stabiliser
- protection against mania > protection against depression
- antidepressant augmentation in MDD
- prophylactic effect not as good as its acute anti manic effect
> Li is 1st line treatment for all phases of BP disorder
reduces risk of attempted and completed suicide in BP by 80% and in MDD (slightly smaller effect size)
lithium MoA
- wide range or immediate and long-term effects
- however, their relative contributions, if any, to the therapeutic benefits of Li remain unclear
effects include:
- increase in 5-HT and GABA neurotransmission
- decrease in Glu and DA neurotransmission (probs by effects on adenylate cyclase, inositol metabolism and protein kinase C activity)
- decreased oxidative stress
- increase in trophic and protective factors eg. BDNF and the anti-apoptosis factor B-cell lymphoma-2 (Bcl-2) — preserves or increases the volume of brain structures involved in emotional regulation such as the prefrontal cortex, hippocampus and amygdala
SE of lithium at normal levels
SE are mild
- fine tremor
- mild GI upset
- clinically evident nephrogenic diabetes insipidus (NDI) (reversible) — increased thirst, polyuria and reduced urinary concentrating ability. renal tubule mechanism : Li probably inhibits a G-protein coupled pathway that is activated by ADH to increase aquaporin channels in the collecting ducts
- mild cognitive effects
- metallic taste
- ankle oedema
- weight gain
- increased risk of hypothyroidism and hyper parathyroid is
- potential risk of decreased renal function with chronic use
what are signs of lithium toxicity?
- increasing anorexia, nausea, diarrhoea
- muscle weakness, drowsiness, ataxia, course tremor, muscle twitching
- at 2.0 mmol/L — increased disorientation, seizures, coma, death
it is a medical emergency
most patients never experience this
what is hypothyroidism treated with?
thyroxine
what is valproate a generic term used to describe?
- valproic acid
- sodium valproate
- valproate semisodium (a coordination complex of valproic acid and sodium valproate in a 1:1 molar relationship) AKA. Depakote (UK)
valproate is the conjugate base in all these salts and the pharmacologically active moiety
early MAOIs and tricyclic ADs were introduced for ___ and ____ rather than depression
TB and psychosis
indications for valproate
- acute manic episodes (moderately effective). usually used 3rd line in resistant mania and added to lithium when Li and APs have not been adequately effective
- maintenance/prophylaxis - indicated when Li has not been affected or is poorly tolerated (moderate protection against manic relapse, less protective against depressive relapse)
valproate MoA
what are the very common SE of valproate
nausea, tremor, weight gain
SE of valproate in pregnancy
valproate in women of childbearing potential
