Bipolar Disorders

Question 1

What are bipolar and related disorders (DSM-5)?

Answer 1

Bipolar I Disorder
Bipolar II Disorder
Cyclothymic Disorder
Substance/Medication-Induced Bipolar and Related Disorder
Bipolar and Related Disorder due to another medical condition
Other Specified Bipolar and Related Disorder
Unspecified Bipolar and Related Disorder.

Question 2

What is euthymia?

Answer 2

Good/normal mood (placed in the center of a mood chart. Above is hypomania and mania, and below is dysthymia and depression. If have tendency for above it is a risk factor for bipolar disorders, if have tendency for below it is a risk factor for depressive disorders.

Question 3

What is a manic episode?

Answer 3

At least one of the following: elevated, expansive mood/irritable mood, or abnormal and persistent goal-directed activity of energy - targeting energy toward achieving a particular goal.
At least 3/4 for the following: Inflated self-esteem or grandiosity, decreased need for sleep, excessive talkativeness, flight of ideas/racing thoughts – mass of great ideas, distractibility, increased goal-directed activity or agitation – fidgety, risky behaviour (shopping, sex, business, etc.). Need to be present consistently for a week or more

Question 4

What does a manic episode cause?

Answer 4

Marked impairment in social or occupation functioning, often do not perceive that they are ill/resist efforts to be treated, and cognitive impairment is an important aspect but not part of the criteria.

Question 5

What is an hypomanic episode?

Answer 5

Less severe and of shorter duration than a manic episode. 4 days or more. There is change in functioning noticeable by others but does not cause marked impairment in social or occupational functioning.

Question 6

What is a mixed episode?

Answer 6

Meets criteria for both a manic episode and a major depressive episode. Display both symptoms at the same time.

Question 7

What is bipolar I disorder?

Answer 7

Manic or mixed episode and major depressive episode - do not happen at the same time, usually there is a major depression preceding manic episode.

Question 8

What is bipolar II disorder?

Answer 8

Major depressive disorder accompanied by a hypomanic episode. Less intense symptoms. Feature of impulsivity (suicide), average onset in mid-20s, usually begins with depressive episode which leads to false diagnosis in about 12%. Anxiety, eating, substance disorders may precede. Greater chronicity of illness and spend more time in the depressive state which can be severe and disabling.

Question 9

What is cyclothymic disorder?

Answer 9

Milder combination of bipolar I and II disorders. Altering between a hypomanic episode and a dysthymic episode. Longer term - 2 years for adults and 1 year for children.

Question 10

What are key facts about bipolar disorder I?

Answer 10

Heterogeneous disorder characterised by mood instability and cognitive dysfunction. Onset in early adulthood. Psychotic symptoms seem in minority. High comorbidity with anxiety and substance-related disorders in about 1/2 of BD patients (also cardiovascular disease and diabetes mellitus and thyroid dysfunction). High morbidity associated with the depressive episodes – 5-17% suicide rate. Life expectancy is reduced by 10 years or more – because of comorbidity and suicide rate. Poor prognosis – high rates of relapse, cognitive impairments and low quality of life.

Question 11

What are bipolar disorders?

Answer 11

Prevalence of about 1-4% - spectrum of bipolar disorder, depends how many criteria a person display. Diagnosing difficulties mainly due to the manic episodes – lack of dysphoria. Rapid cycling – more than 4 episodes of either mania or depression within 1 year. If untreated – typically gets worse due to cycle acceleration. The frequency of episodes increases due to shortening of the length of symptom-free intervals.

Question 12

What is the kindling hypothesis?

Answer 12

At beginning disorder may be triggered by environmental events, and once we experience that episode, if this happens again the symptoms may be triggered alone, in the absence of environmental events.

Question 13

What are episode-free intervals?

Answer 13

Still decreased social functioning and decreased cognitive abilities - not symptom free. Many misconceptions and focus on the episodes. Although many return to a fully functional level, 30% show severe impairment which prevents them from working. Lag between recovery from symptoms and functional recovery.

Question 14

What is disruptive mood dysregulation disorder (DSM-5 - depressive disorders)?

Answer 14

In children there has been an over diagnosis of BD. In an effort to deal with it, a new diagnosis of disruptive mood dysregulation given up to 12 years. Characterised by persistent irritability (in males) and frequent episodes of extreme behavioural dyscontrol. Typically develop depressive disorders rather than BD in adulthood.

Question 15

What are gender-related features in BD?

Answer 15

Although considered to be equally common, there are some differences: in women more likely to be depressive, more suicide attempts, mixed mania and rapid cycling, more thyroid dysfunction, more comorbid anxiety. Comorbid substance use more frequent in men. Postpartum period is a high-risk time for onset of depressive, manic, mixed and psychotic episodes.

Question 16

What is the switch ‘circular insanity’ (Falret, 1854)?

Answer 16

Unique feature of BD which distinguishes it from other disorders and makes it difficult to study - a sudden transition from 1 mood episode to another of opposite polarity - usually from depression to mania. The neurobiology of it is poorly understood. Has not been achieved in animal models yet.

Question 17

What triggers the switch?

Answer 17

Switching from depression to mania can occur spontaneously but can also be precipitated by stress, sleep deprivation, antidepressants, ECT, and substance use. Switching from mania to depression is more rare and is associated with poorer outcome.

Question 18

What is monopolar depression?

Answer 18

Usually after 25 years. Preceded by a long period where symptoms progressively get worse. There is no history of mania or hypomania.

Question 19

What is bipolar depression?

Answer 19

Usually before 25 years. Sudden occurrence in a few hours or days. Could be seasonal. High heritability (family history of the patient). History of behavioural problems, decreased need for sleep etc. are indicative of the presence of BD.

Question 20

What proportion of mood disorders are bipolar?

Answer 20

Traditional paradigm - shifting paradigm. View it as a spectrum of bipolar disorder - shifting in the prevalence. In the past 86% diagnosed as MDD, now 50%.

Question 21

What are environmental factors behind BD?

Answer 21

Childhood adversity, chronic stress and trauma. Mood instability (affective lability) during euthymia - a relatively new finding thanks to smartphones and apps. Being easy to shift your mood during euthymia (normal mood) – more shifts in mood than normal. Sleep disturbances, irregular sleep timing, reduction in sleep duration or travelling across time zones triggers manic episodes. Treatment with antidepressants.

Question 22

What are sleep features of BD?

Answer 22

Shortened sleep is associated with greater severity of symptoms. Sleep abnormalities (too short or too long) associated with poor quality of life. Disruption in sleep continuity. Increased time spent in stage 1 sleep, shortened REM latency – very quickly go into REM, very shallow stage of sleep, increased REM sleep density – how many movements eyes are making.

Question 23

What are genetics of BD?

Answer 23

Mutations of CLOCK in mice results in decreased need for sleep, increased motor activity, low anxiety – comparable to mania and it is restored by lithium. PER3 gene – linked to the early onset of BD I (before 18y) associated with: More psychotic features and higher frequency of mixed episodes, poorer prognosis. There is a genetic basis - 10 times more likely to develop BD if the parent has it (also increased risk if schizophrenia is found in the family). Not Mendelian genetics – multiple loci involved (GWAS).

Question 24

What did Gandal et al. 2018 find about the genetics of BD?

Answer 24

Nothing unique about BD but common loci with ASD and SCZ, i.e. CD4: astrocyte-related module and glial cell differentiation. CD1, CD10 and CD13: neuronal/mitochrondrial (neuronal firing rate, energetic balance, and synaptic transmission).

Question 25

What is the heritability of BD?

Answer 25

Bipolar disorder - 85%, major depression - 37%. BD more highly heritable compared to MDD.

Question 26

What has neuroimaging shown about BD?

Answer 26

Not possible to diagnose through imaging only. However, in manic patients the OFC (orbital frontal cortex) is hypoactive – deficits in No Go Task – people suppose to respond to a stimulus, do an action and respond, and then should inhibit tendency to respond – shows abilities in executive function (BD have lack of this, response when they shouldn’t). Associated with impulsivity and difficulty in response inhibition. Feature associated with risk-taking, pressured speech.

Question 27

What has the pre-pulse inhibition task shown about BD?

Answer 27

Give two auditory stimuli, in healthy control they acknowledge first stimulus and respond much less to second stimulus (noticed it before, don’t have to respond again) – those with BD respond as if it is new to them, don’t inhibit startle stimulus in the same way as healthy controls. When a weak stimulus precedes a startle stimulus by ~100ms the normal response is to inhibit the startle. Euthymic patients with BD do not inhibit the startle either. Gating differences – which stimuli we allow to enter for processing.

Question 28

What does the HPA axis show about BD?

Answer 28

Leads eventually to decrease volume in hippocampus. Schloesser, Martinowich & Manji, 2012 – looked at hippocampal and amygdala volume in BD patients, those who receiving meds and those who weren’t. Those who weren’t receiving treatment seemed to have smaller hippocampus and amygdala, but if taking meds this was reversed.

Question 29

What are therapeutic goals for the treatment of BD?

Answer 29

Full treatment of symptoms, complete reinstatement of the psychosocial functioning of the person, and prophylaxis - prevention of relapse.

Question 30

What is drug therapy for BD?

Answer 30

Mostly drugs used - nothing else is really affective. Mood ‘stabilisers’ - lithium, anti epileptics (anticonvulsants), atypical antipsychotics. Adjuncts (as well as being given the above, get this also): modafinil, thyroid hormone (T3).

Question 31

How do mood stabilisers work?

Answer 31

Don’t know how they work. Share some common mode of action with the antidepressants. Lithium seems to act through second messenger systems to provide neurogenesis.

Question 32

How does lithium work?

Answer 32

Has direct effects on glutamatergic neural transmission - Alters neuronal excitability in hippocampus leading to enhanced excitatory postsynaptic potentials (EPSPs). Other mood stabilizers seem to enhance glutamatergic neurotransmission indirectly. Lithium exerts neurotrophic and neuroprotective effects (enhances BDNF and bcl2)

Question 33

How effective is lithium for BD?

Answer 33

It is effective for 60-80% of patients who respond within 1-2 weeks. The therapeutic window is very small so lithium blood levels should be monitored – can very easily do harm to the person who is taking the drug. Difference in the drug from affective to toxic is very slim.

Question 34

Does lithium have side effects?

Answer 34

Hand tremors, weight gain, excessive urine production, and thirst. Toxic doses: nausea, diarrhea, loss of motor coordination, confusion, and coma. There is no antidote (not an antagonist)– infusion with saline, stomach wash, etc. Non-compliance issues – many people stop taking it due to side effects.

Question 35

What is the combination of lithium and sodium?

Answer 35

Similar to sodium - abrupt fluctuations in concentration (e.g. increase salt etc) should be avoided. Big changes in the intake and loss of sodium should be avoided. If one loses high amounts of sodium due to intense sweating, lithium concentration increases.

Question 36

What is the effectiveness of lithium?

Answer 36

Effective in manic episodes but less effective in people with rapid cycling. Particularly effective in preventing suicide compared to valproate but valproate is more commonly prescribed. Lithium extends circadian rhythms – average 14min delay in sleep/wake rhythms.

Question 37

Is lithium safe to take during pregnancy?

Answer 37

Not recommended during pregnancy – high risk for abnormal development of the circulatory system. Considered to be teratogenic - lowest possible dose and close monitoring of baby, must interrupt a few days before giving birth – risk of abrupt increase in lithium. Breast feeding is not recommended while using lithium.

Question 38

What is valproic acid?

Answer 38

An anti convulsive drug. Believed to enhance GABA (increasing release or blocking reuptake), inhibiting sodium channels. Particularly effective in acute mania, mixed episodes, rapid cyclers and mixed but not depression. Also for those resistant to lithium. Combination of the two may be more effective in the prevention of manic episodes. Side effects: GI problems, weight gain, sedation, lethargy, tremor, hair loss, liver functioning, pancreatitis, cognitive problems.

Question 39

What are the effects of valproate in women?

Answer 39

Especially those that started taking it before the age of 20: Obesity, Polycystic Ovaries, Increased level of androgens, Cognitive functioning. Pregnancy:

	- Teratogen
	- Induce withdrawal symptoms in the symptoms. Has been linked to autism.

Question 40

What is carbamazepine (tegretol)?

Answer 40

Anticonvulsant, hypothesised to act by blocking voltage-sensitive sodium channels. Good for lithium-resistant patients (e.g. rapid cyclers, can be given alone or in combination to lithium.Equally effective to lithium in the prevention of episodes even though lithium is better when it comes to frequency - prophylactic efficacy.

Question 41

What are side effects of carbamazepine (tegretol)?

Answer 41

Mild sedation, GI dysphoria, ataxia, skin problems, nausea, tremor, weight gain, reduction in white blood cells. Interactions: Increases the function of cytochrome P450 (CYP3A4) (major family of enzymes, so may need to up dose to reach therapeutic effect) – increase of dose is required. Teratogen (nervous system).

Question 42

What is lamotrigine?

Answer 42

3rd generation anticonvulsant – considered first line drug for rapid cyclers and for depression in BD but not mania, yet, it is not FDA approved for Bipolar Disorder. Most likely acts on sodium channels. Generally well tolerated but it has side effects such as rashes, tremor, dizziness, headaches, nausea. In contrast to the other anticonvulsants it may improve cognitive functioning. Less negative effects on the fetus – preferred for pregnant women.

Question 43

How are atypical antipsychotics used as mood stabilisers?

Answer 43

Initially assumed to be effective for the psychotic symptoms of mania. Surprisingly, they turned out to be effective for the non-psychotic symptoms of mania and for the maintenance treatment to prevent mania, in a way similar to lithium and anticonvulsants. Some atypical antipsychotics are effective for bipolar depression.

Question 44

Can ketamine be used for treatment-resistant BD?

Answer 44

Ketamine seems to have success with treatment resistant depressed patients. Diazgranados et al 2010: Double blind placebo controlled study with treatment resistant BD found that ketamine was also successful! Again long-term efficacy and safety is unknown.

Question 45

What are compliance issues of ketamine?

Answer 45

Up to 50% interrupt their medications due to memory and other cognitive problems, weight gain, absence of a “high”. Interruption usually means that

	- the symptoms get worse
	- suicide rates increase dramatically. Alternative approaches: ECT, DBS etc.

Question 46

What is an overview of drug therapy for BD?

Answer 46

Today – a combination of drugs, a mood stabilizer + antipsychotic. Goal of treatment is prophylaxis – decrease episode severity and increase the inter-episode interval. Despite treatment many patients experience recurrent episodes. There is time lag to achieve efficacy – difficult when dealing with very severe depressive symptoms. Only a fraction of patients respond by the end of the first week (perhaps glutamatergic drugs).

Question 47

What is psychotherapy?

Answer 47

1990 - NIMH called for novel psychosocial treatments for BD. Psychotherapy – not as effective as in MDD. Psychoeducation – teaching the patients and their families about the disorder (more effective if family is involved) aims to enhance engagement. Strongest evidence supporting psychoeducation in the prevention of relapse in the early years after onset of BD. Psychosocial treatments especially lifestyle interventions. Regimes of stable and adequate sleep.