Bipolar Flashcards
Peak onset of Bipolar disorder
15-19y
(VS schizophrenia 23y)
Bipolar is a __________ mood disorder
Lifelong, cyclical mood disorder with variable course
- Recurrent fluctuations in mood, energy, behavior
- Note that it is usually dominated by depressive episodes (80%)
- Cycle frequency accelerates as illness progresses
Bipolar 1st episode presentation in males and females
Males - commonly manic episodes
Females - commonly depressive episodes
What is “rapid cycling”?
Rapid cycling
- 4 or more mood episodes of mania, hypomanic, or depressive episodes, within 12 months
Risk factors of bipolar disorder
- Genetics
- Treatment-induced mania (antidepressant, ECT)
- Induced by general medical conditions
- History of trauma - perinatal trauma, head trauma, physical abuse
- Physical stressors
- Seasonal changes
Antidepressant-induced mania
- Mechanism
- Onset
Mechanism is unknown: incr in NE and Dopamine transmission
Fast onset: initial few days to 2 weeks (as fast as 3 days)
Use of antidepressant increases the risk of developing mania/bipolar disorder (diagnosis: bipolar depression rather than MDD)
*Antidepressants can induce mania in 1-2 weeks or within 3 days, induce suicidality in 1-2 months
ECT-induced mania
- Mechanism
1 in 4 will switch from depressed to hypomania/manic mood due to the fast release of neurotransmitters from electrical stimulation in the brain
What are some medical conditions that induce mania?
CNS disorders
- brain tumor, stroke, head injuries, multiple sclerosis
CNS infections
- encephalitis, sepsis, HIV
Electrolyte or metabolic abnormalities
- calcium or sodium fluctuations, hyper or hypoglycemia
Endocrine or hormonal dysregulation
- cushing disease (incr ACTH, incr cortisol), hyperthyroidism
Vitamins and nutritional deficiencies
- amino acids, fatty acids, vit B
What are some medications/drugs that induce mania?
- Alcohol intoxication
- Drug withdrawal states (alcohol, a2 agonist, antidepressants, barbiturates, BZDs, opiates)
- Antidepressants
- DA-augmenting agents (CNS stimulants - amphetamines, sympathomimetics; DA agonists)
- NE-augmenting agents (a2 antagonist, B agonists, NE reuptake inhibitors)
- Steroids (esp systemic - cause anxiety, psychosis, depression)
- Thyroid preparations (T3 or T4)
- Xanthines (caffeine, theophylline)
- OTC weight loss and decongestants (ephedra - Ma huang, pseudoephedrine)
- St John Wort
Avoid agents that increases NE and Dopamine activity
Clinical presentation of bipolar disorder
*Key feature is history of mania/hypomania not caused by any other medical conditions/substances
- Abnormal and persistently elevated/expansive/irritable mood
- DIGFAST
- Distractability
- Irresponsibility
- Grandiosity
- Flight of ideas
- Activity increased (incr goal directed activity, or psychomotor agitation)
- Sleep need is decreased (*not the same as insomnia)
- Talkativeness (more talkative than usual, pressured speech)
Manic episode: at least 3 symptoms + elevated/expansive mood OR at least 4 symptoms + irritable mood
Duration of mood episode:
- Major depressive
- Manic
- Hypomanic
- Major depressive: >2 weeks + functional impairment
- Manic: >=1 weeks + functional impairment
- Hypomanic: >=4 days, no functional impairment, no psychosis
Bipolar I vs Bipolar II
Bipolar I - mania +/- depressive episodes
Bipolar II - hypomania + depressive episodes
General assessments
- History of present illness
- Psychiatric history – history of manic/hypomanic episodes - bipolar depression cannot use antidepressants, risk of manic switch
- Substance use – cigarettes, alcohol, substances
- Complete medical history and medication history (Drug allergy? Other medications? Compliance? Surgical history - thyroid glands etc.)
- Family, social, forensic, developmental, and occupational history (1st-degree FH of illness, treatment, and response; review psychosocial circumstances every visit)
- Physical and neurological exam (Injury? Esp head trauma?)
- Mental state exam (Suicidal, homicidal ideations and risks; Reassess MSE every interview to evaluate efficacy and tolerability)
- Labs and other investigations - Vital signs (BP, O2), weight, BMI, FBC, urea, electrolyte, creatinine, LFTs, TFTs, ECG, FBG, lipid panel, urine toxicology, pregnancy test
FBC: rule out anemia, infection
Kidney and Liver function: LFT not required for Lithium
TFTs: rule out hyperthyroidism - manic mood
ECG: cardiac abnormalities (lithium, antipsychotics - ziprasidone, haloperidol) may cause arrhythmias)
Urine toxicology: barbiturates, amphetamines, BZDs, cocaine, cannabinoids
Pregnancy test: valproate and lithium are teratogenic
PGx test: Carbamazepine
Exclude general medical conditions or substance-induced/withdrawal symptoms (e.g., psychosis, depression, mania, anxiety, insomnia)
Goals of treatment in bipolar disorders
- Reduce frequency, severity, and duration of mood episodes (since bipolar is lifelong)
- Prevent suicide
- Maximize adherence with therapy
- Minimize adverse effects
- Acute treatment phase: eliminate mood episode with remission of symptoms
- Maintenance/Continuation treatment phase: goals 1,2 + regain psychosocial functioning, avoidance of stressors or substances that may precipitate an acute mood episode
Non-pharmacological treatment in bipolar
Psychoeducation
- recognize early signs and symptoms of mania and depression
- chart mood changes (e.g., in diary)
- compliance
- psychosocial, physicals stressors, substances/drugs that may precipitate episode
- strategies for coping with stressful life events
- development of a crisis intervention plan
Psychotherapy
- e.g., CBT
Stress reduction techniques
- relaxation techniques
Sleep hygiene
- regular bedtime and awake schedule; avoid alcohol or caffeine intake prior to bedtime
Nutrition
- regular intake of protein-rish foods or drinks and essential fatty acids; supplemental vitamins and minerals
Exercise
- Regular aerobic and weight training at least 3x per week
Pharmacological treatment of bipolar disorder
- Short course of PRN benzodiazepines (adjunctive during acute phase)
- Start mood stabilizer for acute phase treatment
[Pharmacological treatment of bipolar disorder]
Short course of PRN benzodiazepines (adjunctive during acute phase)
- Use?
- Help patient relax and sleep
- Onset within hours
- Short-term symptom relief until mood stabilizers are effective
- Taper off when condition improved and mood stabilizer optimized
[Pharmacological treatment of bipolar disorder]
Start mood stabilizer for acute phase treatment
- List the mood stabilizer options
- Explain choice of mood stabilizer
Goal of acute phase treatment: eliminate mood episode with remission of symptoms, also protects from severe depression
Onset: within 3-5 days to stabilize mood (therefore short-term BZD required before mood stabilizers’ onset of effectiveness)
Mood stabilizers:
(Mania)
- Lithium
- Antipsychotics
- Valproate
- Carbamazepine
(Bipolar depression)
- Lithium
- Antipsychotics
- Lamotrigine
Choice of mood stabilizer based on:
- Response
- Tolerability
- Serum drug levels (TDM)
- Avoidance of DDIs
- Type and trend of mood episodes
- Suicide risk
[Pharmacological treatment of bipolar disorder]
Which antipsychotics may be used in mania?
All antipsychotics can be used for mania
SGA: Olanzapine, Quetiapine, Risperidone, Aripiprazole
(Ran Out Away Quiet)
FGA: Haloperidol
If pt gets well on SGA for acute phase mania, may continue that drug for maintenance, consider using LAI (R 2w) (A 1m)
For long-term maintenance treatment, only OAQ are licensed, the other SGAs and Haloperidol are off-label use in mania
FYI: antipsychotics may relieve agitation within an hour if used alone or with BZD for rapid tranquilization
[Pharmacological treatment of bipolar disorder]
Which is first line in mania?
- Lithium
- Antipsychotics
- Valproate
- Carbamazepine
Lithium is the 1st line for maintenance and relapse/suicide prevention
But if ineffective/poorly tolerated (due to lithium toxicities), Olanzapine/Quetiapine can be considered
Valproate is least preferred
Carbamazepine is last line
[Pharmacological treatment of bipolar disorder]
What combinations may be used in mania?
If monotherapy ineffective, consider:
- Lithium and/or Valproate +/- Antipsychotics
[Pharmacological treatment of bipolar disorder]
Which antipsychotics can be used in bipolar depression?
- Quetiapine
- Olanzapine + Fluoxetine (Symbyax capsule)
- Others (FYI): Lurasidone, Cariprazine
*Olanzapine alone has limited antidepressant properties
*Quetiapine may be sedating + orthostatic hypotension
*Recall Symbyax is also used in treatment-resistant depression
[Pharmacological treatment of bipolar disorder]
Which is first line in bipolar depression?
- Lithium
- Antipsychotics
- Lamotrigine
Lithium is 1st line for maintenance and relapse/suicide prevention
Lamotrigine has NO anti-manic properties
[Pharmacological treatment of bipolar disorder]
What combination can be used in bipolar depression?
Any combination:
- Lithium
- Olanzapine + Fluoxetine
- Quetiapine
- Lamotrigine
[Pharmacological treatment of bipolar disorder]
Maintenance therapy choice
- Lithium
- Antipsychotic for long-term maintenance: Olanzapine, Quetiapine, Aripiprazole are licensed; risperidone, haloperidol and others are off-label
[Lithium]
MOA
- Normalizes/inhibits second messenger systems, reduce protein kinase C
- decreases 5HT reuptake
- decreases dopamine release
[Lithium]
TDM
- Steady state: in 5 days
- Acute mania: 0.8 - 1.0 mEq/L
- Maintenance: 0.6-1.0mEq/L
Narrow therapeutic index
- Sampling time: take samples 12h after the previous dose; 5-7 days after initiation/dose changes/interacting drug
- Monitor serum lithium q3-6m in stable patients
*NOTE: aim lower therapeutic range for the elderly since they are more susceptible to side effects
[Lithium]
Side effects
Side effects are dose-dependent
Common SEs at >0.8mEq/L:
- Fine to coarse tremors
- Polyuria
- Hypothyroidism
- Cardiac effects (ECG changes)
- Nausea
- Weight gain
- Fatigue
- Cognitive impairment
- Diabetes insipidus
Mild (1.5-2.0 mEq/L)
- GI SEs: nausea, vomiting, loose stools
- CNS SEs: lethargy, confusion, coarse hand tremors, drowsiness, light-headedness
Moderate (2.0-2.5 mEq/L)
- GI SEs: severe nausea, vomiting, diarrhea
- CNS SEs: slurred speech, worsening confusion, ataxia, blurred vision, profound lethargy, tinnitus, apathy
Severe (>3.0 mEq/L)
- GI SEs: severe nausea, vomiting, diarrhea
- CNS SEs: seriously impaired consciousness, increase deep tendon reflexes, stupor, coma, seizures, death
Note that toxicity may increase from mild to severe within hours bc fluid and electrolyte loss cause further increase in lithium concentration)
[Lithium]
Counseling points
- Stomach upset/nausea - take with food
- Increased thirst and urination - sip enough water ~2L, but not excessively
- Tremors, nausea - inform Dr if worsens
- Weight gain - healthy diet, exercise
[Lithium]
- Drug interactions
Lithium toxicity (elevated lithium levels) with: STAND
- Sodium depletion
- Thiazide diuretics
- ACEi/ARBs
- NSAIDs
- Dehydration
- also: Fluoxetine
Others:
- Neurotoxicity when combined with lithium: carbamazepine, diltiazem, losartan, methyldopa, metronidazole, phenytoin, verapamil
- Enhance renal elimination of lithium: caffeine, theophylline
[Lithium]
Explain the mechanism of how sodium depletion causes lithium toxicity
Sodium depletion can be due to: diuretics use, salt restriction, excess water intake
Sodium and Lithium are small monovalent cations
In hyponatremia, kidney reabsorbs sodium and inevitably reabsorbs lithium back as well, thereby causing elevated lithium levels and thus lithium toxicity
[Lithium]
- Use in liver and renal impairment
lithium is NOT cleared by the liver, 100% cleared by kidneys
Therefore,
- Lithium can be used in liver impairment
- Caution for use in kidney impairment (half-life of lithium increases in elderly and renal impairment, may cause toxicity)
Note: lithium has no CYP interactions
[Lithium]
What labs/monitoring are required and why?
Physical exam (baseline):
- ECG, pregnancy test, urine toxicology
ECG (annually)
- For lithium if >40y or cardiac disease; as lithium may cause ECG changes
FBC (baseline, 6-12m)
Renal panel and electrolytes + calcium (baseline, q3m for 1st 6m, then q6-12m)
- Monitor low Na+ (risk of lithium toxicity due to sodium depletion)
- Monitor Ca2+ levels
- Renal impairment
TFT (baseline, q3m for 1st 6m, then q6-12m)
- Lithium may cause hypothyroidism
Metabolic - FBG, lipids, BMI (baseline, q3m for 1st 6m, then q6-12m)
- Lithium may cause weight gain, diabetes insipidus
TDM
[Lithium]
Use of lithium in pregnancy
Lithium is teratogenic - ebstein anomaly, fetal thyroid goiter
If pregnant patient is already on maintenance lithium:
- If risk of relapse is high, consider switching to SGA or lower dose of lithium (~0.3mmol/L) to keep recurrence risk low
Because lithium withdrawal causes relapse!
[Lithium]
Administration, bioavailability
Delayed absorption: 60-90%
Food may slow down absorption
[Sodium Valproate]
MOA
Increase GABA levels
Decrease dopamine turnover
May decrease protein kinase C
Normalize Na+ and Ca+ channels
Antikindling properties
[Sodium Valproate]
Loading dose of sodium valproate may be given, but often not done in clinical practice because…?
Benzodiazepine started while waiting for valproate onset
[Sodium Valproate]
TDM
- Steady-state: 3-5 days
- Target: 50-125mcg/mL
- Sampling time: trough sample needed, at least 2-3 days after initiation/changes in dose
TDM required (not routinely required for valproate unless evidence of poor adherence/effectiveness, or toxicity)
[Sodium Valproate]
SEs
- Hepatotoxicity in children
- Rash, SJS/TEN
- Alopecia
High dose:
- GI: nausea - take after food
- Decrease platelets (thrombocytopenia)
- Pancreatitis (abdominal pain)
- Dizziness, somnolence - take at bedtime
- Hyperammonemia
- Ataxia, tremor - if worsen, consult Dr
- Weight gain - healthy diet and lifestyle
[Sodium Valproate]
Metabolism
Metabolized by the liver => inactive metabolites
- Substrate of CYP2C19
- Inhibitor of CYP2C9, 2D6, 3A4, 3A3
Half-life longer in liver impairment
[Sodium Valproate]
Drug interactions
Risk of SJS with Lamotrigine
- Valproate decreases the clearance of Lamotrigine (incr Lamotrigine concentration)
[Sodium Valproate]
What labs/monitoring are required and why?
Physical exam (baseline):
- ECG, pregnancy test, urine toxicology
FBC (baseline, 1st month, q6m, then anually)
- Thrombocytopenia (dcr platelets)
LFTs (baseline, 1st month, q6m, then anually)
- Hepatotoxicity in children
Metabolic - FBG, lipids, BMI (baseline, 6-12m)
- Sodium Valproate may cause weight gain
TDM
[Sodium Valproate]
Use in pregnancy
- Contraindicated in pregnant women for bipolar disorder
- CI in women of childbearing potential, unless conditions of pregnancy prevention program fulfilled
If a pregnant woman is already on VPA,
- consider switching to SGA such as Olanzapine (watch for gestational diabetes)
[Carbamazepine]
MOA
Increase glutamate transport
Block voltage-sensitive Na+ channels
(SODIUM CHANNEL ONLY)
[Carbamazepine]
TDM
- Target >7mg/L for bipolar (VS 4-12mg/L for epilepsy)
- Sampling: trough
- Steady-state: 2-4 weeks (due to autoinduction), look out for toxicity in first 4 weeks
- After initial 4 weeks, steady-state achieved after 3-5 days
Monitor
- q6m for 1st year, then annually
[Carbamazepine]
SEs
- GI: constipation - sip water
- Dry mouth - sip water
- CNS: somnolence - take at bedtime; dizzy - rise up slowly
- Hyponatremia (worse with Oxcarbazepine) => worsen seizure
- Blood dyscrasias (esp aplastic anemia) (agranulocytosis with Clozapine)
- Rash, SJS/TEN - see Dr immediately
- Fever/sore throat - see Dr immediately
[Carbamazepine]
PK - metabolism
Hepatic metabolism
- active metabolite: 10,11-epoxide
- autoinduction (3A4, 2C9)
- inducer of CYP1A2, 2C9, 3A4
- substrate of CYP2C8, 3A4
[Carbamazepine]
Drug interactions
Agranulocytosis with Clozapine
CYP interactions (inducer)
[Carbamazepine]
What labs/monitoring are required and why?
HLA-B*1502 allele
Physical exam (baseline):
- ECG, pregnancy test, urine toxicology
FBC (baseline, 6-12m)
- agranulocytosis
LFTs (baseline, 6-12m)
Electrolytes and renal panel
- Hyponatremia - repeat 2w after initiation, q1m for first 3m
TDM
[Lamotrigine]
MOA
Blocks voltage-sensitive Na+ and Ca+ channels
[Lamotrigine]
TDM
NIL
[Lamotrigine]
SEs
- Rash, SJS/TEN (esp in initial 8w, slow titration, incr dose 2 weekly intervals) - see doctor immediately
- GI: nausea - take with food
[Lamotrigine]
Lamotrigine may be preferred because:
- less sedation
- less weight gain
- safer choice in pregnancy
[Lamotrigine]
Interactions
SJS risk with Valproate
- Valproate increases concentration and half-life of Lamotrigine
- Max 100mg Lamotrigine (dose 50-200mg/day) if combined with VPA
[Lamotrigine]
Metabolism
Hepatic metabolism
- half life longer in hepatic impairment
[Lamotrigine]
What labs/monitoring are required and why?
Physical exam (baseline):
- ECG, pregnancy test, urine toxicology
FBC (baseline only)
LFTs (baseline, 6-12m)
Electrolytes and renal panel (baseline only)
[Antipsychotics]
- MOA
- SE
- Labs, monitoring
MOA:
- dopamine antagonist
- (SGA) 5HT2A antagonist
SEs:
- EPSE
- Incr prolactin
- Metabolic SE: weight gain
Labs, monitoring:
- ECG
- FBG
- Lipid panel
Relatively safe in pregnancy, just watch for gestational diabetes with Olanzapine, mod - Quetiapine
[Treatment approaches to manage POOR response]
- Augmentation
- Switching
If mania has not responded within 2-4 weeks, consider:
- augment with second agent (partial response)
- switch to SGA (no response or intolerable)
Carbamazepine is considered if all of the above failed
[Treatment approaches to manage POOR response]
What non-pharmaco can be considered?
ECT
- rapidly reduces manic/depressive symptoms in severe or treatment-resistant mania/depression
- maintenance ECT can also be considered (esp an option in pregnancy)
Define treatment-resistant bipolar disorder
For Bipolar Disorder, “resistance” is considered following treatment trials for at least 6 weeks in mania, 12 weeks in bipolar depression, and 12 months or more for long-term maintenance treatment
“Treatment-resistance” refers to refractoriness to multiple trials of different mood stabilisers.
Treatment resistance in Bipolar Disorder should be referred to a specialist. (i.e. Undergrad students are not expected to advise on its treatment)
ECT
- What drugs should be omitted prior to ECT?
Omit Lithium, Anticonvulsants, Benzodiazepines (at least 12h) before ECT
(Due to cognitive side effects such as delirium)
Treatment option in bipolar disorder with rapid cycling (4 or more mood episodes per year)
- Avoid antidepressants/stimulants in rapid cycling or history of antidepressant-induced mania
- For antidepressant-induced rapid cycling, avoid and taper off antidepressants and other agents that increase NE or dopamine activity (e.g., CNS stimulants, sympathomimetic, caffeine)
- Evaluate and treat underlying conditions (e.g., hypothyroidism, hormonal imbalance, substance abuse)
- Optimize mood stabilizer treatment: Valproate, Lithium Lamotrigine
[Special populations]
Pregnancy
- Avoid valproate (risk of neural tube defects)
- Avoid lithium (ebstein anomaly, fetal thyroid goiter)
- Avoid carbamazepine (malformation risk)
- Safer options: antipsychotics (quetiapine, olanzapine, risperidone), ECT for severe mania
Refer to specialist for pregnant pt or pt planning pregnancy
[Special populations]
Women of childbearing age
For females of child-bearing potential who requires a mood stabiliser for Bipolar Disorder:
- Avoid Valproate
- Also avoid Carbamazepine (as this is not first-line option anyways)
- Lithium, Lamotrigine and SGA are reasonable options for the non-pregnant patient
[Special populations]
Breastfeeding
All mood stabilizers secreted in breastmilk, weigh risk vs benefits
[Special populations]
Liver impairment
Lithium
- 100% cleared renally, not affected by hepatic impairment
[Special populations]
Renal impairment
Consider Valproate
- Monitor serum levels closely
[Special populations]
Cardiac disease
Consider Valproate
- Monitor BP, HR, peripheral edema
[Special populations]
Children, Adolescents
Consider Lithium, Valproate
[Special populations]
Elderly
Consider Lamotrigine
All psychotropics increase risk of side effects (anticholinergic, sedation)
Avoid renally-excreted drugs (e.g., Lithium)
Avoid Carbamazepine (hyponatremia, DDIs)
[Special populations]
Suicidal behavior
Optimize dose and levels of Lithium
[Special populations]
Aggression/Violence
Optimize dose and levels of existing Lithium or Valproate, consider adding antipsychotic
(Combi)
Which drug option is safest as there is less propensity for acute overdose?
Antipsychotics
Evaluation of therapeutic outcomes
Therapeutic outcomes require regular monitoring by clinician
- Initially 2 weekly, then monthly, then 3 monthly when stabilized
Pts and caregiver should actively monitor for:
- Target symptoms
- Efficacy of treatment
- Adverse effects and drug interactions
- Compliance
