Mood Flashcards
According to the CANMAT bipolar guidelines, what are the 4 first line agents for maintenance therapy?
How about for rapid cycling?
The agents are: Lithium, Divalproex, Olanzapine and Lamotrigine (if patient has mild manias and mainly depression). For
rapid cycling, only divalproex and lithium are 1st line (olanzapine monotherapy is 2nd line)
ADs with increased risk of manic switch?
TCAs and venlafaxine
Anxious distress severity
* Mild - 2 sx * moderate - 3 sx * mod-severe: 4-5 sx * severe: 4-5 sx + agitation
Anxious distress
≥ 2 sx: * tense * restless * diff. [] 2nd worry * fear something bad will happen * fear might lose control of self
Atypical features specifier - DSM criteria
* mood reactivity * ≥ 2 of {wt gain/increased appetite, , hypersomnia, leaden paralysis, long-standing rejection sensitivity} * NO melancholia or catatonia in same episode
BD comorbidities
Anxiety Disorders (most frequent, in 75% of individuals)
o Increased risk of suicide, longer time to recovery, increased risk of relapse.
Alcohol Use Disorders (More than 50% of individuals with bipolar I, F>M, females with bipolar I or II disorder have much higher rates of alcohol use disorder than females in the general population)
Other Substance Use Disorders (5xRR nicotine use disorder)
ADHD
Conduct Disorder
Eating Disorders, both Anorexia and Bulimia Nervosa (F>M)
Borderline Personality Disorder
Medical Conditions: type 2 diabetes, metabolic syndrome (2xRR),
cardiovascular disease (5x RR), hypertension (5x RR), migraine (nearly 25%,
bipolar II > bipolar I)
BD course and prognosis
90% of individuals with a single manic episode go on to have recurrent mood
episodes.
Untreated manic episode lasts about 3 months (K&S) or 13 weeks (CANMAT)
As the disorder progresses, the time between episodes often decreases and
there is less inter-episodic remission - after about five episodes the interepisode
interval often stabilizes at 6 to 9 months.
o 5-15% will be classified as rapid cyclers
BD in the elderly
Have greater levels of cognitive dysfunction than age-matched control subjects.
In post-hoc subgroup analyses, quetiapine is effective in mania
Open-label study found adjunctive lamotrigine to be effective in bipolar I and
bipolar II depressive symptoms
BD prognostic factors
Manic episode with psychotic features is predictive of subsequent episodes with
psychotic features.
o Incomplete inter-episode recovery is more common with moodincongruent psychotic features.
Mixed episode is associated with:
o Poor outcome, increased suicidal risk, and substance abuse/
Lifetime risk of suicide is estimated to be 15-times that of the general
population, may account for 25% of all completed suicides.
o Lifetime risk of suicide is 15% (London Review)
o Past history of suicide attempt, percent days spent depressed in the
past year, alcohol use, and comorbid anxiety disorder are associated
with greater risk of suicide attempts or suicide completion.
o Patients w/ bipolar II disorder may have greater risk of both attempting
and completing suicide than patients with Bipolar I and MDD (K&S)
Individuals perform more poorly than healthy individuals on cognitive tests.
Cognitive impairment occurs throughout the lifespan even during euthymic
periods.
o Even when euthymic cognition 0.7 SD below age matched controls
(London Review)
o Cognitive deficits especially in the domains of attention, verbal memory,
executive function, and information processing speed.
o Cognitive impairment in bipolar II is as severe as in bipolar I, with the
exception of memory and semantic fluency.
Occupational impairment - 30% show severe impairment in work role function,
individuals with bipolar disorder have lower socioeconomic status despite
equivalent levels of education.
Functional recovery lags behind recovery of symptoms
Low level of comorbidity and later onset predict a better outcome
BD treatment in children
Lithium approved ≥ age 12
Atypical antipsychotics improved include:
o Quetiapine for acute manic/mixed episodes in pediatric populations
o Risperdal
o Aripiprazole
o Olanzapine (?second line due to metabolic effects)
Anticonvulsants are not approved by the FDA
o Divalproex has increased risk of PCOS in females under 20 years
Before prescribing antidepressants, explain:
(1) Time lag to antidepressant effect
(2) Common and serious adverse events
(3) Need to continue medication even when feeling better
Bipolar I avg age of onset
18yo
Bipolar I course
* >90% recurrence of mood episodes * ~60% of manic episodes occure right before MDE * high income > low income countries * FHx - strongest risk factor * psychotic features predict future psychotic features * mood-incongruent psychosis –> incomplete recovery
Bipolar I epi (12mo prevalence, gender ratio)
* 12mo prevalence: 0.6%
* M:F = 1.1 : 1
Bipolar I OR II specifiers
* anxious distress * mixed features (≥3 sx of MDE most days during (hypo)manic episode) * rapid cycling (≥4 episodes of any mood in 12 months) * melancholic features (for MDE or mixed) * atypical features (MDE or mixed) * psychotic features * catatonia * peripartum onset * seasonal pattern
Bipolar II age of onset
avg age mid-20s
Bipolar II course
* often starts with MDE * higher lifetime episodes than BD I
Bipolar II prevalence
* 12mo prev: 0.3-0.8%
Bipolar II risk/prognostic factors
* FHx of BD II (not so much MDE/BD I) most predictive * rapid-cycling –> worse prognosis * younger, less severe –> return to baseline fxn * education, less duration, married –> assoc with recovery * F more likely to have mixed or rapid-cycling * 1/3 suicide attempts; more lethal than in BD I
Candidate genes for BD
COMT (psychotic symptoms), BDNF (cognitive
impairment and rapid cycling) , DISC1, CLOCK,
Replicated GWAS studies have implicated CACNA1C (an L-type calcium
channel) and ANK3 (a voltage gated sodium channel)
Carbamazepine dosing
Initial: 200mg PO BID
Range: 400mg - 1600mg
Maximum: 1600mg per day
Carbamazepine side effects
Mild:
(1) Sedation
(2) Headache
(3) Nausea, Vomiting, Diarrhea
(4) Dizziness
(5) Tremor (3%)
Serious:
(1) Leukopenia
Tends to occur in the first three months of initiating treatment
Estimated incidence is 10-20% during this period
Usually resolves on carbamazepine cessation
(2) Agranulocytosis and aplastic anemia
Rarer than leucopenia
Occur in an unpredictable pattern with a more rapid onset
(3) Hyponatremia
SIADH likely main cause
(4) Acute Hepatitits
Immune-mediated
Tends to occur early in treatment (within first eight weeks)
(5) Stevens-Johnson Syndrome (<10%) / SJS/TEN Overlap Syndrome (10-30%) / Toxic
Epidermal Necrolysis (>30%)
Prodromal flu-like systemic symptoms
Mucosal surfaces affected
Characteristic lesions with target-like appearance
1.4 / 10 000 (incidence: lamotrigine > carbamazepine > divalproex)
(6) Osteoporosis / Reduced Bone Density
(7) Drug interactions, including OCP. Recommend using IUD or barrier methods
Mild Weight Gain
Clinical features predictive of BD
- Early age of onset
- Psychotic depression before 25 years old
- Postpartum depression, especially with psychotic features
- Rapid onset and offset of depressive episodes of short duration (<3m)
- Recurrent depression (more than 5 episodes)
- Depression with marked psychomotor retardation
- Atypical features (reverse vegetative signs)
- Seasonality
- Bipolar family history
- High density, three generation pedigrees
- Trait mood lability (cyclothymia)
- Hyperthermic temperament
- Hypomania associated with antidepressants
- Repeated (at least 3 times) loss of efficacy of antidepressants after initial response
- Depressive mixed state (with psychomotor excitement, irritable hostility, racing thoughts and sexual arousal during major depression)
Comorbidities in MDD
Substance Use Disorders, especially Alcohol Use Disorder
Anxiety Disorders, especially panic disorder, social phobia and GAD
OCD
Eating Disorders, both Anorexia and Bulimia Nervosa
Borderline Personality Disorder
Contraindications to lithium
Significant renal impairment
Severe dehydration or electrolyte imbalance
Significant Cardiac Impairment
Psoriasis - Relative Contraindication
Contraindications to psychotherapy in acute phase MDD
Severely suicidal patient
Psychotic depression
Contraindications to rTMS
o Presence of ferromagnetic material in head (cochlear implants, brain
stimulators, electrodes, clips, plates, etc.)
o Cardiac pacemakers
o Increased ICP
o Severe Cardiovascular Disease
o Epilepsy
o Serious Medical Conditions
Contraindications to valproate
Hepatic disease
Cyclothymic d/o course
insidious onset, persistent course
Cyclothymic d/o criteria
* >2 yrs of numerous periods of hypomanic or depressive Sx not meeting criteria for episode * Sx periods present for >50% of the time *
Cyclothymic d/o epi
* lifetime prev: 0.4-1% * M=F
Cyclothymic d/o risk factors
* MDD, BD I and II in 1st degree relatives * increased familial risk of substance use
DBS - how is it applied?
Involves stereotactic neurosurgical implantation of electrodes under MRI
guidance
Following surgery, need to wait 7-14 days before the device is switched on to
allow the localized edema to resolve
Subcallosal cingulate gyrus (SCG) is site that has been evaluated the most
Two additional sites, the nucleus accumbens and ventral caudate / ventral striatum
region have also been examined
DBS level of evidence
Level 3 acute efficacy, Level 3 relapse prevention, Level 3 safety and tolerability
DDx of MDD (medical, substance, psychiatric, other)
(1) Medical Conditions: Especially
A. Hypothyroidism
B. Cushing’s Disease or Addison’s Disease
C. Anemia, Vitamin B12 or Folate Deficiency
D. Infectious Etiology: Mononucleosis, HIV, etc.
E. Pancreatic cancer, brain tumours and other neoplasms
F. Epilepsy (especially with right-sided focus)
G. CVA (especially left frontal)
H. Multiple Sclerosis
I. Parkinson’s Disease
(2) Substance Induced
A. Stimulants (catecholamine depletion, withdrawal): Amphetamine, MDMA, Cocaine
B. Sedatives: Alcohol, Benzodiazepines, Barbiturates
C. Medications: Glucocorticoids, Tetrabenazine, centrally acting antihypertensive
(reserpine, methyldopa), sedative-hypnotics, antiparkinsonian drugs (e.g. L-Dopa)
(3) Normal Sadness
(4) Adjustment Disorder with Depressed Mood
(5) Dysthymia
(6) Bipolar I and Bipolar II Disorder
(7) Schizoaffective Disorder
Differential diagnosis for BD
(1) Medical Conditions: Especially
A. Hyperthyroidism
B. Cushing’s Disease
D. Infectious: HIV, Syphilis
F. Epilepsy (especially with left-sided focus)
G. CVA (especially right frontal)
H. Multiple Sclerosis
(2) Substance Induced
A. Stimulants: Amphetamine, Methamphetamine, Cocaine, Caffeine, Nicotine
B. Sedatives: Alcohol, Benzodiazepines, Barbiturates (withdrawal)
C. Medications: Glucocorticoids, Antidepressants, ECT, rTMS
(3) Attention Deficit Hyperactivity Disorder: Many symptoms overlap with mania
including rapid speech, racing thoughts, distractibility and less need for sleep. Double
counting of symptoms can be avoided by determining whether symptoms represent a
distinct episode and noticeable increase over baseline must be present. Furthermore,
onset of symptoms is in childhood in ADHD, whereas childhood onset is rare in bipolar
disorder.
(4) Borderline Personality Disorder: Mood lability and impulsivity are common in both
conditions. Symptoms must represent a distinct episode and noticeable increase over
baseline must be present. Diagnosis of a personality disorder should not be made during
an untreated mood episode.
(5) Major Depressive Disorder: Sometimes also accompanied by subthreshold hypomanic
or manic symptoms, should be differentiated from bipolar disorder. Also need to ensure
that patients presenting with MDD have not had history of mania or hypomania.
(6) Other Bipolar Disorders: Need to differentiate bipolar I from bipolar II as well as
cyclothymia, other specified bipolar disorders, etc.
(7) Generalized Anxiety Disorder: Anxious ruminations may be mistaken for racing thoughts.
(8) Disruptive Mood Dysregulation Disorder: Severe irritability in children and
adolescents is not diagnostic of mania, distinct episode is needed
Disruptive mood dysregulation disorder - criteria
temper outbursts: - severe and recurrent - ≥ 3x/week - inconsistent with dev. level - irritable most of the time - >12 months - >2-3 settings _ 6-18yo - no manic symptoms >1 day
Divalproex side effects
Mild:
(1) Sedation
(2) Nausea, Vomiting, Diarrhea
(3) Weight Gain
(4) Hair Thinning / Loss (up to 12%)
(5) Tremor
(6) Benign Rash
(7) Benign hepatic transaminase elevation
Serious:
(1) Thrombocytopenia
Dose-dependent - occurs at higher doses and blood levels
Develops over months after initiating treatment
Tends to resolve with dose reduction
Clinically significant bleeding with severe thrombocytopenia <50 000
(2) Hepatotoxicity
Non-immune mediated
Occurs within first 3-6 months of treatment
More common in young children
(3) Acute Pancreatitis
Presents with abdominal pain, abdominal distension, vomiting, or fever
Can be fatal
(4) Hyperammonemic Encephalopathy
Symptoms include confusion, reduced LOC, irritability, agitation, vomiting,
lethargy, and seizures
Develops within days or weeks typically, but can even occur after years
Unrelated to valproate dose or serum levels
Can be fatal, need to discontinue drug to treat
(5) Polycystic Ovary Syndrome
Hyperadrogenism (hirsutism, acne, alopecia)
Chronic Anovulation (oligomenorrhea or amenorrhea)
Polyscystic Overaies on Ultrasonography
Can lead to infertility and metabolic syndrome
Risk of 10.5% in women treated with divalproex
NICE guidelines recommend avoidance of valproate use in women under 18
(6) Stevens-Johnson Syndrome (<10%) / SJS/TEN Overlap Syndrome (10-30%) / Toxic
Epidermal Necrolysis (>30%)
Prodromal flu-like systemic symptoms
Mucosal surfaces affected
Characteristic lesions with target-like appearance
0.4 / 10 000 new users (incidence: lamotrigine > carbamazepine > divalproex)
(7) Osteoporosis / Reduced Bone Density
(8) Interaction with aspirin and warfarin
ASA increases free fraction of serum valproate and decreases clearance - up to 4-fold increase in valproate level and valproate increases unbound fraction of warfarin
Valproate can also effect platelet aggregation, which further excerbates these interactions
DMDD cannot coexist with the following diagnoses
ODD (give Dx of DMDD)
Bipolar disorder (give dx of BD)
Intermittent explosive disorder
Note: CAN coexist with conduct d/o, MDD, ADHD etc
Does combining ECT and ADs increase therapeutic effect?
No
ECT - how do you calculate the initial stimulus, best dose, sz threshold?
Full age method, use mC = age * 5, half age method mC = age * 2.5
o Seizure threshold increases during the course of ECT from 25 to
200%
o Men and older adults have higher seizure thresholds
o Doses of three times the threshold are the most rapidly effective
(K&S)
o Minimal suprathreshold dose causes the fewest and least severe
cognitive adverse events
ECT contraindications
No absolute contraindications
o Heart - pre-ECT ECG for everyone, cardiology consultation in high risk pt
Recent Myocardial infarction - high risk, although risk greatly
diminished two weeks after MI and even more so after 3 months
Hypertension should be stabilized with antihypertensives before
ECT is administered
Cardiac Arrhythmias
Abdominal Aortic Aneurysm
o Brain - neurosurgery consultation recommended in high risk patients
Space occupying lesion - increased risk for edema & herniation
after ECT
Increased ICP - at risk for bleeding during ECT due to increased
cerebral blood flow during the seizure, need to control blood
pressure
o Anaesthetic Hypersensitivity
ECT electrode placement - positions, effects
Bitemporal - 1.5 to 2.5 times threshold, faster in improving symptoms
and more effective than unilateral but associated with more cognitive
effects. Also some evidence that right unilateral suprathreshold is as
effective and associated with fewer side effects.
o Bifrontal - 1.5 to 2.5 times threshold, as effective as bitemporal and
associated with less cognitive side effects
o Unilateral - 6 times above seizure threshold, fewer side-effects
ECT indications
Level 1 Indications:
Acute Suicidal Ideation (level 1)
MDE with psychotic features (level 1)
Treatment resistant depression (level 1)
o Level 3-4 Indications:
Catatonia (level 3)
Prior Favourable Response (level 3)
Repeated Medication Intolerance (level 3)
Rapidly Deteriorating physical status (level 3)
Patient choice (level 3)
During pregnancy for any of these indications (level 3)
ECT stimulus parameters
o Current (500 to 800 mA) o Frequency (20 to 120 Hz) o Pulse Width (0.25 to 2 ms) o Duration (0.5 to 8 or more seconds)
Factors supporting long-term (>2 years to lifetime) antidepressant maintenance
(1) Older age
(2) Recurrent Episodes (3 or more)
(3) Chronic episodes
(4) Psychotic Episodes
(5) Severe episodes
(6) Difficult to Treat Episodes
(7) Significant Comorbidity (psychiatric or medical)
(8) Residual Symptoms
(9) History of recurrence during discontinuation of antidepressant
Some evidence maintenance dose should be same as dose that led to improvement
FASTER-D (bipolar sx)
- *F**light of ideas
- *A**ctivity that is goal-directed increased or Agitated psychomotor-wise
- *S**leep Need Decreased
- *T**alkative or pressured speech
- *E**steem increased or grandiosity
- *R**isky Behaviours
- *D**istractible
Finding the site for optimal stimulation for rTMS?
Identify site for optimal stimulation of abductor pollicis brevis and then measure 5
cm anteriorly along the skull surface in a parasagittal line to locate site for
stimulation (DLPFC on either side)
First line for BD I depression
Monotherapy:
Lithium
Lamotrigine
Quetiapine or Quetiapine XR (4 RCTs: BOLDER I+II, EMBOLDEN I+II)
Combinations and Adjuncts:
Lithium and Divalproex
Lithium or Divalproex + SSRI (except paroxetine)
Lithium or Divalproex + Bupropion
Olanzapine and SSRI (except paroxetine, esp. fluoxetine)
First line for BD II depression
Quetiapine and Quetiapine XR
First line in BD II maintenance
Lithium
Lamotrigine
Quetiapine
First line pharmacotherapy for BD I acute mania
Monotherapy:
Lithium
Divalproex or Divalproex ER
Quetiapine or Quetiapine XR
Olanzapine
Risperidone
Aripiprazole
Ziprasidone
Asenapine
Paliperidone ER
Adjuncts:
Atypical Antipsychotics except Ziprasidone and Paliperidone (negative level 2
evidence for these two) in addition to Lithium or Divalproex
First line psychotherapy for acute phase MDD
(1) Cognitive Behavioural Therapy (level 1)
(2) Interpersonal Therapy (level 1)
First-line add-on agents in MDD
Aripiprazole (level 1)
Lithium (level 1)
Olanzapine (level 1)
Risperidone (level 2)
First-line antidepressants in breastfeeding
Citalopram
o Sertraline
o Paroxetine
o Nortriptyline
Avoid fluoxetine as infants exposed to fluoxetine have higher risk of having
elevated serum levels
First-line antidepressants in children
In children, fluoxetine and citalopram are first-line antidepressants with the best
benefit-risk evidence
o Antidepressants carry 1.5-2 fold risk of increasing suicidal thoughts and
behaviors in children with NNH of 143 - 2004 blackbox warning has
been extended to young adults age 18-24.
o Venlafaxine has higher risk estimate for suicidality and is a third-line
antidepressant in children.
Best outcomes in children have resulted from combining antidepressants with
CBT.
First-line for BD I maintenance
Monotherapy:
Lithium
Divalproex or Divalproex ER
Quetiapine or Quetiapine XR
Lamotrigine (effective at preventing depression)
Olanzapine (effective at preventing mania)
Aripiprazole (effective at preventing mania)
Riperidone Consta / Long Acting Injection (effective at preventing mania)
? Ziprasidone (in text, but not in table 5.5, effective at preventing mania)
Combinations and Adjuncts:
Adjunctive Quetiapine, Aripiprazole, Risperdal LAI, and ziprasidone (adjunctive
olanzapine and risperdal are second line)
First-line pharmacotherapy for MDD
(+ evidence of superiority)
(1) Agomelatine
(2) Bupropion
(3) Citalopram
(4) Desvenlafaxine
(5) Duloxetine,
(6) Escitalopram
(7) Fluoxetine
(8) Fluvoxamine
(9) Mianserin
(10) Milnacipran
(11) Mirtazepine
(12) Moclobemide
(13) Paroxetine
(14) Reboxetine
(15) Sertraline
(16) Tianeptine
(17) Venlafaxine
First-line psychotherapy for maintenance phase in MDD
CBT,
MBCT (2016)
First-line switch agents with evidence of superiority in MDD
Escitalopram (level 1)
Sertraline (level 1)
Venlafaxine (level 1)
Mirtazepine (level 2)
Milnaciprin (level 2)
Duloxetine (level 2)
Frequency and duration of rTMS?
Usually 5 sessions are delivered per week, most trials have been 4-6 weeks in
duration
Frequency of acute phase ECT for MDD?
3 times per week -> faster onset of action
2 times per week -> less cognitive side effects
Gender differences in BD I and II
1.1:1 M:F ratio (DSM-5), 1:1 M:F(K&S)
o Females are more likely to have rapid cycling, mixed states, also more likely to have depressive symptoms and are also more likely to have bipolar II diagnosis
How do you differentiate the Baby Blues from Post Partum Depression?
Baby Blues
30 to 75% of women who give birth
Onset after 3 – 5 days post partum
Lasts days to weeks
No identifiable stressors
No family history
No personal history of mood disorder
No anhedonia
Absent or mild guilt
Rarely infanticidal and suicidal thoughts
Occassional sleep disturbance
Postpartum Depression 10-15% of women who give birth Onset between 3 to 6 months Lasts months Lack of social supports is usually a stressors Often family history of mood disorders Often personal history of mood disorder Often anhedonia Guilt usually present and excessive Suicidal and infanticidal thoughts can be present Frequent sleep disturbance
How is rTMS delivered?
rTMS is delivered in trains lasting for several seconds followed by inter-train
intervals, several trains can be delivered per session.
How many patients with BD start with a depressive episode?
75% of thetime in women,
67% of the time in men
Hypomanic episode criteria
* mood AND energy x >4 days * ≥3 of {grandiosity, sleep, talkative, flight of ideas, distractibility, goal-directed/agitation, painful consequences} * uncharacteristic change in fxn
Initial measurements for monitoring in BD
tial Measurements:
BMI (kg/m2) & Waist Circumference
Blood Pressure
Fasting Glucose
Fasting Lipid Profile (Triglycerides, LDL, HDL, total cholesterol)
CBC / Electrolytes / BUN and Creatinine
Liver Function Tests
Beta-HCG, also ensure appropriate contraception in all patients
(Serum Levels of Lithium and Divalproex) (TSH) (Ca) (Coagulation studies, Urine Toxicology, Urinalysis, Prolactin, ECG if over 40)
Lab workup for MDD
Core workup: CBC, Electrolyes, Creatinine / BUN, Liver Enzymes, TSH, Beta-HCG (if
female)
Specific Workup:
Urine Toxicology for Substance Abuse
Blood Toxicology
Serology for EBV or HIV
Vitamin B12 and Folate
24 hour urine cortisol
Neuroimaging
Lab workup in BD?
Core workup Plus: CBC, Electrolyes, Creatinine / BUN, Liver Enzymes, TSH, BetaHCG (if female) + BMI (kg/m2) & Waist Circumference, Blood Pressure, Fasting
Glucose, Fasting Lipid Profile (Triglycerides, LDL, HDL, total cholesterol)
(Serum Levels of Lithium and Divalproex) (TSH) (Ca) ECG for patients over 40
Specific Workup:
Urine Toxicology for Substance Abuse
Blood Toxicology
Serology for HIV and Syphilis
24 hour urine cortisol
Neuroimaging
EEG
Lamotrigine dosing
Regimens not containing carbamazepine, phenytoin, phenobarbital, primidone, rifampin, lopinavir/ritonavir, or valproic acid:
o 25mg PO daily Weeks 1 and 2
o 50mg PO daily Weeks 3 and 4
o 100mg PO daily Week 5
o 200mg PO daily Week 6 and maintenance
Regimens containing valproic acid:
o 12.5mg PO daily or 25mg every other day Week 1 and 2
o 25 mg PO daily Weeks 3 and 4
o 50mg PO daily Week 5
o 100mg PO daily Week 6 and maintenance
Lamotrigine side effects
(1) Benign Rash
8.3% of patients
(2) Stevens-Johnson Syndrome (<10%) / SJS/TEN Overlap Syndrome (10-30%) / Toxic
Epidermal Necrolysis (>30%)
Prodromal flu-like systemic symptoms
Mucosal surfaces affected
Characteristic lesions with target-like appearance
Occurs in 2.5/10 000 new users (incidence: lamotrigine > carbamazepine > divalproex)
Concurrent valproate increases levels of lamotrigine due to its inhibition of hepatic glucuronidation, this increases risk of SJS
Also more likely in children under 16 years
(3) Sedation
(4) Nausea / Vomiting / Diarrhea
Weight Neutral
Lifetime risk of suicide in BD
15%
Evidence indicates that patients with bipolar II are at greater risk of both attempting and completing suicide tha patients with bipolar I and MDD
Lithium and ECT - effects, management
Lithium may increase post-ictal confusion and delirium, most
practitioners omit one or two doses prior to each ECT session
Lithium dosing and target levels
Dosing - Guided by Plasma Levels
Initial: 300mg PO BID or TID
Range: 900 - 1800mg (once daily or divided BID - QID)
Maximum: 1800mg (UptoDate) 2400 mg (CHOP-D (daily or divided BID - QID)
Usual target lithium levels are
0.8-1.2 mmol/L for treatment of acute mania
0.6-1.0 mmol/L (some recommend 0.8-1.2 as well) for maintenance treatment
Levels should not exceed 1.5, which is the range for toxicity (although toxicity is
a clinical diagnosis and can occur at any serum lithium level)
≥ 2.5 mmol/L is a medical emergency
Lithium monitoring
2 consecutive therapeutic lithium levels (5 days after dose titration and 12
hours after last dose) to establish therapeutic dose
Levels q3-6 months
Renal Function Tests q3-6 months
TSH, Ca, Weight at 6 months and then qYear
Also monitor for signs of lithium toxicity
Lithium side effects
Mild:
(1) Sedation
(2) Nausea / Vomiting / Diarrhea
(3) Fine Tremor
(4) Dry mouth , Excessive Thirst (Polydipsia)
(5) Acne
(6) Cognitive Impairment
Severe:
(1) Chronic Renal Disease
Glomerular and Tubulointerstitial Nephropathy, Nephrotic Syndrome, Renal
Failure.
Longer duration and higher cumulative doses may be risk factors, in addition
to hypertension, DM, use of other nephrotoxic drugs, prior lithium toxicity,
and nephrogenic diabetes insipidus
(2) Nephrogenic Diabetes Inspidius:
Impaired renal concentrating capacity due to distal renal tubule insensitivity to
ADH
Manifests as polyuria and polydipsia
Causes nephrogenic DI through dysregulation of aquaporin 2
Longer duration of treatment and use of other psychotropic agents are risk
factors.
Lithium is the most common cause of acquired nephrogenic diabetes inspidus
(3) Hypothyroidism:
female gender and pre-existing thyroid auto-antibodies are risk factors.
Association between lithium and hyperthyroidism is less clear.
(4) Hyperparathyroidism:
Confirm hypercalcemia by repeated measurements, then can measure PTH
Causes renal calculi, arrhythmias, osetopenia, mental state disturbances (stones,
bones, groans, psychiatric overtones)
(5) Weight gain
+3.8 kg over one year
(6) ECG Changes
Bradycardia and sick sinus syndrome are worrisome complications
20-30% have benign T-wave changes (flattening or inversion) and widening QRS
at therapeutic doses
(7) Psoriasis Exacerbation
Lithium toxicity symptoms
Coarse tremor
Drowsiness
Lethargy
Weakness
Agitation
Muscle Fasciculation
Ataxia
Dysarthria
Vomiting, Diarrhea
Dizziness, Syncope Arrhythmias
Polyuria, Polydypsia
Major depressive disorder - criteria
* 2 weeks + change of previous fxn * 5 of {mood, interest, sleep, wt, psychomotor, energy, guilt/worthlessness, [], SI}
Manic episode criteria
* elevated/irritable mood AND increased energy x >1wk * ≥3 of {grandiosity, dec. sleep, talkative, flight of ideas/racing thoughts, distractibility, goal-directed activity/agitation, painful consequences} * marked impairment or hospitalization or psychosis
MDD - course
* variable course *
40% recover in 3mo, 80% in 1yr *
poor prognosis: episode duration, psychosis, anxiety, personality d/o, severity *
BD more likely if mixed features, psychosis, FHx of BD
MDD Age of onset, age differences in symptoms and prevalence
Incidence peaks in 20s (in Canada 15-45yo)
Likelihood decreases after puberty but can still have first onset in late life
Prevalence in 18-30 = 3x Prevalence >60 (decreases with age)
Younger: hyper-somnia & -phagia
Older: melancholic sx, esp psychomotor
MDD gender distribution
1.5-3:1 F:M ratio (DSM-5), 2:1 F:M (K&S)
Difference decreases with age
MDD genetic markers (genes & alleles)
5HTTLPR short allele + stressful life events
If long allele - better response to SSRIs with fewer side effects (but not nortriptyline)
BDNF - met/met + stressor high risk (cf val/met and val/val)
MDD heritability
40%
1st degree relatives: 2-4x chance of having MDD
one parent: 10-25% risk, both: 20-50%
MDD Prevalence (lifetime, 12mo, US and Canada)
Lifetime: U.S. - 16.9 % (NCS), Canada - 10.8% (CCHS 1.2)
12-Month: U.S. - 6.8% (NCS), 7% (DSM-5), Canada - 4.0% (CCHS 1.2)
MDD- specifiers
* anxious distress * mixed features * melancholic features * atypical features * mood-congruent psychotic features * mood-incongruent psychotic features * catatonia * peripartum onset * seasonal pattern
Melancholic features
* during most severe period of MDE: * 1 of {anhedonia or lack of reactivity to pleasurable stimuli} * ≥ 3 of {despair/empty mood, worse in AM, AM awakening, psychomotor agitation or retardation, we loss , excessive guilt}
Mixed features in MDD
* ≥ 3 manic sx during most of MDE
Monitoring for divalproex or carbamazepine
2 levels to establish therapeutic dose (4 weeks apart for CBZ), then as clinically indicated
Weight*, CBC LFT, menstrual history* q3 months (monthly for CBZ for first 3 months) for first year than annually (*Divalproex only), lytes + RFTs - CBZ
Bone densitometry if risk factors
Monitor for Rash (and for lamotrigine)
Monitoring when treating with atypical antipsychotics
Weight monthly for first 3 months, than q3months
BP and fasting glucose q3months for first year than annually
Fasting lipid profile after 3 months and then annually
ECG and prolactin level as clinically indicated
neuroimaging findings in MDD
Structural:
Decreased hippocampal volume
Functional:
Increased activity in Amygdala and Medial Prefrontal Cortex
Reduced activity in Dorsolateral Prefrontal Cortex
Persistent depressive d/o - epidemiology
* 0.5% 12mo prevalence for dysthymia * 1.5% for chronic MDD * early, insidious course
Persistent depressive disorder
* >2 years depressed mood (1yr for child) * 2 sx of {appetite change, sleep change, fatigue, low self-esteem, poor [] or decision making, hopelessness} *
Persistent depressive disorder - specifiers
* all specifiers as MDD * early/late onset (21yo) * pure dysthymic syndrome (no MDE in past 2 years) * persistent MDE (meets criteria for full 2 years) * intermittent MDE, with/ wi/o current episode * severity
PMDD prevalence
* 12mo prevalence: 2-6%
PMDD risk factors
stress, trauma, seasonal changes, no OCP
Premenstrual dysphoric disorder
* most cycles in past 1 yr , ≥5 sx in final wk, improve in a few days * ≥ 1 of {affective lability, irritability, depressed mood/hopelessness, anxiety/tension/keyed up}\ * ≥ 1 of {anhedonia, []. energy, appetite, sleep, overwhelmed, phys. sx} *
Prevalence of BD I and II
Lifetime: 1.0% bipolar I, 1.1% bipolar II (NCS-R)
12-Month: 0.6% bipolar I (NCS-R & DSM-5), 0.8% bipolar II (NCS-R)
Putative biomarkers for BD
Structural (London Review):
White Matter Hyperintensities
Anterior cingulate cortex is reduced in volume
Lateral and 3rd ventricles are larger
Functional (London Review):
Increased activity in Amygdala and Parahippocampal Gyrus in mania during emotional tasks, normal activation during euthymia
Hypoactivation of ventrolateral prefrontal cortex during emotional and cognitive tasks
MR Spectroscopy (London Review):
Increased Glutamate Levels
Decreased NAA levels
Putative biomarkers in MDD
BDNF - decreased; antidepressant tx reverses this
Proinflammatory cytokines, eg IL-6 and TNF-alpha: increased
HPA axis regulation impaired:
dexamethasone non-suppression (not specific)
and hypercortisolemia (40-60% of depressed inpatients, 20-40% of depressed outpatients)
Rank the risk factors for postpartum psychosis (greatest to least)
a. History of postpartum psychosis (70%)
b. History of postpartum depression (50%)
c. History of bipolar disorder (20-50%)
d. History of MDD (30%)
Rapid cycling course and treatment
- Less likely to be symptom free in 2-5 year follow-up studies (usually have shortening of cycles for 4-6 episodes before stabilization)
- Lithium vs. Valproate study Calabrese 2005: The hypothesis that divalproex would be more effective than lithium in the longterm management of rapid cycling bipolar disorder is not supported by these data. Preliminary data suggest highly recurrent refractory depression may be the hallmark of rapid cycling bipolar disorder (Am J Psychiatry 2005)
- Cites several guidelines including “Evidence based guidelines for treating bipolar disorder revised second edition recommendations from British association for psychopharmacology
- Firstline: Minimize or eliminate potential cycling-promoting agents (subclinical hypothyroidism, substance abuse, steroids, stimulants, antidepressants, activities that interfere with sleep-wake cycle). Lithium or valproate monotherapy.
Second-Line: Lithium or valproate + lamotrigine. Combine two traditional mood stabilizers (#1 valproate + lithium), #2 carbamazepine + lithium). Add Risperdal Constan (Macfadden 2009), Add olanzapine or quetiapine
Rapid cycling risk factors
•: 3F>M,
earlier age of onset of illness,
premorbid cyclothymic temperament,
bipolar II> I (inconsistent),
hypothyroidism ? (inconsistent),
comorbid substance abuse,
longterm use of antidepressants (especially TCAs),
abrupt discontinuation of medications?,
childhood physical or sexual abuse?
Response/remission rates in rTMS
- Response rates are 25% for treatment resistant depression
- w/o maintenance relapse is common, median 3 months
- w/ maintenance rTMS - better outcomes; sustain remission in 60% of responders, 70% of remitters
Risk factors for MDD
Core:
Early-Onset Adversity/Childhood Maltreatment (esp. losing a parent before 11)
Stressful Life Events (esp. loss of a spouse & unemployment which has 3-fold
relative risk of depression versus people who are employed)
o Stressful life events more often precede the first rather than
subsequent episodes of mood disorders both in MDD and Bipolar I.
Family History (first degree relatives have 2-4x greater chance of having MDD)
Specific:
Female Gender
Temperament: Neuroticism (negative affectivity)
Chronic Medical Conditions
Substance Use especially Alcohol Use
Anxiety Disorders
Borderline Personality Disorder
rTMS stimulus calculation?
Stimulus is based on individual motor threshold (stimulus required to produce
twitches), usually 90 to 120% of motor threshold
Scales for MDD
BDI-II
HAM-D
MADRAS
Zung Self-Rating Depression Scale
PHQ-9
Seasonal pattern
* regular temporal relationship w/ season ( not psychosocial stressors) * full remissions or (hypo)mania * in last 2yrs, 2 MDE w/ temporal relationship and no MDE out of season * seasonal > non-seasonal episodes
Second line for BD I depression
Lurasidone (1 RCT in AJP positive for monotherapy in bipolar I depression -
found improvement in depressive symptoms as early as week two vs. placebo)
Divalproex
Adjunct:
Lurasidone (in addition to Lithium or Divalproex)
Quetiapine + SSRI
Lithium or Divalproex + Lamotrigine
Adjunctive Modafinil
Second line for BD I maintenance
Carbamazepine (similar efficacy to lithium maintenance for rates of relapes, but
more dropouts due to adverse effects with carbamazpeine, also difficult to
combine with other psychotropics so second line)
Paliperidone ER
Adjunct:
Lithium and Divalproex (BALANCE study - combination therapy was not
significantly more effective than lithium alone, but more effective than divalproex
monotherapy in preventing relapse)
Adjunctive Olanzapine, Risperidone
Second line for BD II depression
Lithium
Lamotrigine
Divalproex
Combinations
Second line for BD II maintenance
Divalproex
combinations
second line pharmacotherapy for BD I acute mania
Haloperidol
Carbamazepine or Carbamazepine ER
ECT
Lithium + Divalproex
second line psychotherapy for acute phase MDD
(1) Bibliotherapy (level 1)
(2) Behavioural Activation (level 2)
(3) Cognitive-behavioural analysis system of psychotherapy (CBASP) (level 2)
(4) Computer-Assisted CBT (level 2)
(5) Telephone-delivered CBT and IPT (level 2)
(6) Combination of CBT or IPT with medication is second line (level 1)
Second line psychotherapy for maintenance phase MDD
(1) Interpersonal Therapy (IPT) (level 2)
(2) Behavioural activation (level 2)
(3) Cognitive-behavioural analysis system of psychotherapy (CBASP) (level 2)
Second line switch agents in MDD
Amitriptyline (level 2)
Clomipramine (level 2)
MAOIs (level 2)
Second-line add-on agents in MDD
Bupropion (level 2)
Mirtazapine (level 2)
Mianserin (level 2)
Quetiapine (level 2)
Triiodothronine (level 2)
Other antidepressant (level 3)
Second-line pharmacotherapy for MDD
(1) Tricylcic Antidepressants
(2) Quetiapine XR
(3) Selegiline Transdermal
(4) Trazodone
Side effects of ECT
o Mortality is very low (0.2/100 000 treatments), approximates risk of
general anaesthesia
o Nausea
o Headache
o Muscle Pain / Persistent Myalgia
o Marked confusion in up to 10 percent of patients within 30 minutes of
the seizure (K&S)
o Memory impairment - can be both anterograde and retrograde including
deficits in autobiographical memory, most often reported by patients
who have experienced little improvement with ECT (K&S)
Can reduce cognitive impairment by reducing frequency to two per
week, using right unilateral or bifrontal positioning of electrodes,
and using lower dose stimuli
Side effects of rTMS?
o No evidence of cognitive impairment
o Headaches and scalp pain are most common short-terms side-effects.
o Should use ear plugs due to concerns about hearing loss during process.
o Case reports of seizures
SSRI discontinuation symptoms
FINISH (flu-like, insomnia, nausea, imbalance, sensory disturbance, hyperarousal)
Substance/Medication induced bipolar and related d/o
* prominent mood disturbance: elevated/irritable OR depressed OR anhedonia * related to intox or withdrawal of substance capable of producing the Sx * NOTE: ?? no need for full criteria of (hypo)mania/MDE
Target areas for rTMS?
o Left DLPFC -> high frequency stimulation (most evidence)
o Right DLPFC -> low frequency stimulation
Recommendations from CANMAT:
First-line
o Start with high frequency rTMS to left DLPFC (level 1)
o Superior outcome for 20 vs. 10 sessions (level 2)
o Minimal evidence for maintenance and relapse prevention (level 3)
Second-line
bilateral (left high-freq, right low-freq)
The only neurostimulation
method with level 1 evidence for relapse prevention?
ECT
Third line pharmacotherapy for acute mania
Clozapine
Tamoxifen / Adjunctive Tamoxifen
Not Recommended:
Lamotrigine
Gabapentin
Topiramate
Verapamil
Tiagabine
Meta-analysis showed that haldol was more effective than lithium, divalproex,
quetiapine, aripiprazole ziprasidone, carbamazepine, asenapine and lamotrigine/ Given this strong data it has been upgraded to second line, but should only be used on a short term basis to treat acute mania since long-term use increases risk of depressive episode
Third-line add-on agents in MDD
Buspirone (level 2) (-)ve RCT, less favourable outcomes STAR*D
Modafinil (level 2)
Stimulants (level 3) two RCTs of methylphenidate showed no
difference in outcome vs. placebo, Cochrane review equivocal
Ziprasidone (level 3)
Third-line pharmacotherapy for MDD
(1) Phenelzine (Nardil)
(2) Tranylcypromine (Parnate)
Third-line psychotherapy for acute phase MDD
(1) Acceptance and commitment Therapy (ACT) (level 3)
(2) Motivational Interviewing (level 4)
(3) Psychodynamic therapy (level 2)
(4) Emotion-focused therapy (level 2)
Third-line psychotherapy in maintenance phase MDD
Long-term psychodynamic psychotherapy
Types of rTMS stimuli
o Low frequency (below 5 Hz): transient reduction in cortical excitability
o High frequency (above 5 Hz): transient increase in cortical excitability
Valproate dosing and target levels
Dosing:
Initial: 250mg-375mg PO BID
Range: 1000-3000mg daily or divided BID
Maximum: 3000mg daily (60mg/kg/day)
Valproate Levels:
Therapeutic level is from 400-700 mmol/L
VNS - how is it applied?
Wire connected to subclavicular pulse generator which delivers intermittent
electrical signals to left vagus nerve (chosen due to its limited cardiovascular
effects)
VNS - most common side effect
Hoarseness (54-68%) is most common side-effect
Many side-effects are related to stimulation parameters and can be minimized by
reducing the intensity of the stimulus being delivered
VNS level of recommendation
Level 3 acute efficacy, Level 2 relapse prevention, Level 2 safety and tolerability
VNS response rate
In RCT, response rate of 15% compared with 10% sham treatment
What antipsychotic is now first-line in the CANMAT bipolar guidelines for acute bipolar depression & what
is the recommended target dose?
Quetiapine at 300 mg daily.
What are 10 factors that are predictive of Bipolar Disorder?
a. Early onset mood symptoms
b. Psychotic depression prior to age 25
Study Notes 2008
Page 24 of 61
c. Post-partum depression (especially if psychotic features present)
d. Rapid onset and offset of depressive symptoms
e. Depression with psychomotor retardation
f. Antidepressant induced hypomania
g. Repeated loss of efficacy of antidepressants
h. Family history of bipolar disorder
i. Trait mood lability or hyperthymic temperament
j. Seasonality of mood symptoms
k. Atypical depressive symptoms (reverse vegetative symptoms)
What are 3 risk factors for rapid-cycling bipolar disorder?
Hypothyroidism
Substance use
Female gender
What are recurrence rates for major depression at 6 months, 2 years and 5 years?
i. 6 months – 25%
ii. 2 years – 50%
iii. 5 years – 70%
What are risk factors for depression following abortion (MCQ question)?
a. Prior psychiatric history (e.g. MDD)
b. Younger age at time of abortion
c. Second trimester > first trimester
d. Lack of social supports
e. Sociocultural groups antagonistic to abortion
*Psychological problems immediately post-abortion is not a risk factor
What are the best acute treatment options for rapid-cycling bipolar disorder?
a. Valproic acid
b. Olanzapine
c. ECT
d. If no other options, use lithium & valproic acid combination
What are the Melancholic Features for Major Depressive Disorder?
- Lack of pleasure in all activities OR lack of reactivity to pleasurable stimuli
- 3 of 6 of the following
- Distinct quality of depressed mood
- Early morning awakening
- Worse mood in AM
- Guilt is excessive or inappropriate
- Anorexia or weight loss
- Psychomotor retardation
What are the ranges for the BDI-II in terms of depression?
<7-10 is nondepressed
10-14 is mildly depressed
15-22 is moderately depressed
23+ is severely depressed
Note: CES-D (Centre for Epidemiologic studies scale for depression) is another validated self-report scale. It is a 20-item
scale scored from 0-3 with scores ranging from 0-60. Scores of 16 or higher indicates depressive illness. Designed for
community samples as opposed for psychiatric patient populations, which is the case for the BDI
What are the scoring ranges for the HAM-D
a. 0-7 = no depression
b. 8-13 = mild depression
c. 14-18 = moderate depression
d. 19-22 = severe depression
e. >23 = very severe depression
What is a self-report and clinician administered rating scale for mania?
a. Mood disorder questionnaire (MDQ)
i. Self-report
ii. 3 questions - Question 1 has 13 yes-no items
iii. Positive test = Q1 at least 7/13 + Q2 “yes” (all at same time) + Q3 at least moderate problems
iv. Informs you to screen more closely for mania and bipolar disorder
b. Young Mania Rating Scale (YMRS)
i. Clinician rated
ii. 11 items with 7 items 0-4 and 4 items 0-8
iii. Scoring cut-offs: <13 = not significant symptoms, 13 = minimal severity, 20 = mild, 26 =
moderate and 38 = severe (max = 60)
What is first-line treatment for acute bipolar II depression in CANMATS?
None. Lithium, DVP, LTG, quetiapine, antipsychotic + antidepressant, Li + DVP and Li/DVP + antidepressant are all 2nd
line. LTG and Li are recommended for bipolar II disorder maintenance
What proportion of patients with BD only have manic episodes?
10-20%
What to do in failure to induce seizure in ECT?
Check contact between electrodes
o Increase intensity by 25 to 100%
o Change anaesthetic agent to minimize increases in seizure threshold
o Hyperventilation lowers seizure threshold
o IV caffeine sodium benzoate 500-2000mg 5 to 10 minutes before the
stimulus also lowers seizure threshold.
When to avoid antidepressants in BD I?
mixed episode or history of rapid cycling
CANMAT 2018
Acute mania treatment
First & 2nd line
CANMAT 2018
DSM-5 Specifiers (11)
Bipolar and related disorders
CANMAT 2018
Features of depression that may increase suspicion of a bipolar illness (6/2/1)
CANMAT 2018
DDx of Bipolar Disorder (8)
CANMAT 2018
Main factors associated with suicide attempts (17) and suicide deaths in bipolar disorder (8)
CANMAT 2018
Chronic Disease Management Model (6)
CANMAT 2018
Level of evidence for psychological treatment in bipolar disorder (10)
CANMAT 2018
Level of recommendation for short term management of actute agitation (4/6/4)
CANMAT 2018
Acute mania treatment
3rd line (8)
Not recommended (8)
CANMAT 2018
Risk factors for partial or non-adherence to medication (7)
