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