Bipolar Disorder & Mood

Stabilizers
4/3/2020
Jason Compton
jcompton@health.ucsd.edu
I. Bipolar Disorder
History
Emil Kraepelin
• Dementia Praecox
• Schizophrenia
• Episodic psychosis with periods of
melancholia and periods of mood
elevation
• “Manic Depressive Insanity and
Paranoia” in 1921 
Famous Individuals with Bipolar Disorder
• Sir Isaac Newton
• Vincent Van Gogh
• Edgar Allen Poe
• Frank Sinatra
• Jackson Pollock
• Mel Gibson
• Kanye West
DSM
• Phenomenological
• Defined by the experiences of the patient’s consciousness
• Based on SYMPTOMS
• Subjective report from patient vs objective observation from
psychiatrist
• Communication
• Used for research, for guiding treatment, for billing…
• Subject to change based on cultural and political
influences
• For diagnosis, a disorder must impair function
• Not all DSM diagnoses exist per se as a disease entity
in reality
Phenomenology
Bipolar Disorder
• Must have had at least one episode of Mania characterized by
persistently elevated, expansive, or irritable mood, and at least 3 of:
• Decreased need for sleep
• Grandiosity
• Pressured speech
• Distractibility
• Flight of Ideas or subjective report of racing thoughts
• Impulsivity
• Abnormal, persistent, goal-directed behavior
• Manic Episode: lasts at least 1 week, can last months
• With the presence of a manic episode, no need for a hx of a
depressive episode to make diagnosis
• Prevalence: 1-2.5% in the US
Phenomenology
• Types of Bipolar Disorder
• Bipolar 1 Disorder
• with Euphoric Mania
• with Mixed States
• Irritability and depressive symptoms concurrent with
manic symptoms
• with Psychotic Features
• Rapid Cycling
• >= 4 episodes of mania and/or depression within 12
months
• Bipolar 2 Disorder and Cyclothymia
• “hypomania”
• Bipolar disorder is a disease with a spectrum of severity
• Not all patients diagnosed with BP2 have a bipolar
mood disorder
Similar Presentations
What Causes Bipolar Disorder?
Genetic-Stress Model
Heritability in Twin Studies
Genes implicated in Bipolar Disorder
• CNS voltage-gated calcium channels
• Circadian rhythm
• CLOCK, PER, CRY
• High heritability
Second Hit (triggers rather than causes)
• Sleep disruption
• Substance use
• Psychosocial stress
Limbic System
Bipolar Circuit
• Sleep deprivation is a common
cause of mania
• Red eye flights
• Residency
• Suprachiasmatic nucleus in the
hypothalamus sets the
circadian rhythm
• Receives input from
environment
• Light, temperature, social cues
Bipolar Circuit
Oscillators in Suprachiasmatic Nucleus
• SCN has two separate pacemakers determine the Circadian Rhythm
(oscillators) that “set the clock” of the
circadian rhythm
• Abnormalities in genes for CLOCK, PER,
& CRY in Bipolar Disorder
• Result: these pacemakers drift apart more
easily
• Determines sleep-wake cycle as well as
regulating
• the limbic system
• aspects of the HPA
• autonomic output
Bipolar Circuit
Delusions Impulsivity

• Disruption of the sleep-wake cycle in Salience PMA

Prefrontal Networks
Bipolar Disorder -> Limbic dysfunction Mood
• Limbic dysfunction ->
• Elevated mood, irritability LIMBIC STRUCTURES
Cingulate gyrus Basal
• Increased goal-directed behavior
Amygdala ganglia
• Psychomotor agitation Nucleus Accumbens
• Abnormal functioning in prefrontal networks
-> Impulsivity, aggression
• Aberrant salience -> Delusions
Sleep-Wake Cycle
• Further disturbance of the sleep-wake
cycle
-> further limbic dysfunction…. HYPOTHALAMUS
SCN
Sleep & Mood
Environmental cues (zeitgebers)
INTERNAL CIRCADIAN RHYTHM
synchronizes biological rhythms CLOCK genes, chronotype,
• Light/dark, social and melatonin secretion

interpersonal factors,
temperature
• Effects melatonin secretion and MOOD REGULATION ZEITGEBERS
chronotype Onset, frequency , and Light/dark, social cues,
• BP: later and lower melatonin duration of depressive psychosocial stress
and manic episodes
secretion, have a “phase-advanced
rhythm” (later chronotype)
Sleep & Mood
Light/Dark Therapy
INTERNAL CIRCADIAN RHYTHM
• Light therapy & sleep deprivation CLOCK genes, chronotype,
decrease depressive sx melatonin secretion
• Dark therapy & sleep shorten mania
duration
Lithium lengthens period of circadian
rhythm and MOOD REGULATION ZEITGEBERS
Onset, frequency , and Light/dark, social cues,
• Inhibits GSK-3beta -> increased duration of depressive psychosocial stress
expression of CLOCK genes and manic episodes
Melatonin improves sleep sx in BP
• Ramelteon (MT1, MT2 agonist) helps
prevent relapse of mania
I. Treatment
Mood Stabilizers
Acutely and prophylactically treat mood Treatment Strategy Cheat Sheet
elevation and lability without worsening Acute Mania
depression • Lithium +/- Antipsychotic
• Lithium Rapid Cycling or Mixed Features
• AED • Valproic acid +/- Antipsychotic
• Valproic acid Bipolar depression
• Carbamazepine • Lamotrigine, quetiapine,
lurasidone, lithium
• Oxcarpazapine
• Avoid antidepressants -> can be
• Lamotrigine activating, increase risk of mania
• (Second generation) antipsychotics • PRN benzodiazepines for
sedation and agitation
Lithium
Lithium
Mechanism of action not entirely understood
• Inhibits GSK3, p53, and affects other second messengers
(inositol monophosphate)
• Regulation of gene expression
• Bcl-2, BDNF
• Modulation of DA signals
• Regulates circadian rhythm
• Alters nerve conduction
• Changes cortisol and monoamine metabolism
• Increases serotonin
• Neurotrophic
• Thickens cortex
Lithium
Indicated for acute mania and maintenance in BP
• Also for depression augmentation, other causes of mood lability
like borderline personality disorder
• Suicidality
Dosing: typically start 600 mg nightly
• Serum range: 0.8 – 1.2 (0.6 – 1.4) mEq/L
• Very small therapeutic range
• Toxic at >1.5, can be lethal at >2.0
Monitoring
• Pre-treatment work-up: Basic Metabolic Panel, TSH, UPT
• 5 days after initiation or dose adjustment (steady state)
• Li serum level, 12 hour trough
• Cr, GFR
Lithium
Lithium is not metabolized, is excreted in active form in the urine

Increases Li Decrease Li
• Medications • Medications
• ACE-inhibitors • Osmotics (Xanitol)
• Thiazide diuretics • Xanthines (caffeine)
• NSAIDs • CAI (acetazolamide)
• Metronidazole • High salt diet
• CKD
• Dehydration
Lithium
Side Effects (at therapeutic doses)
• Acute: GI upset, sedation
• Chronic: hair loss, weight gain, exacerbates acne
and lupus
• Tremor – fine, cerebellar, intention, not at rest
• Treat with propranolol
• Hypothyroidism, reversible
• Treat with levothyroxine
• Leukocytosis, PMN dominant
• Nephrogenic diabetes insipidus -> polyuria
• EKG changes: QT prolongation, T wave changes,
SA nodal block
Lithium
Toxicity/OD
• Acute toxicity: severe nausea, vomiting
• Chronic/ acute-on-chronic:
• Neurologic: coarse tremor, fasciculations, ataxia, hyperreflexia, nystagmus, speech latency
-> permanent neurologic deficits, dementia in 10%
• Interstitial nephritis
• Mortality from VF, seizures, and coma
Treating lithium toxicity/OD
• IVF bolus, maintenance fluids, decrease GI absorption if soon enough
• Dialysis, CRRT for Li > 4.0, seizures, coma, or RF
• High volume of distribution, rebound of lithium from leeching out of tissues, CNS levels
lag behind serum levels
Anti-Epileptic Drugs for Mood Stabilization
• Limbic Kindling
• Repeated stimulation of the limbic
system -> increased sensitivity to future
stimuli -> eventual over-activation and
spontaneous firing
• Various inputs (external and internal)
act as stimuli for the limbic system
• AEDs dampen overactive limbic
circuits
Valproic Acid (Depakote, Divalproex)
Mechanism of Action
• Increases synaptic levels of GABA
• Inhibits degradation and stimulates synthesis/release
• Inhibits voltage-gated Na channels
• Decreasing neuronal firing
• Reduces low-threshold Ca currents, which mediate
repetitive neuronal firing
• Affects kynurenine pathway
• Increases monoamine production
• Promotes BDNF expression
• Decreases Glu-mediated neurotoxicity
• Histone deacetylase inhibitor
• Neuronal dedifferentiation and plasticity
Valproic Acid (Depakote, Divalproex)
Indicated for acute mania and maintenance in
BP
• other causes of mood lability, aggression in
TBI and dementia, hyperactive delirium,
migraine prophylaxis, seizure disorders
Dosing: load with 20-30 mg/kg/d
• Serum range: 80 – 120 ug/mL
Monitoring
• Pre-treatment work-up: CBC, LFT, UPT
Only about 10% of total VPA is not bound to Albumin
• 4-5 days after initiation or dose adjustment EXCEPT at serum levels above 120—once Albumin
• VPA serum level, 12 hour trough binding sites begin to saturate VPA levels can increase
• CBC, LFT rapidly!
Valproic Acid (Depakote, Divalproex)
Excretable byproducts

Common Side Effects glucuronidation

• Acute: VPA Ammonia

• GI upset
Carnitine
• Sedation
• Rash Fluoxetine
• transient transaminitis -increases
VPA level Beta-ox
• Chronic: by P450
• weight gain CYP2C9
• hyperandrogenism (hirsutism)
• Alopecia – supplement with
selenium/zinc/folate Lamotrigine
-decreases Excretable byproducts
Drug-drug interactions with protein VPA level
bound medications (Warfarin!) Mitochondria
Valproic Acid (Depakote, Divalproex)
Excretable byproducts
Lactulose
Serious, Rare Side Effects glucuronidation

• Thrombocytopenia and agranulocytosis, VPA Ammonia

dose-related
Supplement Carnitine
• SJS
• PCOS
• SIADH -> hyponatremia Beta-ox
by P450
• Hepatotoxicity, hemorrhagic pancreatitis
CYP2C9
• Hyperammonemic Encephalopathy
• Treat with lactulose acutely, carnitine
supplementation chronically
Excretable byproducts
Check Na and Ammonia if there are mental
status changes (not routinely) Mitochondria
Carbamazepine & Oxcarbazepine
• About equal mood stabilizing efficacy • Decreases impulsivity but is NOT a
as Li or VPA mood stabilizer
• Active metabolite of carbamazepine
Carbamazepine (Tegretol)
Mechanism of Action Drug Serum
• Prolongs inactivation of VGNaCh Range
• reduces current through NMDA channels,
Lithium 0.8 - 1.2
• Adenosine A1 antagonist
• Decreases metabolism of DA and 5HT
Dosing: start 200 mg BID Carbamazepine 8 - 12
• Titrate to serum range 8 – 12 ug/mL
Monitoring
• Pretreatment: CMP, CBC, EKG in elderly, UPT
Valproate 80 - 120
• Frequent serum levels because CBZ is an autoinducer!
Carbamazepine (Tegretol)
Auto-induction of metabolism by CYP3A4
• Also decreases levels of many other RX
• Phenothiazine antipsychotics, lamotrigine, quetiapine, trazadone, alprazolam,
triazolam
Side Effects
• Ataxia, slower cognition (leads to discontinuation)
• Rash -> SJS in patients with HLA-B1502
• Thrombocytopenia, agranulocytosis, aplastic anemia – rare but fatal
Toxicity: delirium, tremor, mydriasis, stupor, nausea, seizure
Lamotrigine (Lamictal)
Mechanism of Action
• Blocks VGNaCh
• Decreases aspartate and glutamate release
• Weak GABAa agonist, weak 5HT3 antagonist
Indicated for bipolar depression – not effective for
mania
• Often used to treat mood lability in borderlines,
safe(r) in pregnancy
Dosing: start 25 mg/d, no serum levels needed
• SLOW titration to decrease risk of SJS
• Must start titration over if >=5 days missed
Lamotrigine (Lamictal) Excretable byproducts

glucuronidation
Metabolized by glucuronidation and CYP3A4
• CBZ induces metab -> decreases LMT VPA LMT
• VPA inhibits metab -> increases LMT
• VPA both inhibits beta oxidation and
glucuronidation -> doubles LMT levels
• Even slower titration required
Side Effects Beta-ox Beta-ox
by P450 by P450
• Headache (aseptic meningitis) CYP2C9 CYP3A4
• Neurocognitive sx, ataxia, diplopia
• Rash, SJS LMT VPA
Excretable byproducts
• DRESS
Mood Stabilizers and Pregnancy
Lithium
• Risk of cardiac abnormalities in 1st TM
• Risk is lower than once believed (increased from about 1 -> 2%)
• Must weigh risk vs risk to baby if mother has a manic episode
• PREFERRED in women of child-bearing age with mania
Valproic acid
• NTD, doubles rate of ASD, 10 pt lower IQ
• Contraindicated without reliable contraception
Carbamazepine
• NTD (high rate of Spina Bifida)
• Decreases plasma levels of hormonal contraceptives!
Lamictal
• Safest MS in pregnancy but less effective mood stabilizer
Other Rx
Second Generation Antipsychotics
Acute Mania
• Olanzapine, risperidone
Bipolar Depression
• Lurasidone, quetiapine,
olanzapine/fluoxetine
Adjunctive to Li or VPA
• Quetiapine, aripiprazole,
ziprasidone
Benzodiazepines
• GABA potentiation
• Used for sedation in mania
• Lorazepam (Ativan) preferred
• No P450 metabolism, glucuronidation only
Other AEDs
• Gabapentin a 3rd line adjunctive therapy
• Topiramate and others are ineffective as a
mood stabilizer
Kanye’s Grandiose Flight of Ideas