Introduction to Mood

Stabilizers and Anxiolytics

Michael Shabbits MD FRCPC

michael.shabbits@vch.ca
February 17, 2016
What is a Mood Stabilizer?

No universally agreed upon definition

Definitions often based upon:

– Anti-manic properties
– Anti-depressant properties
– Prophylaxis against future
manic/depressive episodes
note that there are some antipsychotic meds which are used as mood stabilizers

2013 CANMAT Recommendations

for Pharmacological Treatment of
Bipolar I Depression

First line: lithium, lamotrigine, quetiapine, quetiapine XR, lithium
or divalproex + SSRIA, olanzapine + SSRIA, lithium + divalproex,
lithium or divalproex + bupropion

Second line: lurasidone, quetiapine + SSRIA, divalproex, lithium
or divalproex + lamotrigine, adjunctive modafinil, lithium or
divalproex + lurasidone

Third line: Carbamazepine, olanzapine,
lithium + carbamazepine, lithium + pramipexole, lithium or
divalproex + venlafaxine, lithium + MAOI, ECT B, lithium or
divalproex or AAP+TCA, lithium or divalproex or carbamazepine +
SSRIA + lamotrigine, quetiapine + lamotrigine

Not recommended: Gabapentin, aripiprazole, ziprasidone
adjunctive ziprasidone, adjunctive levetiracetam

SSRI = selective serotonin reuptake inhibitor; MAOI = monoamine oxidase inhibitor;
ECT = electroconvulsive therapy; AAP = atypical antipsychotic; TCA = tricyclic antidepressant.

The management of a bipolar depressive episode with antidepressants remains complex. The
clinician must balance the desired effect of remission with the undesired effect of switching.

AExcept paroxetine; BCould be used as first or second-line treatment in certain situations

Bipolar Disorders 2013;15:1-44

 2013 CANMAT Recommendations for
Pharmacological Treatment of Acute
Mania

First line: lithium, divalproex, divalproex ER, olanzapine,
risperidone, quetiapine, quetiapine XR, aripiprazole, ziprasidone,
asenapine, lithium or divalproex + risperidone, lithium or
divalproex + quetiapine, lithium or divalproex + olanzapine,
lithium or divalproex + aripiprazole, lithium or
divalproex + asenapine

Second line: Carbamazepine, Carbamazepine ER,

electroconvulsive therapy, haloperidol, lithium + divalproex

Third line: chlorpromazine, clozapine, oxcarbazepine,

tamoxifen, cariprazine (not approved in Canada)

Not recommended: gabapentin, topiramate, lamotrigine,

verapamil, tiagabine, risperidone + carbamazepine,
olanzapine + carbamazepine
Bipolar Disorders 2013;15:1-44
 2013 CANMAT Recommendations
for Maintenance Pharmacotherapy
of Bipolar Disorder

First line: Lithium, lamotrigine (limited efficacy in preventing
mania), divalproex, olanzapine, quetiapine , aripirazoleA,
risperidone LAI A, lithium or divalproex + quetiapine, lithium or
divalproex + risperidone LAIA, lithium or divalproex + aripiprazoleA,
lithium or divalproex + ziprasidoneA

Second line: Carbamazepine, paliperidone ER,
lithium + divalproex, lithium + carbamazepine, lithium or
divalproex + olanzapine, lithium + risperidone,
lithium + lamotrigine, olanzapine + fluoxetine

Third line: Asenapine (monotherapy or adjunctive), Adjunctive

phenytoin, Adjunctive clozapine, Adjunctive ECT, Adjunctive
topiramate, Adjunctive omega-3-fatty acids, Adjunctive
oxcarbazepine, Adjunctive gabapentin

Not recommended: Adjunctive therapy: flupenthixol

Monotherapy: gabapentin, topiramate or antidepressants
LAI = long acting injection A mainly for preventing mania
Bipolar Disorders 2013;15:1-44
 Atypical Antipsychotics
?Mood Stabilizer?

Several atypical/2nd or 3rd generation antipsychotics
are recommended for use in Bipolar Disorder
2013 Bipolar Bipolar Bipolar
CANMAT Depression Mania Maintenance
Risperidone 1st line 1st line
Olanzapine 1st line 1st line
Quetiapine 1st line 1st line 1st line
Aripiprazole 1st line 1st line *
* Mainly for preventing mania

2013 CANMAT Guidelines include other

recommendations for use of antipsychotic
medications for Bipolar mania, depression and
maintenance
 igoscience

Lithium

Used in 19th century to
treat a variety of
ailments
– Uremia, renal calculi,
gout, rheumatism

Used in mid-20th century
as an alternative to salt
Am J Psychiatry 1999
in cardiac patients
– Withdrawn after deaths
reported

John Cade 1949

FDA approval in about
1970
Lithium

Uses
– Bipolar Mania
– Bipolar Depression
– Bipolar Maintenance
– Major Depressive Disorder augmenting
agent
Lithium – Mechanism of Action

Hypothesized to interact with second

messenger systems to stabilize
neuronal ion flow

G-proteins, protein kinase C, Na-K-
ATPase, phosphatidyl inositol, GABA

Pro-serotonergic
Lithium

Available in two forms

– Lithium carbonate

Capsules: 150 mg, 300 mg

Tablets: 300 mg

Sustained release tablets: 300 mg

– Lithium citrate

Oral solution
citrate is dosed in mmol, not mg, so make sure to not overdose a patient
Lithium - Dosing

Guided by plasma level
– Adult

Acute: 0.8 to 1.2 mM

?Maintenance: 0.6 to 1 mM
– Geriatric

Adult dosing usually 300 mg to 2400 mg per day

?divided doses initially – eventually one dose/day

Renal insufficiency
– Adjust dose
– Give dose after dialysis
Lithium

Predictors of response
Less responsive
– Classic mania
– History of response in
1st degree relative
– Few prior mood episode
and complete recovery
between episode
– Dyphoric/psychotic mania
– Mixed states
– Rapid-cycling
– Multiple prior episodes
– Comorbid medical conditions
– Adolescents
– Substance abuse
– High anxiety

 Often 10 to 14 days until complete effect is

observed
Lithium Discontinuation

No significant withdrawal

Risk of recurrence within months

Increased risk of suicide in first year

Risk increased with rapid (<2 weeks)
withdrawal

Some patients reported to become
refractory if lithium is discontinued
– controversial
Lithium

Readily absorbed through GI system

Tends to distribute evenly in total body
water space

Almost entirely excreted by kidneys
– 80% reabsorbed in proximal tubules and loop of
Henle
– No absorption in distal renal tubules

t1/2 = 24 h (young 18 h – old 36 h)
– Increases with duration of therapy
it takes 5 half-lives to reach steady state, so wait at least 5 half-lives to get a
serum lithium level
Lithium – Side Effects

CNS
– Fine tremor (up to 65%)
– Cognitive
– Drowsiness - weakness

CVS
– Bradycardia
– ECG (25%) t-wave
changes, QRS widening

Endocrine
– Hypothyroidism (34%)
– Hyperparathyroisdism with
hypercalcemia
– Menstrual cycle
abnormalities

Teratogenicity

Renal
– Usually seen after chronic use
– Polyuria and polydipsia
– Interstitial fibrosis, tubular
atrophy, glomerulosclerosis
– Nephropathy
– Changes in distal tubular function

Impaired urine concentrating
ability

GI
– Nausea, vomiting, diarrhea
– Excessive thirst
– Weight gain (incidence up to
60% with 25% excessive and
mean 7.5 kg)

Dermatological
– Dry skin, psoriasis (exascerbation
or new onset), acne, folliculitis
Lithium Toxicity

Lithium has a narrow therapeutic

index
– Be careful

Lithium toxicity risks
– Drug interactions

Medication changes – e.g. diuretics, NSAIDs
– Dehydration – flu, heat
– Remind patient to talk to their pharmacist
– Over the counter medications

ibuprofen
very narrow therapeutic window:
target: 0.6-1.0. toxicity starts at 1.5.

Lithium Toxicity

Mild (1.5 mM to 2 mM – occasionally in normal range)
– Ataxia, coarse tremor, confusion, diarrhea,
drowsiness, fasciculation, slurred speech

Moderate/Severe (> 2 mM)
– Delirium, coma, hyperreflexia, seizures, ECG
changes - arrhythmias, cardiovascular collapse,
NMS, acute tubular necrosis – renal failure
– Persistent neurological (CBL and Basal Ganglia)
dysfunction
– Death
Lithium Toxicity - Management

Reduce absorption, restore fluid

balance, correct sodium depletion and
remove drug from the body

Hemodialysis

Delayed distribution in CNS
– Accumulation ⇒ serum ≠ tissue levels
so even if Li level drops after dialysis, there is still high level of Li in the tissues
Lithium – Monitoring

CBC benign leukocytosis

Serum electrolytes hyponatremia

Creatinine

ECG

Calcium parathyroid

TSH hypothyroidism

Lithium level
– Drawn 12 hours after last dose

?Pregnancy screen
Bipolar Disorder - Anticonvulsants

Many patients don’t respond to lithium

Early theories postulated that bipolar
illness bore some resemblance to
kindling phenomenon seen in seizure
disorders

CBZ reported to treat mania in 1970s
Valproate

Uses
– Bipolar Mania
– Bipolar Maintenance
Valproate

Mechanism of action
– GABA-ergic activity
– Indirectly blocks

Voltage-dependent Na channels, Ca channels

Glutaminergic system

Metabolized by liver
– Free valproate level doubles in renal impairment
– t1/2 1 to 4 hours (valproic acid)
– t1/2 3 to 8 hours (divalproex and extended release)

Plasma levels
– Correlate with anticonvulsant effects
– Relationship with anti-manic effect is less clear
– 350 to 800 mM
– Dose range: usually 500 to 3000 mg per day
(max 60mg/Kg)
Valproate – Dosage
Forms and Strengths

Divalproex Sodium
– Capsules

125 mg, 250 mg, 500 mg
– Extended-release tablets

250 mg, 500 mg

Valproic Acid
– Capsules

250 mg, 500 mg
– Oral syrup

Valproate Sodium
– Parenteral used for anti-convulsive, not mania
Valproate – Adverse Effects

CNS
Hematologic
– Sedation, cognitive – Thrombocytopenia,
blunting, tremor,
encephalopathy, anemia
hyperactivity, ataxia,
Dermatological
dysarthria,
incoordination, diplopia, – Rash, SJS-TENS-
asterixis, nystagmus Hypersensitivity syndrome

GI – Hair loss
– Nausea, Weight gain,
Teratogenic
Hepatic transaminase
elevation, hepatitis,
PCOS
Serum ammonia
Endocrine
elevation

Cardiovascular – Weight gain, dyslipidemia,
menstrual disturbance,
– Rarely dizziness, androngenism,
vasculitis
hyperinsulinemia
Lamotrigine this is one of the few mood stabilizers that is
good for bipolar DEPRESSION

Uses
– Bipolar Depression
– Bipolar Maintenance

Limited efficacy in preventing mania
Lamotrigine

Mechanism of action
– GABA-ergic activity
– Indirectly blocks

Voltage-dependent Na channels, Ca channels

Glutaminergic system

Metabolized by liver
– Acute t1/2 33 h; Chronic t1/2 26 h

Dose range
– 50 to 500 mg per day in single or divided doses
– Slow titration to lower risk of SJS

25 mg per week

12.5 mg per week (if on valproate)
– Drug interaction with valproate --> valproate doubles the potency
of lamotrigine. this is a common
combination for bipolar
Lamotrigine – Adverse Effects

Dermatological
– Rash (up to 10%)
– Stevens-Johnsons
Syndrome

0.1% (adults more in
kids)

Increased risk with
valproate
– Erythyma multiforme,
hypersensitivy
syndrome

GI
– Nausea, vomiting,
diarrhea

CNS
– Sedation, headache,
diploplia, nystagmus,
cognitive blunting, tremor,
agitation, ataxia, asthenia

Anticholinergic

Hematologic
– Neutropenia, pancytopenia,
thrombocytopenia, anemia
(hemolytic/aplastic)

Teratogenic

Cardiac
– Dizziness, conduction
changes, breathlessness
 Carbamazepine

Uses
– Bipolar Mania (2nd line)
– Bipolar Maintenance (2nd line)
– Bipolar Depression (3rd line)

one of the first drugs for mania, now it's not used as much. messy side effects
Carbamazepine

Mechanism of action
– GABA-ergic activity, blocks voltage-dependent Na channels

Metabolized by liver
– Induces its own metabolism
– Acute t1/2 15 to 35 h; Chronic t1/2 10 to 20 h

Plasma levels
– Correlate with anticonvulsant effects
– Relationship with anti-manic effect is less clear
– 17 to 54 mM
– Dose range: 300 to 1600 mg per day in divided doses
Carbamazepine – Adverse Effects

CNS
Hematologic
– Sedation, cognitive – Leukopenia – agranulocytosis
blunting, confusion, (contraindicated with
agitation, tremor, clozapine)
ataxia, dystonia, – Aplastic anemia,
dyskinesia, paresthesias thrombocytopenia,

Anticholinergic eosinophilia

GI
Dermatological
– Hepatic transaminase – Rash – SJS-TENS-
elevation, hepatitis Hypersensitivity syndrome

Teratogenic – Hair loss
– Photosynsitivity

Hyponatremia

Cardiovascular

Drug Interactions – Slowed cardiac conduction
– Vasculitis
CBZ - Monitoring

CBC

Liver Panel

Serum electrolytes

ECG

? Pregnancy screen

CBZ level
– Weekly for first 2 months, monthly for 6
months then at discretion (min q 6
months) or with medication changes
Oxcarbamazepine

Metabolite

?Evidence

Early data suggests similar
pharmacological activity as CBZ with
lower potential for serious adverse
effects

15 to 35 mg/ml
 Clinical Handbook of Psychotropic Drugs 19th revised edition 2012

Monitoring Recommendations
Lithium Valproate Carbamazepine Lamotrigine Antipsychotic

Work- 1) CBC 1) CBC including platelets and 1) CBC including platelets and None required Fasting
up 2) ‘Lytes differential differential glucose/lipids,
3) Ca2+ 2) Liver function 2) Electrolytes, urea, creatinine electrolytes,
4) Urea 3) Total and HDL cholesterol and 3) Liver function creatinine, TSH,
5) Creatinine triglycerides 4) ECG (in patients over age 45 Liver function,
6) TSH 4) Body weight/BMI in females or with a cardiac history) body weight
7) EKG 5) Consider serum testosterone 5) Bone density
8) Body weight level in young females (Not applicable
6) Bone density for Clozapine)
Follow- a) #1, #2, #6 1) Repeat test #1 and #2 monthly Repeat CBC, LFT, electrolytes, None required Baseline, at 3
up and #8 at for 2 months, then 2 to 3 times urea creatinine monthly for 3 months then
3months then a year months, then annually annually
q6months 2) Test #3 and #4 q3months for Bone density if risk factors for
b) #3, #4 and #5 first year osteopenia are present (Not applicable
q6months 3) Test #5 if symptoms of for Clozapine)
c) #7 q5years hyperandrogenism or menstrual
irregularities occur; also test
prolactin, LH and TSH as well as
for insulin resistance syndrome
and hypertension
4) Ammonia level in event of
lethargy, mental status changes

Plasma Weekly for first 2 Two levels at least 3-5 days after Two levels 4 weeks apart after None required None required
level weeks, then q 3 – start of therapy then as per follow- start then q 6 months andafter
monitor 6 monthly and up #1 and 5 days after change in change in dose or addition/deletion (Not applicable
ing addition/deletion dose or addition/deletion of any of any other drug for Clozapine)
of other drug or other drug Consider a check serum levels of
dose change other drugs if CBZ is added
Anxiolytics and Sedatives

Sedatives, Hypnotics and Anxiolytics

defined by the DSM
– Anxiolytic defined as an agent that reduces
anxiety

Many SSRI antidepressants have been
shown to be effective in treating specific
anxiety disorders

Pregabalin (Generalized Anxiety Disorder)

Risperidone (OCD adjunctive agent)
buspirone is not a benzo. it acts on serotonin.

Buspirone (Buspar)

5 – 30 mg in divided doses

Not useful as a PRN

Partial agonist at 5HT1A autoreceptor

Mild presynaptic dopamine antagonist

Generally well tolerated

GAD
Anxiolytics and Sedatives

Chlordiazepoxide (Librium) first

introduced in 1960’s

Barbiturates popular
– Low therapeutic indices
– High addictive potential

GABA receptor complex
GABA-ergic System

30% of neurons in cerebral cortex,

substantia nigra and hippocampus

Major inhibitor of neurotransmission in
the CNS
GABA Pathways
GABA-ergic System

Neurotransmitter: GABA

Three known GABA receptor subtypes
– GABAA, GABAB, GABAC

GABAA
– gatekeeper for chloride channel
– allosterically modulated by:

Benzodiazepines, Barbiturates, Alcohol and
“Z-drugs”

GABAB binds selectively to Baclofen
GABAA Receptor

Alcohol Health & Research World 1997

Benzodiazepine Receptors

>/ 5 different BDZ receptor subtypes

BDZ 1 (Ω 1)
– Predominately in cerebellum
– Anxiolytic
– Sedative-hypnotic

BDZ 2 (Ω 2)
– Predominately in spinal cord and striatum
– Muscle relaxant

BDZ 3 (Ω 3)
– Abundant in kidney
Benzodiazepines

Uses:
– Anxiety
– Muscle spasm, dystonia, restless leg
– Insomnia
– Seizure
– Alcohol withdrawal
– Akathisia
– Psychotic agitation
Benzodiazepines –
Labeled Indications

Compendium of Pharmaceticals and Specialities 2010

Benzodiazepines

Clinical Handbook of Psychotropic Drugs 18th revised edition 2009

Benzodiazepines

Pharmacokinetics
– Marked inter-individual variation
– Duration of action determined mostly by
distribution not by elimination half-life
– Metabolized by hepatic oxidation,
reduction and conjugation
Why is this important? In liver failure, the redox pathway is more damaged than conjugation.
So in liver failure, the LOT drugs are safer (loraz, oxazepam, temazepam)

Oxidation/Reduction Conjucation

Lorazepam

Glucuronide

Temazepam
Pharmacokinetic Properties of Benzodiazepinesa

Compendium of Pharmaceticals and Specialities 2007

Benzodiazepines

Little correlation between plasma

concentration and clinical effects

Duration of action determined mostly
by distribution not t1/2

Shorter t1/2: withdrawal, rebound
anxiety addiction

Longer t1/2: accumulation in elderly
increasing falls and memory loss
Benzodiazepines –
Adverse Effects

Over-sedation

Cognitive processing, perceptomotor performance,
anterograde amnesia, visuaospacial and visuomotor abilities

Behavioural dyscontrol (paradoxic effect)

Confusion

Depression

Respiratory depression

Dysarthria, muscle weakness, ataxia, nystagmus

Anticholinergic effects

Synergistic effects with alcohol

Dependence
– Controversial issue
– Dose escalation/abuse

risk once symptomatic control is reached
lots of GPs are getting attacked by the college for over-prescription of benzos
“Z-drugs”

Zaleplon, zopiclone, zolpidem

Act at omega 1 but not omega 2
receptors

Omega 1
– Sedation

Omega 2
– Concentrated in brain areas regulating
cognition, memory and motor functioning
“Z-drugs”

Faster onset and shorter duration

Partial agonist to BDZ receptor
– Less:

rebound insomnia

dependence

withdrawal
“Z-drugs”

Zopiclone
Zaleplon
– Peak level: 1.5 h – Peak level: 0.9 – 1.5 h
– t1/2 3.8 – 6.5 h – t1/2 0.9 – 1.1 h
– Adult dose: 3.75 - 15mg – Adult dose: 5 to 10 mg

Eszopiclone Max dose is
Zolpidem
– Peak level: 1 h now 7.5 mg, – Peak level: 1.6 h
as told by the
– t1/2 5 - 7 h – t1/2 1.5 - 4 h
college
– Adult dose: 2 - 3 mg – Adult dose: 5 to 20 mg
Barbiturates

Low therapeutic index

Dependence

Low dose side effects:
– Euphoria, restlessness, violence

High dose side effects:
– Delirium, respiratory depression

Rash
 Hypnotics

Tricyclic Antidepressants
Antihistamines
– low dose – Hydroxyzine 10 – 400 mg

Trazodone – Diphenhydramine 25 – 200 mg
– 50 to 100 mg
Melatonin

Chloral Hydrate – Mixed reviews
– 0.5 – 2 g
L-tryptophan
– Onset: 30 mg – 1 to 5 g
– t1/2 4 – 12 h – No tolerance
– Caution in hepatic, renal, – Peak level: 1.8 – 3.3 h
PUD, cardiac distress – t1/2 2.2 – 7.4 h
– Tolerance/withdrawal

*Off Label*
Hypnotics

Ramelteon
– Melatonin receptor
– Low dependence
– 8 mg
– Peak level: 0.5 - 1.5 h
– t1/2 1 – 2 h (M-II 2 – 5 h)

exciting drug: low addiction potential, short half life so less hangover effect in the
morning. not approved yet in Canada.