Mood Stabccccccccccffffffffddddilizers.pdf

Mood Stabilizers
Med III & IV
Neuropharmacology

Introduction
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Depression & Mania represents the extremes on a continuum of
affect and are the principle focus.
The main symptoms of major or clinical depression are:
Prolonged feeling of worthlessness and guilt
Disruption of normal feeding habits
Sleep disturbances
A general slowing of behaviour
And frequent thoughts of suicide
UNZA-SoM Dept of Psychiatry & Behavioral sciences 2

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Mania by contrast is a mental state of extreme excitement
characterized by excessive euphoria
An affected person often formulates grandiose plans and behaves with
uncontrolled hyperactivity.
In Bipolar disorder, periods of mania may switch, sometimes
abruptly, into periods of depression and back again, or may
alternate with periods of regular behavior.

SIGNS AND SYMPTOMS OF MOOD
EPISODES ASSOCIATED WITH BIPOLAR
DISORDER
A.
B.
A.
C.
D.
Mania
Usually begins abruptly and symptoms escalate over several
days
A decreased need for sleep with an increase in goal directed
activity may be ﬁrst to appear or be reported.
This can be described as sleep-deprived energy enhancement and
should be differentiated from insomnia (i.e., patient feels tired and
sleep is wanted).
Patients may describe being euphoric, elated, or irritable
Engagement in multiple new projects may occur and is
perpetuated by inﬂated self-esteem or delusional grandiosity

E. Rapid, pressured, and loud speech
F. Racing thoughts may lead to ﬂight of ideas (i.e., accelerated
speech with a shifting of ideas connected only remotely)
G. Increased motor activity, sexuality, physical restlessness, and
distractibility
H. Psychotic symptoms can be seen in severe episodes but
resolve as mood improves
I. Co-occurring depressive symptoms may be present (i.e., with
mixed features)

A.
B.
A.
C.
Hypomania
Signs and symptoms of hypomania are similar to those for a
manic episode
Reduced need for sleep, rapid and/or pressured speech,
increased motor activity, physical restlessness, aberrant thought
process, and distractibility are present.
The symptoms are for a reduced period of time and with reduced
severity (i.e., hospitalization is not required and there are no psychotic
features).
Co-occurring depressive symptoms may be present (i.e., with
mixed features)

A.
B.
C.
Depression
Signs and symptoms characterized the same as depressive
episodes seen in major depressive disorder
Psychotic features and suicide attempts are more common in
bipolar depression than in unipolar depression
Co-occurring manic symptoms may be present (i.e., with
mixed features)

TREATMENT GUIDELINES
1.
1.
2.
3.
Acute manic Episode
Selection of pharmacotherapy for rapid control of behavioral
symptoms, sleep restoration, and mood stabilization/episode
resolution
Initial treatment is targeted at reducing agitation, aggression, and
impulsivity to prevent harm to self or others
The pharmacotherapy options for manic episodes vary by guideline
but in general ﬁrst-line options include lithium, valproate, or a second
-generation antipsychotic (SGA)
The combination of lithium or VP A with an SGA may be more
effective than these agents alone

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First-generation antipsychotics (FGAs) have ant manic
properties and certain guidelines consider these agents as a
second- or third-line option
BZDs have ant manic properties and may be helpful as a short-
term adjunctive treatment for psychomotor agitation, anxious
features, or sleep restoration.
A voidance of BZDs is recommended in patients at risk for or with a
history of an SUD

a.
b.
2. Limited data exist guiding the management of treatment
resistant mania
Treatment guidelines state that electroconvulsive therapy (ECT) or
clozapine should be considered for refractory cases
More recent clinical studies suggest that ECT may be considered
earlier in treatment with less risk of a manic episode that has been
previously thought

3. Monotherapy with gabapentin, Lamotrigine, levetiracetam,
verapamil, Tiagabine, and Topiramate are not recommended for
treatment of an acute manic episode

A 34-year-old woman with bipolar disorder has been controlled on
lithium 600 mg 2 times daily for the past 18 months after failing
other medication trials. She presents to her primary care
physician for increased nausea and vomiting. The lithium
concentration is 1.1 mEq/L, and she is found to be approximately
4 weeks pregnant. Her past psychiatric history is complicated
with six hospitalizations since the age of 18 for both manic and
depressive episodes, all severe with mixed features. She has
attempted suicide three times. What is the best course of action
in this patient?

a. Begin a slow cross-taper to Divalproex sodium
b. Discontinue lithium and begin a clozapine titration
c. Start a slow taper of lithium to a target concentration of 0.6
mEq/L
d. Stop the lithium and avoid the use of psychotropic medication

C .Start a slow taper of lithium to a target concentration of 0.6 mEq/L:The best
course of action today is to attempt to decrease the lithium to a lower serum
concentration.
This will decrease fetal exposure while providing treatment to the mother. Abrupt
discontinuation or dose changes should be avoided in patients with signif i
cant
illness. The
patient is at a high risk of relapse; immediate cessation of lithium is not warranted.
Clozapine has limited data in pregnancy and has other risks which outweigh its
benef it in this situation, including agranulocytosis, dose-related seizures, and
gestational diabetes. The patient has a complicated psychiatric history; abrupt
discontinuation could result in acute decompensation and high risk for self-harm
The complete avoidance of psychotropic medication is not a realistic treatment goal
for this patient. Divalproex sodium should be avoided in pregnancy secondary to the
risk of neural tube defects and risk of reduction of IQ in the offspring.

A 26-year-old patient is being discharged today after being
hospitalized for treabnent of a manic episode associated with
bipolar disorder. The patient is being discharged on lithium,
olanzapine, and lorazepam with an outpatient clinic follow-up in 2
weeks. The patient expresses a new interest in having a healthy
lifestyle, to include a regimen of dieting and exercise. What would
be the most important patient education point related to
medication safety over the next 2 weeks to provide?

a.
b.
c.
d.
Describe the risk of excessive caffeine intake that may result
in elevated lithium concentration
Caution to not abruptly reduce or fully eliminate sodium from
the diet, because this may result in decreased lithium
concentration
Describe the signs/symptoms of lithium toxicity and the
importance of adequate hydration during exercise, as
overexertion with dehydration may result in increased lithium
concentration
Support the decision to take on a healthier lifestyle, and advise
that the metabolic effects of olanzapine may contribute to
cardiovascular disease

Describe the signs/symptoms of lithium toxicity and the importance of
adequate hydration during exercise, as overexertion with dehydration may
result in increased lithium concentration:
Exercise without adequate hydration may result in increased lithium
concentration. All patients on lithium should be counseled on the
signs/symptoms of lithium toxicity. Caffeine intake may reduce lithium
serum concentration; excessive caffeine intake may interfere with sleep
and contribute to a relapse of illness. The patient should be counseled
regarding abrupt changes in dietary sodium, however, a signif icant
reduction or elimination of sodium from the diet would result in increased
lithium serum concentration. While diet and exercise will be important
steps to minimize the long-term consequences of metabolic syndrome
from second-generation antipsychotics, this would not directly impact
medication safety prior to the 2-week follow-up

Classic Mood stabilizers.
Lithium

A.
A.
B.
C.
D.
E.
F.
G.
Mechanism of Action - The exact mechanism of action of
lithium is not fully understood.
Enhances neuronal resilience, plasticity, proliferation
Modulates second messenger systems
Decreases 5-HT reuptake and increases post-synaptic 5-HT receptor
sensitivity
Inhibits DA synthesis, decreases DA receptor sensitivity
Decreases central nervous system (CNS) adrenergic activity
Enhances GABA activity
Alters calcium cellular function
UNZA-SoM Dept of Psychiatry Behavioral sciences 19

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B. Dosing
Lithium should be adjusted to target goal serum concentration
or titrated to effect:
Target for acute mania is 0.8-1.2 mEq/L and maintenance therapy is 0.6
-1.0 mEq/L
In full mania some patients may require, and tolerate, lithium
concentration of 1.2-1 .5 mEq/L .
In healthy adults, the steady-state concentration occurs after
approximately 5 days of stable dosing.
Serum concentration may be obtained sooner to assess the trajectory
of an initiated dose or when there is suspicion for toxicity, presence of
a drug interaction, or development of electrolyte/renal abnormalities.

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Serum concentration should be drawn in the morning as a 12-
hour post-dose concentration.
Lithium follows ﬁrst-order linear kinetics, and after a dose
change, the steady-state concentration is expected to change
proportionally.
Example: A healthy adult is taking 600 mg of lithium daily with a
steady state concentration of 0.4 mEq/L, doubling the dose will
likely result in a serum concentration of approximately 0.8
mEq/L. A stepwise titration to 1200 mg may improve tolerability

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Lithium clearance may be impacted by dehydration, sodium
depletion, and cardiac and renal dysfunction resulting in lithium
toxicity.
When tolerated, lithium can be given as a single dose.
Structural and functional kidney changes are more prominent in
patients who receive lithium in divided doses.
Once daily dosing reduces the occurrence of polyuria and may improve
adherence.

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Lithium pharmacokinetic properties are altered during
pregnancy.
Dose requirements will change during pregnancy compared with pre-
pregnancy dosing.
Glomerular ﬁltration rate (GFR) increases early in pregnancy and
begins to return to normal late in the third trimester.
Volume of distribution increases during pregnancy.
Lithium can be empirically decreased by at least 30% with close
evaluation of serum concentration after delivery

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Contraindications
Hypersensitivity to lithium.
Severe/unstable renal or cardiovascular disease, severe
debilitation, dehydration or sodium depletion

Warnings/Precautions
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Boxed Warning- Lithium toxicity; concentration should be
routinely monitored.
Lithium may unmask Brugada syndrome, a genetic disease
characterized by an abnormal, often asymptomatic,
electrocardiogram (ECG) and an increased risk of sudden
cardiac death.
Decreased renal concentrating ability that may present as
nephrogenic diabetes insipidus (NDI).
Acute and chronic reductions of GFR may occur. Renal monitoring
should be conducted.

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Warning/Precaution cont.
Use with caution in patients with significant fluid loss because
of increased risk of toxicity
Avoid medications that significantly alter lithium concentration.
Increased risk of fetal malformations with lithium therapy (i.e.,
cardiac abnormalities - Ebstein's anomaly)

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Onset of Action
Mania- Relatively slow onset of action (6-10 days) compared
with antipsychotics and VPA.
Full resolution of symptoms may take up to 3 weeks.
Depression - Greater than one month may be required for
maximal improvement

Adverse Events-Lithium
A.
A.
B.
C.
D.
Dermatologic
Acne- occurs in up to 33% of patients
Lithium may induce new acne or worsen current acne.
Patients between the ages of 20 and 30 years are more commonly
affected
Onset is typically within 2 weeks after initiation of lithium.
Resolution within 1 month after stopping or reducing the dose but
given the beneﬁts of lithium therapy, treatment of the acne should be
considered

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B. Psoriasis - Estimated to effect 1.8-6% of patients.
More common in patients greater than 50 years of age.
Exacerbation may not occur until after 1 month and up to 10
months for new induction.
Mild to moderate psoriasis can be treated with topical or
systemic therapy.
Severe cases warrant a dermatology consultation.
Dose reduction or discontinuation generally results in a return to
baseline or resolution

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C. Alopecia/thinning hair - Occurs in up to 19% of patients and is
more common in women.
Thyroid function should be tested because lithium-induced
hypothyroidism causes hair changes.

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a.
b.
a.
c.
d.
Cardiovascular
Caution is warranted in patients with known cardiac disease
Atrioventricular block or other conduction issues occur in about 28
-40% of patients. Lithium has been safely continued with the
exception of third degree heart block.
Bradyarrhythmia may result from sinus node dysfunction.
Monitor for severe bradycardia and syncope events that may be exacerbated
by hyperkalemia and hypothyroidism.
Brugada syndrome may be unmasked with lithium therapy. Lithium
should generally not be used in patients with Brugada syndrome, a
family history of Brugada syndrome, or family history of sudden
death at a young age.
Lithium toxicity can result in ECG changes, arrhythmias, and QTc
prolongation

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Gastrointestinal (GI)
Nausea may occur early in therapy. Changing to an ER
formulation may reduce nausea.
Supratherapeutic lithium concentration should be suspected with
severe nausea, vomiting, and diarrhea.
Dry mouth/thirst - Occurs in 35-75% of patients.
Education related to adequate hydration and use of other non-
pharmacologic techniques (e.g., hard candy) can help manage this side
effect.

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Genitourinary
Polyuria - Occurs in 30% of patients.
Initial strategies to reduce urinary frequency and output include:
Targeting lower serum concentration (0.45-0.75 mEq/L) and once daily
dosing.
Amiloride may be used to manage lithium-induced polyuria.
Monitor for a urine output of greater than 1.5 liters daily that may
indicate NDI
Acute kidney injury is most common in the setting of toxicity
and possibly as a result of direct tubular epithelial damage.
Other forms of kidney injury (e.g., acute tubular necrosis,
nephrotic syndrome) rarely occur.

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Chronic kidney disease (CKD) induced by lithium is controversial
and is challenging to study because of the longitudinal nature of
obtaining data.
Creatinine clearance decreases modestly over years.
Grade 3 CKD has been reported in a higher percentage of
lithium-treated patients (34.4%) compared with controls (13.1
%).
End stage renal disease related to lithium is rare and estimated
to occur in 0.2-1% of patients prescribed lithium for greater than
15 years

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Endocrine/Metabolic
Hypothyroidism - Occurs in 8-19% of patients.
Lithium may alter the conversion of T4 to T3, iodine
concentration, or directly affect thyroid hormone release.
Pre-existing hypothyroidism is not a contraindication for starting
lithium

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Hyperparathyroidism- Occurs in up to 9% of patients
Hypercalcemia may occur in up to 24% of patients.
Baseline and routine calcium serum concentration monitoring is
recommended.
Obtain parathyroid hormone (PTH) serum concentration if the patient
exhibits Hypercalcemia
Weight gain- Frequent and occurring within the ﬁrst 2 years of
treatment.
The average weight gain is approximately 4.6 kg.

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Hematologic - A benign leucocytosis may be seen.
Neurologic - Generally concentration-dependent with tremor,
seizures, coma, delirium, confusion

Lithium Toxicity
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Toxicities may be apparent at different serum concentrations
Initial presentation: Fine hand tremor, polyuria, mild thirst.
Serum concentration 1.5-2.0 mEq/L: Mild to moderate toxicities
including diarrhoea, vomiting, drowsiness, muscle weakness,
and decreased coordination.
Serum concentration 2.0-2.5 mEq/L: Moderate to severe
toxicities including ataxia, blurred vision, tinnitus, and ECG
changes.
Serum concentration greater than 3.0 mEq/L: Neurological
changes, coma

Management includes-supportive care
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Activated charcoal does not bind lithium and is of little value in
lithium overdose.
Sodium polystyrene sulfonate has demonstrated beneﬁt in a
limited number of reports
Forced diuresis is not recommended
Hemodialysis (HD) is effective in removing lithium and
recommended when the serum concentration is greater than 4
mEq/L or greater than 2.5 mEq/L with serious
cardiac/neurologic symptoms.
After one HD session, there is a signiﬁcant decrease in the lithium
concentration. However, a rebound effect generally occurs because of
the redistribution of intracellular lithium to the vasculature
necessitating repeated HD treatments.

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Permanent neurotoxicity can occur with lithium therapy in the
setting of both chronic and acute toxicity
i. Persistent symptoms described in rare cases include chronic
impairments of short-and long-term memory, ataxia, dysarthria,
and tremor
ii. These clusters of signs and symptoms are described in the
literature as the syndrome of irreversible lithium-effectuated
neurotoxicity (SILENT).

Patient Education
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Duration of Therapy- Once a diagnosis of bipolar disorder is
established, treatment is life-long.
If lithium is used to treat an acute episode, continue medication
without interruption unless not tolerated, adverse events, or
nonadherence.
Reassess therapy if patient experiences worsening mood or
inadequate response.

Patient Education cont…
1.
2.
3.
4.
1.
5.
Lithium should be taken at the same time every day as
prescribed
Take with food if this medication causes an upset stomach
SR products should not be crushed, chewed, or split
In your diet, avoid excessive caffeine or abrupt changes of
intake that can alter lithium serum concentration.
Let your provider know if you signiﬁcantly change your sodium intake,
because changing to a low salt diet can increase your lithium
concentration.
Report any changes or worsening of nausea, vomiting,
diarrhea, tremor

6. Maintain adequate hydration, and avoid dehydration but report
excessive thirst and/or the presence of signiﬁcant urination
7. A void over-the-counter (OTC) anti-inﬂammatory agents
8. Be sure that all of your providers are aware you are prescribed
lithium
9. Contact your provider if you are breast-feeding, become
pregnant, or plan to become pregnant
I 0. Report any worsening of sleep, depressive, or manic
symptoms

VALPROIC ACID (VPA)
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A. Mechanism of Action, many proposed:
Increases GABA concentration in the plasma and CNS.
Inhibits GABA catabolism.
Increase synthesis and release.
Prevent GABA reuptake.
Enhances the action of GABA at the GABAA receptor
Normalizes sodium and calcium channels
Reduces intracellular inositol and PKC isozymes.
Modulate gene expression.
Anti-kindling properties that decrease rapid cycling and mixed
states

1.
2.
3.
4.
5.
B. Contraindications
Hepatic disease or signiﬁcant hepatic dysfunction
Hypersensitivity to the agent
Urea cycle disorders
Mitochondrial disorders caused by mutations in mitochondrial
DNA polymerase-gamma (POLG) or children younger than 2
years of age suspected of having a POLG-related disorder
Pregnancy when used exclusively for prevention of migraine
headaches. Teratogenic effects including neural tube defects
are seen with in utero exposure

1.
2.
3.
4.
5.
6.
C. Warnings/Precautions
Boxed Warnings -hepatic failure, pancreatitis, teratogenic
effects
Dose-related thrombocytopenia
Hyperammonemia/encephalopathy
Hypothermia
Multi-organ hypersensitivity reactions (i.e., drug reaction with
eosinophilia and systemic symptoms (DRESS])
Increased risk of suicidality - FDA issued a warning in 2008

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7. Teratogenicity - Neural tube defects and decreased intelligence
quotient (IQ) scores.
VPA should be avoided in women of childbearing age unless
there are contraindications to alternative agents or the use is
essential for the management of the patient's illness.
D. Onset of Action - Can be seen as early as 3 days with loading

Adverse Events of VPA
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Dermatologic
Stevens Johnson Syndrome (SJS)Toxic Epidermal Necrolysis (TEN)
Alopecia is estimated to occur in 6% to 24% of treated patients
Gastrointestinal
Nausea (29%), vomiting (18%), diarrhoea (10-23%), constipation (10%)
Transaminitis and hepatotoxicity - highest risk is in pediatric patients.
Pancreatitis - occurs in up to 5% of patients

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Endocrine/metabolic
Signiﬁcant weight gain can occur in up to 50% of patients with an
average weight gain of 6-8 kg
Hyperammonemia- may occur with toxicity, higher dosing, and
concomitant enzyme inducing AEDs or topiramate.
Thrombocytopenia - incidence of 1-30%
a. Risk factors include advanced age and higher doses
b. VP A can be continued with mild to moderate thrombocytopenia,
however closer monitoring is recommended

• Neurologic- ataxia (15%), diplopia (16%), dizziness (44%),
sedation (32%), tremor (9-57% [higher doses])

Lamotrigine
• Mechanism of Action - Exact mechanism unknown:
l. Blocks voltage sensitive sodium channels
2. Modulates or decreases presynaptic aspartate and glutamate release
3. Anti-kindling properties to decrease rapid cycling and mixed states
4. Little to no effect on the release of GABA, DA, acetylcholine, or NE
5. Weak dihydrofolate reductase inhibitor in vitro.

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Adverse Events
Dermatologic
a. Benign rash (7%)
b. SJS/TEN and other serious rashes occur in 0.08% of patients with
bipolar disorder on monotherapy.
GI side effects are lower with the ER formulation
Hematologic- agranulocytosis (rare with estimated rate of
11280,000 patient-years of exposure)
Neurologic

Carbamazepine
Mechanism of Action - Complex
1. Blocks voltage sensitive sodium channels
2. Blocks calcium inﬂux through the N-methyl-D-aspartate (NMDA)
glutamate receptor and decreases calcium serum concentration
3. Modulates or decreases presynaptic aspartate and glutamate
release
4. Anti-kindling properties to decrease rapid cycling and mixed
states

Pharmacokinetics
• Before initiation, testing for the presence of HLA-B*1502 (an
inherited allelic variant of the HLA-B gene found almost
exclusively in Asians) is required in Asian patients. A positive
test confers an almost 10-fold increased risk of developing
SJS/TEN, and the use of CBZ should be avoided.

Contraindications
1. Bone marrow suppression
2. Hypersensitivity to CBZ or other tricyclic compounds
3. Concomitant use with MAOI’s, nefazodone, or lurasidone
4. Concomitant use of delavirdine or other non-nucleoside reverse
transcriptase inhibitors
Onset of Action - mean onset of action in mania is 7 days

Adverse Events
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Dermatologic
GI- nausea (29%), vomiting (18%), constipation (10%), dry
mouth (8%)
Hematologic- agranulocytosis/aplastic anemia and other mild
to moderate effects on the bone marrow. Risk is 5-8 times
greater than in the general population.
Neurologic- ataxia (15%), dizziness (44%), seizure (rare),
somnolence (32%), tremor (3%).
Osteomalacia /Osteoporosis-CBZ may lead to vitamin D
deﬁciency.

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