MOOD STABILIZER

MOOD STABILIZERS:
DEFINITION, CLASSIFICATION,
MECHANISM OF ACTION,
SIDE EFFECTS
AMIT CHOUGULE
MBBS,DPM
PG Registrar
Department Of Psychiatry
CMC,Vellore

LAYOUT
 BACKGROUND
 DEFINITION
 CLASSIFICATION
 MECHANISM OF ACTION
 SIDE EFFECTS
 MOOD STABILIZERS IN PREGNANCY AND LACTATION
 RE-DEFINING THE MOOD STABILIZER
 CONCLUSION

BACKGROUND
 Feeling is the subjective experience of emotion
 Emotion is a stirred-up state caused by physiological
changes occurring as a response to some event
 Emotion has behavioral, somatic, and psychic components
that affects the behaviour
 Mood is a pervasive and sustained emotion that colours
the person’s perception of the world
 Mood is frequently the reported emotional state
 Affect is defined as the patient’s present emotional
responsiveness (short-lived emotion)

MOOD INSTABILITY
 In the Adult Psychiatric Morbidity Survey (APMS) 2007
population rate of 13.9% was found
 Mood instability is part of:
1. Bipolar disorder
2. ADHD
3. Depressive disorder
4. Borderline personality disorder
 Mood instability is ‘rapid oscillations of intense affect,
with a difficulty in regulating these oscillations or their
behavioural consequences’

DEFINITION OF A MOOD STABILIZER
 “Mood stabilizer” – is not recognized by the FDA
 Single widely agreed upon definition does not exist
 IDEAL MOOD STABILIZER:
1. Would work in all phases of the illness and in all stages
of treatment
2. Would not aggravate or worsen any feature of the
illness

 A more relaxed definition by Sachs (1996)
 “Any medication that was able to decrease vulnerability
to subsequent episodes of mania or depression and not
exacerbate the current episode or maintenance phase of
treatment”
 Such a definition does not require absolute antidepressant
or antimanic efficacy

 The therapeutic benefits of lithium inspired definitions of a
mood stabilizer as:
“Any agent that possesses “triple threat” properties
(antimanic, antidepressant, prophylactic) in the
management of bipolar disorder (Keck & McElroy, 2003)”
a) The lack of such triple-threat mood stabilizers
b) Criticisms of lithium’s antidepressant powers
 Led to definitions of mood stabilizers of a uniphasic nature
–
“Efficacy in at least one pole of bipolar disorder without
exacerbating another phase (Keck & McElroy, 2003)”

 Ketter and Calabrese (2002) suggested:
 The term “Class A” mood stabilizers are agents that:
1. Stabilize mood from above baseline
2. Possess marked antimanic properties without causing
a worsening of depression
 The term “Class B” mood stabilizers are agents that:
1. Stabilize mood from below baseline
2. Possess marked antidepressant properties without
destabilizing the course of illness by inducing switches
into mania or episode acceleration

 Bauer and Mitchner (2004) proposed a “two-by-two”
definition by which an agent is considered a mood stabilizer
if:
1. It has efficacy in treating acute manic and depressive
symptoms and in prophylaxis
2. Lithium is the only agent that is able to meet this
definition
 The issue of precisely defining mood stabilizers while
avoiding indiscriminate use of the term
 We are still unable to define mood stabilization at a
molecular or even physiological level (Goodwin & Malhi,

CLASSIFICATION
 Lithium
 Anticonvulsants
1. Carbamazepine
2. Divalproex
3. Lamotrigine
 Typical antipsychotics
1. Chlorpromazine
2. Haloperidol
 Atypical Antipsychotics
1. Aripiprazole
2. Lurasidone
3. Olanzapine
4. Olanzapine+fluoxetine
5. Quetiapine
6. Risperidone
7. Ziprasidone
8. Asenapine

CLASSIFICATION
1. Mood Stabilizers for Acute Mania
2. Mood Stabilizers for Acute Bipolar Depression
3. Mood Stabilizers for Maintenance Treatment of
Bipolar Disorder
4. Mood Stabilizers for Rapid Cycling Bipolar
Disorder

MOOD STABILIZERS FOR ACUTE MANIA
 The meta-analysis demonstrated that:(Scherk et al., 2007)
1. Atypical antipsychotics were significantly more effective
than placebo
2. Had comparable efficacy to mood stabilizers
3. Combination of atypicals and mood stabilizers was
more effective than mood stabilizers alone
 A multiple-treatments meta-analysis was used to rank all
antimanic drugs based on: (Cipriani et al., 2011)
1. Efficacy (mean change on mania rating scales)
2. Acceptability (overall dropout rate)

MOOD STABILIZERS FOR ACUTE MANIA
 Antipsychotics were more effective than lithium and
anticonvulsants
 Risperidone, olanzapine and haloperidol outperformed
other drugs
 In terms of acceptability, olanzapine, risperidone, and
quetiapine were better than haloperidol
 Asenapine, ziprasidone, valproate, and lithium showed
generally inferior efficacy and acceptability profiles
 Lamotrigine, topiramate, and gabapentin were not superior
to placebo in reducing manic symptoms

MOOD STABILIZERS FOR ACUTE BIPOLAR
DEPRESSION
 Bipolar depression remains an area of unmet need
 Limited data to provide a strong evidence base to treat
bipolar depression
 (Olanzapine plus Fluoxetine), quetiapine, and lurasidone
have shown efficacy
 Patients with bipolar depression are more sensitive and
less tolerant of atypical antipsychotics than those with
bipolar mania or schizophrenia
(Gao et al., 2008a, 2008b; Wang et al.,
2011)

MOOD STABILIZERS FOR MAINTENANCE
 Eight agents have been
demonstrated to have
efficacy in maintenance
treatment
 Based on evidence from
large, randomized,
double-blind, placebo-
controlled studies
1. Lithium
2. Divalproex
3. Lamotrigine
4. Olanzapine
5. Aripiprazole
6. Quetiapine
7. Ziprasidone
8. Risperidone/Paliperid
one

MOOD STABILIZERS FOR MAINTENANCE
 The BALANCE:
 Valproate as monotherapy was relatively less effective
than lithium or the combination of lithium and valproate
 Valproate is not licensed for prophylaxis (2nd line)
 Olanzapine, quetiapine and Aripiprazole are:
1. Licensed for prophylaxis
2. Appear to protect against both mania and depression
 Carbamazepine is considered to be third line
 Lamotrigine seems only to prevent recurrence of
depression
 Lithium plus a SGA is probably the polypharmacy regimen

MOOD STABILIZERS FOR RAPID CYCLING
BIPOLAR DISORDER(RCBD)
 Frequently recurring and refractory depressive episodes are a
“hallmark” of RCBD
 RCBD may be exacerbated by antidepressant use (Calabrese et
al., 2001a)
 Divalproex is more effective in RCBD (Calabrese & Delucchi,
1990)
 More recent double-blind comparator study did not find
divalproex to be superior to lithium in the long-term management
of RCBD (Calabrese et al., 2005b)
 Lithium, divalproex, lamotrigine, and the atypical antipsychotics
are the current mainstays of treatment

MECHANISM OF
ACTION
AND
SIDE EFFECTS

LITHIUM- MECHANISM OF ACTION
 Lithium introduced for the treatment of “Psychotic
excitement”
 Antimanic effect was confirmed by a team led by Mogen's
Schou
 Approved for use in mania by the FDA in 1970
 Targets have shifted from ion transport and presynaptic
neurotransmitter-regulated release to postsynaptic receptor
regulation, to signal transduction cascades, to gene
expression and neuroplastic changes
 Research strategy has evolved from a focus on a class of

NEUROTRANSMITTER SYSTEM
 Interaction with various neurotransmitter systems
 NORADRENERGIC
 Little is known about the effects on noradrenergic
neurotransmission
 DOPAMINE
1. Lithium appears to reduce presynaptic dopaminergic activity
2. Acts postsynaptically to prevent the development of receptor
up-regulation and supersensitivity
 CHOLINERGIC
1. Lithium enhances receptor-mediated responses at
neurochemical, electrophysiologic, and behavioral levels
2. Increases acetylcholine synthesis and uptake

NEUROTRANSMITTER SIGNALING
 SEROTONERGIC:
 Increases central serotonergic transmission
 GABA AND GLUTAMATE:
1. Increases GABAergic inhibition
2. Reduce excitatory glutamergic neurotransmission
 Changes in receptor sensitivity are associated with chronic
administration
(Greenspan et al., 1970; Beckmann et al., 1975; Bowers &
Heninger, 1977)

CIRCADIAN RHYTHM
 Lengthen the circadian period across species- unique
property
 Lithium- Phase delay in the circadian cycle
 Effects noted after long-term exposure and within the
range of concentrations (0.6 to 1.2 mM)
 BPD is characterised by phase advance of the central
pacemaker within the suprachiasmatic nucleus
 Lithium may achieve its therapeutic and prophylactic
effects by:
1. Altering the balance of neurotransmitter signaling in
hypothalamus

SYNAPTIC SIGNALING AND SIGNAL
TRANSDUCTION
 Untreated manic patients may have raised:
1. Myo-inositol
2. Phospho-mono-ester (PME) concentrations
 Effectiveness is due to normalizing actions on the:
1. Phosphoinositol second messenger system
2. Arachidonic acid cascade

TRANSDUCTION
 Molecular targets for lithium in phosphoinositide
(PI)signaling
 Three major sites for an inhibitory action of lithium:
1. Inositol 1-monophosphatase (IMPase)
2. Inositol polyphosphate 1-phosphatase (IPPase)
3. Glycogen synthase kinase 3 (GSK-3)
 Inhibition of IMPase and IPPase results in reduction of
myo-inositol (myo-Ins) and subsequent changes in the
kinetics of:
1. Receptor-activated phospholipase C (PLC)
2. Breakdown of phosphoinositide-4,5-bisphosphate to
(DAG)

TRANSDUCTION
 DAG directly activates protein kinase C (PKC)
 This activation results in downstream post-translational
changes in proteins that affect:
1. Receptor complexes
2. Ion channel activity
3. Transcription factors
 Transcription factors alter gene expression of proteins
such as MARCKS (myristoylated alanine-rich C-kinase
substrate)
 MARCKS are integral to long-term neuroplastic changes in
cell function

TRANSDUCTION
 Inhibition of GSK-3:
1. Alters gene transcription and neuroplastic events
through an increased expression of downstream
proteins such as catenin
2. Mediate cell growth and survival

TRANSDUCTION
 Lithium has significant:
1. Inhibitory effects on the (cAMP)-generating system
which is induced by various neurotransmitters and
hormones
2. Increases basal cAMP in several regions of the brain
with chronic administration
 Signal transduction may thus be stabilized by lithium via a
balancing effect of increasing basal activity while inhibiting
stimulated activity
(Forn & Valdecasas, 1971; Marmol et al., 1992, (Mork et al., 1992)

ADVERSE EFFECTS OF LITHIUM
 Neurological
1. Benign, nontoxic: Dysphoria, lack of spontaneity, slowed
reaction time, memory difficulties
2. Tremor: Postural, occasional extrapyramidal
3. Toxic: Course tremor, dysarthria, ataxia, neuromuscular
irritability, seizures, coma, death
4. Miscellaneous: Peripheral neuropathy, benign
intracranial hypertension, myasthenia gravis-like
syndrome, altered creativity, lowered seizure threshold
 Cardiovascular
1. Benign T-wave changes
2. Sinus node dysfunction
 Dermatological
 Acne, hair loss, psoriasis, rash

 Metabolic:
1. Lithium increases the risk of hypothyroidism
2. In middle‐aged women, the risk may be up to 20%
3. Testing thyroid autoantibodies in this group
recommended
4. TFTs usually return to normal when lithium is
discontinued
5. Increased risk of hyperparathyroidism
6. Chronically increased serum calcium include renal
stones, osteoporosis, dyspepsia, hypertension and

 RENAL:
1. Reduction in urinary concentrating capacity
(nephrogenic diabetes insipidus)
2. Thirst and polyuria
3. Polyuria more frequent with twice‐daily dosing
4. Reversible in the short to medium term but may be
irreversible after long‐term treatment (>15 years)
5. Reduction in the glomerular filtration rate (GFR)
6. A very small number of patients may develop interstitial
nephritis
7. Lithium levels of >0.8 mmol/L are associated with a
higher risk of renal toxicity

LITHIUM TOXICITY PROFILE:
A SYSTEMATIC REVIEW AND META-ANALYSIS
(THE LANCET, 2012, MCKNIGHT ET.AL)
 Lithium is associated with increased risk of reduced urinary
concentrating ability, hypothyroidism, hyperparathyroidism
and weight gain
 There is little evidence for a clinically significant reduction in
renal function in most patients, and the risk of end-stage
renal failure is low
 The risk of congenital malformations is uncertain
 Consistent finding of a high prevalence of
hyperparathyroidism; calcium concentrations should be
checked before and during treatment

ANTIEPILEPTIC DRUGS (AED) IN BPAD
 ECT is one of the most effective treatment of mania
 With every application of ECT the seizure threshold
increases
 Manic patients show an increase in seizure threshold with
fading manic symptomatology
 Clinical rationale for using anticonvulsants in the acute
treatment of mania
 Not all anticonvulsants have been able to demonstrate
efficacy for mood disorder
 Complex differences in the mechanisms of action of these

MECHANISM OF ACTION OF AED IN BPAD
 Valproate is the first anticonvulsant to be approved as a
treatment for bipolar mania by the FDA in 1995
 Large-scale, randomized, double-blind parallel group study
found divalproex to be equivalent to lithium in superiority
over placebo for the management of acute mania
(Bowden et al., 1994)
 Divalproex and carbamazepine provide antimanic mood
stabilization based on randomized, double-blind, placebo-
controlled studies with adequate sample size
 AEDs like lamotrigine, topiramate, and gabapentin have not
demonstrated strong evidence

MECHANISM OF ACTION OF VALPROATE
(VPA) AND CARBAMAZEPINE (CBZ)
 GABA
1. CBZ is a positive modulator of the GABA-A receptor
2. Increases the GABA-A receptor–mediated chloride
current
3. VPA increases GABA release in different areas of the
brain
 EXCITATORY AMINO ACIDS
1. CBZ leads to inhibition of N-methyl-D-aspartate
(NMDA) receptor
2. VPA leads to decrease in aspartate release
3. Effect mediated by the blockade of sodium channels
 DOPAMINE:
1. In many brain areas, dopamine turnover is increased
by VPA

EFFECTS OF AED ON INTRACELLULAR
MESSAGING SYSTEMS
 Disturbed intracellular calcium homeostasis may be a final
common pathway in BPAD
 Anticonvulsants have potentially beneficial effects through
interference with intracellular calcium signaling
 AEDs affect voltage-dependent calcium channels directly
 CBZ exerts strong calcium channel antagonism on L-type
calcium channels
 VPA exerts calcium-antagonistic effects through blockade
of another voltage-dependent calcium channel the T
channel

 A decreased Na/K ATPase activity has been described as
a state marker in acutely ill bipolar patients
 CBZ is capable of stimulating Na/K ATPase causing a
reduction in intracellular calcium

Sensitization And Kindling—Behavioral
Models Explaining The Recurrence Of
Bipolar Disorder
 Kraepelin (1921)-
1. Marked psychosocial stressor usually preceded the
first affective episode
2. Subsequent episodes showed minor or even absent
notable life events
3. Frequency of episodes tends to increase leading to
rapid cycling
4. Decrease in efficacy of mood stabilizing drugs
 Kindling reflects a cumulative and progressive unfolding of
physiological and behavioral changes in response to
repeated stimulation over time that eventuates in seizures,
initially triggered then occurring spontaneously

 The correlate on the synaptic level is an increase in
glutamatergic transmission with a parallel decrease in
inhibitory GABAergic transmission
 AED useful in BPAD exert antikindling potencies
 Tolerance or drug resistance is observed with long term
treatment and/or discontinuation of lithium, CBZ and VPA

SIDE EFFECTS OF VALPROATE
 Hepatotoxicity
1. Rare, idiosyncratic event
2. Estimated risk 1:118,000 (adults)
3. Greatest risk profile (polypharmacy, younger than
2 yrs of age, mental retardation)→ 1:800
 Pancreatitis
1. Rare, similar pattern to hepatotoxicity
2. Incidence in clinical trials data is 2 of 2,416
(0.0008%)
3. Asymptomatic amylase not predictive

 Hyperammonemia
1. Rare—
2. more common in combination with carbamazepine
(Tegretol)
3. Associated with coarse tremor
4. Associated with urea cycle disorders
5. Divalproex is contraindicated in patients with urea
cycle disorders
 Somnolence in the elderly
 Thrombocytopenia
 More likely with valproate levels ≥ 110 μ g/mL (women)
and ≥ 135 μ g/mL (men)

 GI distress
 Tremor
 Weight gain
 Alopecia (hair loss)
 PCO syndrome
 Hepatic enzyme elevation; < 3 times
 Risk (1:600) in children < 2 yrs of age for fatal hepatitis
 Hypothermia

SIDE EFFECTS OF CARBAMAZEPINE
1. Dizziness, ataxia, diplopia
2. Fatigue, sedation
3. Benign rash
4. Severe rash
5. Benign WBC suppression
6. Agranulocytosis
7. Aplastic anemia
8. Weight gain
9. Hyponatraemia
10. Thyroid hormone suppression
11. Tremor
12. Hepatitis
13. Memory disturbance

MECHANISM OF ACTION ANTIPSYCHOTICS
IN BPAD
 D2 antagonism in combination with 5HT2A antagonism
accounts for the mood-stabilizing properties
 Prevents manic switches by producing a regionally
selective balance between dopamine and serotonin circuits
(Brugue & Vieta, 2007, Yatham et al., 2005, Xu et al., 2002; Qing
et al., 2003)

MOOD STABILIZERS IN PREGNANCY AND
LACTATION
 Effects are discussed only for risk during the first trimester
 Psychotropics are harmful even after organogenesis
 Intrauterine exposure during the second and third trimester
can lead to postnatal complications
1. Teratogenicity:
“Risk of congenital physical deformities over the base
line rate of 2.0–2.5%”
2. Obstetrical complications
3. Perinatal syndrome
4. Long-term behavioral sequelae

 No psychotropic drug has been approved by (FDA) for use
during pregnancy
 Most antipsychotics are classified as category C
 Mood stabilizers like lithium, valproate and carbamazepine
are classified as category “D” drugs

LITHIUM
 Major congenital anomalies with prenatal exposure is
Ebstein’s anomaly
 Cohen et.al meta-analysis - between 1/1000 (0.1%) and
1/2000 (0.05%) births
 10–20 times higher than the risk of Ebstein’s anomaly in the
general population
 Absolute risk is small (0.05–0.1%)
 Lithium has been associated with congenital abnormalities
like:
1. Large for gestational age infants
2. Anencephaly
3. Oromandibular-limb hypogenesis
4. Premature closure of arterial duct

 Exposure during labor and delivery is associated with the
risk of “floppy baby” syndrome
 Follow-up studies of children (for 3.5–5 years) exposed to
lithium during pregnancy lack evidence for significant:
1. Behavioral problems
2. lower scores on the performance intelligence quotient
(IQ)
3. Growth and general development
 Lithium is considered to be the safest mood stabilizer for
use during pregnancy

VALPROATE
 Increased risk of causing neural tube defects in the range of 1.0–
5.0%,
 About 2–10-fold higher than the general population (0.5%)
 Prenatal exposure to valproate has been associated:
1. Cardiovascular malformations- ASD
2. Intrauterine growth retardation
3. Genital anomalies
4. Hydrocephalus
5. Spina bifida
6. Cleft palate
7. Hypospadias
8. Polydactyl
9. Craniosynostosis
10. Limb defects (radial ray effects, fibrous aplasia of lower limbs)
11. Pulmonary atresia

CARBAMAZEPINE
 Risk of neural tube defects at a rate of about 0.5–1.0%
 Infants are also at increased risk for:
1. Craniofacial abnormalities
2. Fingernail hypoplasia
3. Developmental delay
4. Growth retardation
5. Microcephaly
6. Spina bifida
7. Cardiac abnormalities
 Risk increases in a dose–dependent pattern with higher
risk with doses 400 mg/day and above

NON-PHARMACOLOGICAL –MOOD
STABILISERS
1. Sleep-wake cycle
stabilization
2. Exercise
3. Substance abstinence
4. Specific psychological
interventions
 Cognitive behavioural
therapy
 Interpersonal-social
rhythm therapy
 Family-focused therapy,
mindfulness-based
therapies
 Psychoeducation
5. Non-specific psychosocial
interventions
 Activity scheduling
 Sleep hygiene
 Social skills training
 Therapeutic
engagement
 Supportive therapies
 Compliance strategies
 Problem-solving
 Basic stress
management

REDEFINING MOOD STABILIZERS
 Goodwin and Malhi (2007) “What is a mood stabilizer?”
 Effectively highlighted the limitations of various definitions
 Flaws in the term “mood stabilizer”
 They concluded that only lithium just barely qualifies for
the strictest definition proposed by Bauer and Mitchner
(2004) –
“a mood stabilizer should treat both poles of bipolar
disorder acutely and prevent recurrence”
 Term should be reserved only for agents that have been
compared with lithium and have performed adequately in

PARTIAL MOOD STABILIZER
 Term “mood stabilizer” should be used in general
discussions about the search for an ideal agent that is
effective in all poles of illness
 Recognize that no complete mood stabilizer has been
discovered
 Current psychotropic agents are partial mood stabilizers at
best
 Term “Partial mood stabilizer”
“Lack of mood destabilizing effects plus efficacy in at
least one area of bipolar disorder management”

REFERENCES
1. Psychiatry / edited by allan tasman, jerald kay, jeffrey A.
Lieberman, michael B. First, michelle B. Riba.–Fourth edition.
2. Kaplan & sadock’s comprehensive textbook of psychiatry /
[edited by] benjamin james sadock, virginia alcott sadock,
pedro ruiz. – 9th ed.
3. The maudsley prescribing guidelines in psychiatry / david
taylor, carol paton, shitij kapur. – 12th edition.
4. Robert h. Lenox, alan frazer. Mechanism of action of
antidepressants and mood stabilizers.
Neuropsychopharmacology: the fifth generation of progress
5. Sandeep Grover, Ajit Avasthi. Mood stabilizers in pregnancy
and lactation. Indian J Psychiatry 57 (Supplement 2), July 2015
6. Heinz Grunze,MD, PhD; Sandra Schlösser, MA; Benedikt
Amann, MD; Jörg Walden,MD, PhD. Anticonvulsant drugs in
bipolar disorder. Dialogues in Clinical Neuroscience - Vol 1-
No. 1

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