2. LAYOUT
BACKGROUND
DEFINITION
CLASSIFICATION
MECHANISM OF ACTION
SIDE EFFECTS
MOOD STABILIZERS IN PREGNANCY AND LACTATION
RE-DEFINING THE MOOD STABILIZER
CONCLUSION
3. 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)
4. 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’
5. 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
6. DEFINITION OF A MOOD STABILIZER
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
7. DEFINITION OF A MOOD STABILIZER
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)”
8. DEFINITION OF A MOOD STABILIZER
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
9. DEFINITION OF A MOOD STABILIZER
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,
11. 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
12. 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)
13. 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
14. 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)
15. 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
16. 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
17. 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
20. 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
21. 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
22. 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)
23.
24. 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
25. 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
26. SYNAPTIC SIGNALING AND SIGNAL
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)
27.
28. SYNAPTIC SIGNALING AND SIGNAL
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
29. SYNAPTIC SIGNALING AND SIGNAL
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
30.
31. SYNAPTIC SIGNALING AND SIGNAL
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)
34. ADVERSE EFFECTS OF LITHIUM
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
35. ADVERSE EFFECTS OF LITHIUM
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
36. 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
37. 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
38. 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
39. 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
40. 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
41. 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
42. 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
43. 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
44.
45.
46. 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
47. SIDE EFFECTS OF VALPROATE
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)
48. SIDE EFFECTS OF VALPROATE
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
50. 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)
51. 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
52. 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
53. 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
54. 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
55. 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
56. 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
58. 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
59. 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”
60. 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
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