MOOD STABILIZER

MOOD STABILIZERS: DEFINITION, CLASSIFICATION, MECHANISM OF ACTION, SIDE EFFECTS

AMIT CHOUGULE MBBS,DPMPG RegistrarDepartment Of PsychiatryCMC,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 emotionEmotion 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 stateAffect 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 foundMood instability is part of:1. Bipolar disorder2. ADHD3. Depressive disorder4. Borderline personality disorderMood 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 FDASingle 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

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 stabilizersb) 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 baseline2. Possess marked antimanic properties without

causing a worsening of depressionThe term “Class B” mood stabilizers are agents that:

1. Stabilize mood from below baseline2. Possess marked antidepressant properties without

destabilizing the course of illness by inducing switches into mania or episode acceleration

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 prophylaxis2. Lithium is the only agent that is able to meet this

definitionThe issue of precisely defining mood stabilizers while avoiding

indiscriminate use of the termWe are still unable to define mood stabilization at a molecular

or even physiological level (Goodwin & Malhi, 2007)

CLASSIFICATION

Lithium Anticonvulsants1. Carbamazepine2. Divalproex3. Lamotrigine Typical antipsychotics1. Chlorpromazine2. Haloperidol

Atypical Antipsychotics1. Aripiprazole2. Lurasidone 3. Olanzapine 4. Olanzapine+fluoxetine5. Quetiapine6. Risperidone7. Ziprasidone8. Asenapine

CLASSIFICATION 1. Mood Stabilizers for Acute Mania2. Mood Stabilizers for Acute Bipolar

Depression3. Mood Stabilizers for Maintenance

Treatment of Bipolar Disorder4. 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 aloneA 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 needLimited data to provide a strong evidence base to treat

bipolar depression (Olanzapine plus Fluoxetine), quetiapine, and lurasidone have

shown efficacyPatients 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. Lithium2. Divalproex3. Lamotrigine4. Olanzapine5. Aripiprazole6. Quetiapine7. Ziprasidone8. Risperidone/

Paliperidone

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 prophylaxis2. Appear to protect against both mania and

depressionCarbamazepine is considered to be third lineLamotrigine seems only to prevent recurrence of

depressionLithium plus a SGA is probably the polypharmacy

regimen of choice

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

Combination strategies are most often necessary

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 to alteration in pattern of signaling in critical regions of the brain

(Cade, 1949, Schou et al., 1954)

NEUROTRANSMITTER SYSTEM Interaction with various neurotransmitter systems NORADRENERGIC

Little is known about the effects on noradrenergic neurotransmission

DOPAMINE1. Lithium appears to reduce presynaptic dopaminergic activity2. 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 inhibition2. Reduce excitatory glutamergic

neurotransmissionChanges in receptor sensitivity are associated with

chronic administration (Greenspan et al., 1970; Beckmann et al., 1975; Bowers & Heninger, 1977)

CIRCADIAN RHYTHMLengthen the circadian period across species-

unique property Lithium- Phase delay in the circadian cycleEffects 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 hypothalamus2. Resynchronizing the physiologic systems

underlying recurrent affective illness

SYNAPTIC SIGNALING AND SIGNAL TRANSDUCTION

Untreated manic patients may have raised:1. Myo-inositol2. Phospho-mono-ester (PME) concentrations

Effectiveness is due to normalizing actions on the:1. Phosphoinositol second messenger system2. Arachidonic acid cascade


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)3. Inositol-1,4,5-trisphosphate


DAG directly activates protein kinase C (PKC)This activation results in downstream post-

translational changes in proteins that affect:1. Receptor complexes2. Ion channel activity3. 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


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


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 LITHIUMNeurological

1. Benign, nontoxic: Dysphoria, lack of spontaneity, slowed reaction time, memory difficulties

2. Tremor: Postural, occasional extrapyramidal3. Toxic: Course tremor, dysarthria, ataxia,

neuromuscular irritability, seizures, coma, death4. Miscellaneous: Peripheral neuropathy, benign

intracranial hypertension, myasthenia gravis-like syndrome, altered creativity, lowered seizure threshold

Cardiovascular1. Benign T-wave changes2. Sinus node dysfunction

Dermatological Acne, hair loss, psoriasis, rash

ADVERSE EFFECTS OF LITHIUM

Metabolic:1. Lithium increases the risk of hypothyroidism2. In middle‐aged women, the risk may be up to 20%3. Testing thyroid autoantibodies in this group recommended4. TFTs usually return to normal when lithium is discontinued5. Increased risk of hyperparathyroidism6. Chronically increased serum calcium include renal stones,

osteoporosis, dyspepsia, hypertension and renal impairment

ADVERSE EFFECTS OF LITHIUMRENAL:

1. Reduction in urinary concentrating capacity (nephrogenic diabetes insipidus)

2. Thirst and polyuria3. Polyuria more frequent with twice‐daily dosing4. 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 nephritis7. 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

No significant increased risk of alopecia, or skin disorders

ANTIEPILEPTIC DRUGS (AED) IN BPAD

ECT is one of the most effective treatment of mania With every application of ECT the seizure threshold increasesManic patients show an increase in seizure threshold with fading

manic symptomatologyClinical rationale for using anticonvulsants in the acute treatment

of maniaNot all anticonvulsants have been able to demonstrate efficacy

for mood disorderComplex differences in the mechanisms of action of these drugs

(Muzina et al., 2005)

MECHANISM OF ACTION OF AED IN BPADValproate is the first anticonvulsant to be approved as a

treatment for bipolar mania by the FDA in 1995Large-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 ACIDS1. CBZ leads to inhibition of N-methyl-D-aspartate

(NMDA) receptor2. VPA leads to decrease in aspartate release3. Effect mediated by the blockade of sodium

channels DOPAMINE:

1. In many brain areas, dopamine turnover is increased by VPA

2. Effect not seen with CBZ3. Evidence for role of dopamine D4 receptor gene

and the dopamine transporter gene in BPAD

EFFECTS OF AED ON INTRACELLULAR MESSAGING SYSTEMSDisturbed intracellular calcium homeostasis may be a

final common pathway in BPADAnticonvulsants have potentially beneficial effects

through interference with intracellular calcium signalingAEDs affect voltage-dependent calcium channels directlyCBZ exerts strong calcium channel antagonism on L-type

calcium channelsVPA 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 DisorderKraepelin (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 drugsKindling 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 potenciesTolerance or drug resistance is observed with long

term treatment and/or discontinuation of lithium, CBZ and VPA

SIDE EFFECTS OF VALPROATEHepatotoxicity

1. Rare, idiosyncratic event2. Estimated risk 1:118,000 (adults)3. Greatest risk profile (polypharmacy,

younger than 2 yrs of age, mental retardation)→ 1:800

Pancreatitis1. Rare, similar pattern to hepatotoxicity 2. Incidence in clinical trials data is 2 of 2,416

(0.0008%)3. Asymptomatic amylase not predictive

SIDE EFFECTS OF VALPROATE

Hyperammonemia1. Rare—2. more common in combination with

carbamazepine (Tegretol)3. Associated with coarse tremor4. Associated with urea cycle disorders5. Divalproex is contraindicated in patients with

urea cycle disordersSomnolence in the elderlyThrombocytopenia

More likely with valproate levels ≥ 110 μ g/mL (women) and ≥ 135 μ g/mL (men)

SIDE EFFECTS OF VALPROATE

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

hepatitisHypothermia

SIDE EFFECTS OF CARBAMAZEPINE

1. Dizziness, ataxia, diplopia2. Fatigue, sedation3. Benign rash4. Severe rash 5. Benign WBC suppression6. Agranulocytosis7. Aplastic anemia8. Weight gain9. Hyponatraemia10. Thyroid hormone suppression11. Tremor12. 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 complications1. Teratogenicity:

“Risk of congenital physical deformities over the base line rate of 2.0–2.5%”

2. Obstetrical complications 3. Perinatal syndrome4. 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

LITHIUMMajor congenital anomalies with prenatal exposure is

Ebstein’s anomalyCohen et.al meta-analysis - between 1/1000 (0.1%)

and 1/2000 (0.05%) births10–20 times higher than the risk of Ebstein’s anomaly

in the general populationAbsolute risk is small (0.05–0.1%)Lithium has been associated with congenital

abnormalities like:1. Large for gestational age infants2. Anencephaly3. Oromandibular‑limb hypogenesis4. 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 problems2. 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- ASD2. Intrauterine growth retardation3. Genital anomalies 4. Hydrocephalus 5. Spina bifida6. Cleft palate7. Hypospadias8. Polydactyl9. Craniosynostosis10. Limb defects (radial ray effects, fibrous aplasia of lower limbs)11. Pulmonary atresia

CARBAMAZEPINERisk of neural tube defects at a rate of about 0.5–

1.0% Infants are also at increased risk for:

1. Craniofacial abnormalities2. Fingernail hypoplasia3. Developmental delay4. Growth retardation5. Microcephaly6. Spina bifida7. 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. Exercise3. Substance abstinence 4. Specific psychological

interventionsCognitive behavioural

therapy Interpersonal-social

rhythm therapyFamily-focused

therapy, mindfulness-based therapies

Psychoeducation

5. Non-specific psychosocial interventionsActivity schedulingSleep hygieneSocial skills trainingTherapeutic

engagementSupportive therapiesCompliance

strategiesProblem-solvingBasic stress

management

REDEFINING MOOD STABILIZERSGoodwin and Malhi (2007) “What is a mood

stabilizer?”Effectively highlighted the limitations of various

definitionsFlaws 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 such a comparison

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”

REFERENCES1. 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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MOOD STABILIZER