mood stabilizer
TRANSCRIPT
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
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
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)”
DEFINITION OF A MOOD STABILIZER
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
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)3. Inositol-1,4,5-trisphosphate
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 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
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
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)
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”
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