MOOD STABILIZER

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

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

3. BACKGROUND F eeling is the subjective experience of emotion E motion 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: Bipolar disorder ADHD Depressive disorder B orderline 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 S ingle widely agreed upon definition does not exist IDEAL MOOD STABILIZER: Would work in all phases of the illness and in all stages of treatment W ould not aggravate or worsen any feature of the illness

6. DEFINITION OF A MOOD STABILIZER A more relaxed definition by Sachs ( 1996) “ A ny 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 )” The lack of such triple-threat mood stabilizers C riticisms of lithium’s antidepressant powers L ed 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: Stabilize mood from above baseline P ossess marked antimanic properties without causing a worsening of depression The term “Class B” mood stabilizers are agents that: S tabilize mood from below baseline P ossess 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: It has efficacy in treating acute manic and depressive symptoms and in prophylaxis 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 , 2007)

10. CLASSIFICATION Lithium Anticonvulsants Carbamazepine Divalproex Lamotrigine Typical antipsychotics Chlorpromazine Haloperidol Atypical Antipsychotics Aripiprazole Lurasidone Olanzapine Olanzapine+fluoxetine Quetiapine Risperidone Ziprasidone Asenapine

11. CLASSIFICATION Mood Stabilizers for Acute Mania Mood Stabilizers for Acute Bipolar Depression Mood Stabilizers for Maintenance Treatment of Bipolar Disorder Mood Stabilizers for Rapid Cycling Bipolar Disorder

12. MOOD STABILIZERS FOR ACUTE MANIA The meta-analysis demonstrated that : ( Scherk et al., 2007 ) Atypical antipsychotics were significantly more effective than placebo Had comparable efficacy to mood stabilizers 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) Efficacy (mean change on mania rating scales) 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 L imited data to provide a strong evidence base to treat bipolar depression (Olanzapine plus Fluoxetine), quetiapine , and lurasidone have shown efficacy P atients 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 B ased on evidence from large, randomized, double-blind, placebo-controlled studies Lithium Divalproex Lamotrigine Olanzapine Aripiprazole Quetiapine Ziprasidone Risperidone/ P aliperidone

16. MOOD STABILIZERS FOR MAINTENANCE The BALANCE: V alproate as monotherapy was relatively less effective than lithium or the combination of lithium and valproate V alproate is not licensed for prophylaxis (2 nd line) Olanzapine , quetiapine and Aripiprazole are: Licensed for prophylaxis 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 of choice

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 ) D ivalproex is more effective in RCBD (Calabrese & Delucchi , 1990 ) M ore 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

18. MECHANISM OF ACTION AND SIDE EFFECTS

19. LITHIUM- MECHANISM OF ACTION Lithium introduced for the treatment of “ P sychotic 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 R esearch 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)

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

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

22. 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 m M ) BPD is characterised by phase advance of the central pacemaker within the suprachiasmatic nucleus Lithium may achieve its therapeutic and prophylactic effects by: A ltering the balance of neurotransmitter signaling in hypothalamus R esynchronizing the physiologic systems underlying recurrent affective illness

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

24. SYNAPTIC SIGNALING AND SIGNAL TRANSDUCTION Molecular targets for lithium in phosphoinositide ( PI)signaling T hree major sites for an inhibitory action of lithium: I nositol 1-monophosphatase ( IMPase ) I nositol polyphosphate 1-phosphatase ( IPPase ) G lycogen 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: R eceptor-activated phospholipase C (PLC ) B reakdown of phosphoinositide-4,5-bisphosphate to (DAG) Inositol-1,4,5-trisphosphate

25. SYNAPTIC SIGNALING AND SIGNAL TRANSDUCTION DAG directly activates protein kinase C ( PKC) T his activation results in downstream post-translational changes in proteins that affect: R eceptor complexes I on channel activity T ranscription 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

26. SYNAPTIC SIGNALING AND SIGNAL TRANSDUCTION Inhibition of GSK-3: A lters gene transcription and neuroplastic events through an increased expression of downstream proteins such as catenin Mediate cell growth and survival

27. SYNAPTIC SIGNALING AND SIGNAL TRANSDUCTION Lithium has significant: I nhibitory effects on the ( cAMP )-generating system which is induced by various neurotransmitters and hormones 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 )

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

29. ADVERSE EFFECTS OF LITHIUM Metabolic: Lithium increases the risk of hypothyroidism In middle‐aged women , the risk may be up to 20% T esting thyroid autoantibodies in this group recommended TFTs usually return to normal when lithium is discontinued Increased risk of hyperparathyroidism Chronically increased serum calcium include renal stones, osteoporosis, dyspepsia, hypertension and renal impairment

30. ADVERSE EFFECTS OF LITHIUM RENAL: R eduction in urinary concentrating capacity (nephrogenic diabetes insipidus) T hirst and polyuria Polyuria more frequent with twice‐daily dosing R eversible in the short to medium term but may be irreversible after long‐term treatment (>15 years) R eduction in the glomerular filtration rate ( GFR) A very small number of patients may develop interstitial nephritis Lithium levels of >0.8 mmol/L are associated with a higher risk of renal toxicity

31. 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 C onsistent 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

32. 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 C linical 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 drugs ( Muzina et al., 2005)

33. 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

34. MECHANISM OF ACTION OF VALPROATE (VPA) AND CARBAMAZEPINE (CBZ) GABA CBZ is a positive modulator of the GABA-A receptor Increases the GABA-A receptor–mediated chloride current VPA increases GABA release in different areas of the brain EXCITATORY AMINO ACIDS CBZ leads to inhibition of N -methyl-D-aspartate (NMDA) receptor VPA leads to decrease in aspartate release Effect mediated by the blockade of sodium channels DOPAMINE: In many brain areas, dopamine turnover is increased by VPA Effect not seen with CBZ Evidence for role of dopamine D4 receptor gene and the dopamine transporter gene in BPAD

35. EFFECTS OF AED ON INTRACELLULAR MESSAGING SYSTEMS Disturbed intracellular calcium homeostasis may be a final common pathway in BPAD A nticonvulsants 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

36. 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

37. Sensitization And Kindling—Behavioral Models Explaining The Recurrence Of Bipolar Disorder Kraepelin (1921)- Marked psychosocial stressor usually preceded the first affective episode Subsequent episodes showed minor or even absent notable life events F requency of episodes tends to increase leading to rapid cycling D ecrease 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

38. 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

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

40. SIDE EFFECTS OF VALPROATE Hyperammonemia Rare— more common in combination with carbamazepine ( Tegretol ) Associated with coarse tremor Associated with urea cycle disorders 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)

41. 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

42. SIDE EFFECTS OF CARBAMAZEPINE Dizziness, ataxia, diplopia Fatigue, sedation Benign rash Severe rash Benign WBC suppression Agranulocytosis Aplastic anemia Weight gain Hyponatraemia Thyroid hormone suppression Tremor Hepatitis Memory disturbance

43. 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)

44. MOOD STABILIZERS IN PREGNANCY AND LACTATION Effects are discussed only for risk during the first trimester Psychotropics are harmful even after organogenesis I ntrauterine exposure during the second and third trimester can lead to postnatal complications Teratogenicity: “Risk of congenital physical deformities over the base line rate of 2.0–2.5%” O bstetrical complications Perinatal syndrome L ong‑term behavioral sequelae

45. 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

46. 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: Large for gestational age infants Anencephaly Oromandibular‑limb hypogenesis Premature closure of arterial duct

47. 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: Behavioral problems lower scores on the performance intelligence quotient (IQ ) Growth and general development Lithium is considered to be the safest mood stabilizer for use during pregnancy

48. 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: Cardiovascular malformations- ASD Intrauterine growth retardation Genital anomalies Hydrocephalus Spina bifida Cleft palate Hypospadias Polydactyl Craniosynostosis Limb defects (radial ray effects, fibrous aplasia of lower limbs) Pulmonary atresia

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

50. NON-PHARMACOLOGICAL –MOOD STABILISERS Sleep-wake cycle stabilization E xercise Substance abstinence Specific psychological interventions C ognitive behavioural therapy Interpersonal-social rhythm therapy F amily-focused therapy, mindfulness-based therapies P sychoeducation Non-specific psychosocial interventions A ctivity scheduling S leep hygiene S ocial skills training T herapeutic engagement S upportive therapies C ompliance strategies P roblem-solving B asic stress management

51. REDEFINING MOOD STABILIZERS Goodwin and Malhi (2007) “What is a mood stabilizer ?” Effectively highlighted the limitations of various definitions F laws 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

52. PARTIAL MOOD STABILIZER T erm “ mood stabilizer” should be used in general discussions about the search for an ideal agent that is effective in all poles of illness R ecognize that no complete mood stabilizer has been discovered C urrent 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”

53. REFERENCES Psychiatry / edited by allan tasman , jerald kay , jeffrey A. Lieberman, michael B. First, michelle B. Riba .–Fourth edition. Kaplan & sadock’s comprehensive textbook of psychiatry / [edited by] benjamin james sadock , virginia alcott sadock , pedro ruiz . – 9th ed. The maudsley prescribing guidelines in psychiatry / david taylor , carol paton , shitij kapur . – 12th edition. Robert h. Lenox, alan frazer . Mechanism of action of antidepressants and mood stabilizers. Neuropsychopharmacology : the fifth generation of progress Sandeep Grover, Ajit Avasthi. Mood stabilizers in pregnancy and lactation. Indian J Psychiatry 57 (Supplement 2), July 2015 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