" Psychopharmacotherpay in the management of Bipolar Disorders " by Prof. K.Y. Mak

1. "Psychopharmacotherpay in the management of Bipolar Disorders" by Prof. K.Y. Mak (Chairman, Society for Advancement of Bipolar Disorders; Chairman, Asian Network of Bipolar Disorders)

2. What is a mood-stabilizer? • No formal definition • A medication that alleviates the frequency &/or intensity of manic, hypomanic, depressive or mixed episodes in bipolar disorder patients, and does not increase frequency or severity of any of the types bipolar disorder episodes (Bowden C, 1998, Neuropsychopharmacol, 19, 194-199) • NB ECNP (2000) a mood stabilizer needs not be efficacious for acute mania or depression

3. Classification of mood stabilizers • Class A: the primary acute & prophylactic effect by treating the depressed phase, preventing or delaying manic episodes without destabilizing the overall course of the illness by exacerbation of depression. E.g. lithium • Class B: the primary acute & prophylactic effect by treating the manic phase, preventing or delaying depressive episodes without destabilizing the overall course of the illness. By exacerbation of manic. E.g. lamotrigine • Ref.: Ketter & Calabrese (2002) J. Clin. Psychiat., 63, 146-151.

4. I. Lithium • 1st medication for manic-depressive disorder • Discovered by Cade in Australia • Neurotoxic if overdose – thus serum level monitoring needed • Common side-effects: polyuria & polydipsia, hand tremor • Toxic side-effects: neuroleptic malignant syndrome (+ haloperidol) • ?controversy as 1st line treatment (especially in primary care)

5. II. Anti-epileptic Drugs • It was noted that AED improves mood in some epileptic patients, & was helpful in stabilizing mood in patients with epilepsy & bipolar disorder • Antiepileptic actions: • enhance inhibitory process (mainly GABA mediated), involving Cl- ion fluxes • Decrease excitatory process (mainly glutamate mediated), involving Mg++ & Ca++ ion fluxes • Modulate membrane cation conductance (Na+, Ca++ or K+) by effects on membrane receptors or transport mechanisms for these ions which modulate signal transduction in the neuron system

6. Various anti-epileptics • valproate (divalproex) - esp. mania/mixed • carbamazepine /oxcarbazepine - esp. mania/mixed • lamotrigine - esp. BP-D/rapid cycling • topiramte - mania/mixed, esp. rapid cycling • Gabapentine/pregabalin - analgesic & ?anxiolytic effect

7. Common s/e • GI upset: lithium valproate (SSRIs) • Weight gain: valproate, lithium, carbamazepine; clozapine, olanzapine, quetiapine & risperidone • Glucose dysregulation: (antipsychotics) • Sexual dysfunction: (SSRIs, antipsychotics) • Cognitive impairment: lithium, topiramate, carbamazepine (typical antipsychotics) • Dermatologic reactions: lamotrigine, valproate, carbamazepine • Tremor: lithium, valproate

8. 1. Sodium valproate (Epilim) • Also in the form of divalproex sodium (delayed release) • Dose range: start with 500 – 2000 mg per day (25mg/kg/day) • Normal blood level: 45-125 μg/ml, but level affected by protein binding (reduced in the elderly & those with renal/liver disease, and hyperlipidaemia (thus neurotoxicity can occur in apparently normal serum level, and free valproic acid level maybe more important). • Contraindicated in acute liver disease or family history of liver dysfunction, thus LFT at baseline and during first 6 months; perhaps pancreatic function • Half-life shortened by CBZ & others

9. Comparing lithium with VPA • Li > VPA in suicide (high risk in mixed state, bipolar depression & those with comorbidities) • VPA > Li in longterm maintenance Rx of mania & prevent relapse • VPA > Li in comorbid alcohol abuse (only 1 study by Salbourn et al, 2005) • VPA = Li in rapid cycling • High dropout rate for Lamotrigine in rapid cycling

10. 2. Carbamazepine (Tegretol) • 600mg – 1600 mg/day (4-12 μg/ml serum level) • S/e: nausea/vomiting, fatigue, dizziness, tremor, cognitive changes; rash (15%), Stevens-Johnson syn (0.1-0.5%) • plasma concentration can decrease over time even with fixed dosage, because of autoinduction of liver enzymes • drug-drug interaction (3A4 P450): • increased concentration with verapamil, cimetidene, erythromycin, isoniazid, etc • decreased concentration with phenytoin, phenobarbitone, etc.

11. 3. Oxcarbazepine (Trileptal) • A prodrug (congener), improve tolerability cf to carbamazepine • May induce thrombocytopenia, but no need for monitor haematologic parameters • Start with 600mg bid up to 2,400mg/day (50% higher than CPZ) • 27% cross sensitivity with CPZ, some induction at CYP3A4, less drug-drug interactions, leucopenia or rash • Switching from CPZ can be immediate (overnight) or progressive (in a few weeks), though high dose of CPZ may be switched slowly because of its autoinduction effects (Albani et al. Seizure, 2004, 13, 254-163)

12. 4. Lamotrigine (Lamictal) • As mono or adjunctive therapy, dosage: 100-400mg/day (slow titration upwards); minimal s/e profile (esp body wt & cognitive function), thus better compliance • Acute Rx of bipolar depression I, as maintenance Rx & for rapid-cycling BP II (no antimanic properties), & perhaps BP I recently manic or depressed • Less effective for mixed episode, rapid cycling • perhaps for borderline PD & schizoaffective disorder, also for migraine, impulsivity & compulsivity • Linear pharmacokinetics & a half-life of 24 hours allows a once-daily dosing; rapid absorption & no clinical significant drug-drug interactions

13. Dosing of lamotrigine in adults & adolescents (once daily nocte) • Week Daily dose (mg) • 1 25 • 2 25 • 3 50 • 4 50 • 5 100 • 6 200 • NB 50% dose with valproate & 200% with carbamazepine; cautin if on birth control pills (increased during the active hormone days, but reduced during the off hormone days) • Ref: Calabrese et al, J Clin Psychiat 2002, 63, 1012-1019

14. 5. Gabapentine (Neurontin) • High therapeutic index: not bound to protein, no hepatic metabolism • benign s/e profile (somnolence, dizziness, ataxia & fatigue) • Other s/e: thyroiditis, renal impairment (nephrotic syndrome), sex dysfunction, 1 case of catatonia • Not potent as monotherapy mood stabilizer (perhaps better for depression than with mania) • Good: as adjunctive if comorbid anxiety (or neuropathic pain)

15. 6. Topiramate (Topamax) • Minimal drug interactions, 200-300mg/day • s/e: slow thinking (memory), sedation, nausea, diarrhoea, headache, paraesthesia & tremor • rare s/e: metabolic acidosis (carbonic anhydrase inhibition increase excretion of bicarbonate) – urinary stones, acute myopia & secondary angle closure glaucoma (mostly reversible), metabolic acidosis and oligohidrosis • a few reported cases of severe hepatotoxicty, but usually in combination with other medications(Bjoror et al, Lancet, 1998, 352: 1119; Doan & Clendenning, Can J Psychiat, 2000, 45, 937-938)

16. Combination AEDs/Li • Lithium + valproate: increasing use (Solomon, 1997) • Lithium + carbamazepine: effective for resistant BAD (Bochetta 1997), for rapid-cycling (Schifano); but risk of neurotoxicity • Valproate + carbamazepine: synergistic effect; but interaction via enzymatic induction/inhibition

17. Monitoring of AED • Lithium: serum level q3 months (0.4-0.8 mmol/l); TSH & electrolytes, RFT q6-12mo • CBZ: serum level q3 months (17-50umol/l); LFT q3-6 mo; CBP q3-6mo; electrolytes q3-6mo • VAP: serum level q3mo (300-700umol/l); LFT q3-6mo; CBP q3-6mo • Lamotrigine: nil needed • Ref: Roayl Australian & New Zealand College of Psychiatrists Clinical Practice Guidelines Team for Bipolar Disorder. ANZJPsychiat, 2004, 38, 280-305

18. III. Neuroleptics • Usually during the acute manic stage (esp mixed state), faster effect, similar efficacy as lithium, good for control of severe anxiety, agitation /aggression, hyperactivity and psychotic features • Onset is faster, but high dosage needed, with risks of EPS • Typicals useful for manic episode, but may trigger depressive swing • Atypicals appears better including olanzapine, quetiapine, ziprasidone, etc.

19. Atypical antipsychotics • DA antagonistic effects help hypomania and psychotic symptoms • 5HT2A/2C antagonistic activities: improve anxiety and mood symptoms • Probably inhibit NE reuptake also improve mood • Thus may also be called Mood Stabilizers • especially good for acute mania & manic mixed state, rapid cycling & perhaps treatment resistant cases

20. AED cf neuroleptics (1) • AED • Avoid symptomatic Rx (whole life history) • Prevent switching • Evidence-based: lithium still most effective monoRx, good for suicide (Goodwin et al, 2003, JAMA) • Prevention after acute depression • Neuroprotection • Less expensive & side-effects profile good (for some)

21. AED cf neuroleptics (2) • Atypicals • Early onset of action & symptom relief • Easy drug titration – relatively safe, especially atypicals • Some bimodal action • Wide spectrum of effects, particularly for agitation & psychotic s/- • Side-effect profile better (for some), though occasional severe e.g. NMS • A few available in IMI form (early or delayed effect) • NB typicals may sometimes be more effective for acute mania (in the short-term)

22. AED + atypicals • Good for preventing swing • Especially if antidepressants (TCA in particular) given • But lithium may induce side-effects of antipsychotics, including TD • Neuroleptic malignant syndrome?

23. Maintenance with atypicals • After a severe psychotic manic episode • Relapse after discontinuation of antipsychotic • Those with predominant manic episodes • Partial/full refractory to mood stabilizers • Those who tolerate antipsychotics well • NB include long-acting injections

24. Clozapine (Clozaril) • No documented double-blind trials so far • Low D2 antagonist effect • Left ventricular shortening • Perhaps useful for acute mania • Can be an adjunctive to lithium & AED

25. Risperidone (Risperdal) • Effective as monotherapy for moderately severe mania; effective as combination therapy (with anticonvulsants) for moderate & severe mania • Adverse effects: somnolence, EPS, weight gain • Use of risperidone monotherapy for severe mania or in maintenance treatment remains to be elucidated • Ref: Nguyen LN & Guthrie, SK (2006) Ann Pharmacother, 4f0, 674-682

26. Olanzapine-fluoxetine combination • Atypical + SSRI for bipolar depression • OFC (Symbyax) for BP I depression found OFC statistically & clinically significant cf to olanzapine or placebo, without sig differences in treatment-emergent mania Ref: Token et al (2003) Arch Gen Psychiat, 60, 1079-1088

27. Quetiapine (Seroquel) • Quetiapine is an antipsychtoic and antimanic by virtue of its dopamine D2 and serotonin 5HT2A antagonism; and • Low dose – antihistaminergic effect; high dose – antidopaminergic effect • appears to exert its antidepressant activity in bipolar depression via its active metabolite norquetiapine (N-desalkyl quetiapine), which is a potent inhibitor of NE transporter & a partial agonist of 5HT1A receptor. (Goldstein et al, Biological Psychiatry 2007;61:124S-125S) • Nor-quetiapine also is a 5HT2C antagonist & alpha-2 adrenergic receptor antagonist.

28. Ziprasidone (Zeldox) • A benziso-thiazolyl piperazine • Potent 5HT2A & D2 antagonist • A full agonist for 5HT1A & antagonist for %HT2C & 1D, with >10-fold higher affinity than for DA • Low affinity for α1-adrenoceptor – thus less orthostatic hypotension • Also in vitro SNRI (clinical extent not clear) • Effective for bipolar I manic or mixed episodes with or without psychosis • Metabolised via CYP3A4, but minimal drug-drug interaction

29. Aripiprazole (Abilify) • 3 week, multicenter double-blind RCT 262 acute manic /mixed episode • 30mg/day aripiprazole (reduced to 15mg if needed for tolerability) cf to placebo • Results: statistically significant YMRS improved (-8.2 vs -3.4) & higher response rate (40% vs 19%), efficacy obvious by day 4 & completion rate was higher (42% vs 21%). Discontinuation & changes in BW no difference • Ref: Keck et al (2003) Am J Psychiat, 160, 1651-1658).

30. III. Benzodiazepines • Clonazepam, diazepam & lorazepam act on GABA post-synaptic receptor complexes, enhancing release of GABA & opening of Cl channels • Good for acute mania (as for neuroleptics) as brief adjunct therapy, but high dose needed • Not recommended for maintenance dose

31. IV. Antidepressants for BP • Antidepressants are effective, but may trigger a switch into mania (especially TCA, SNRI) • Combine antidepressant with a mood stabilizer (Li or anticonvulsant or antipsychotic) to avoid mania • Paroxetine/fluoxetine & risperidone may increase risperidone serum level, but decrease level of its active metabolite, thus lower dosage of risp &/or SSRI

32. V. Guidelines - acute mania • CBZ, VPA & Li are equipotent, but limitations as monotherapy • Li relatively ineffective in mixed disorder • Oligotherapy (minimal number of medications used) rather than polypharmacy is better: mood stabilizer & neuroloptics & another mood stabilizer (eg Li & CBZ)

33. Guidelines for BP depression • Lithium or lamotrigine • 2nd mood stabilizer (especially for rapid cyclers); • Adjunctive antidepressants (not recommended except with lithium for more serious condition or those intolerant of high lithium dose) • Adjunctive antipsychotics if psychotic features present (though quetiapine found useful as monotherapy) • Atypicals for refractory condition (or psychotic features) • Augmentation with tri-iodothyronine may be considered • BDZ for coexisting anxiety or insomnia • ECT & TMS (transcranial magnetic stimulation)

34. Guidelines for maintenance Rx • Monotherapy with lithium or valproate • Newer atypicals as alternatives • Optimize medications effective in most recent episode • Combination therapy for sub-threshold symptoms or breakthrough mood episodes • Avoid antidepressants as monotherapy

35. Discontinuation of maintenance • Risk-benefits balance e.g. planned pregnancy • Should be tapered down, at least 2 weeks • Abrupt withdrawal of lithium often induce manic episode • Risk of relapse remains, even after years of sustained remission

36. AED & pregnancy • Safest is ECT • Crude rates for risk of major congenital malformation were 4% for 1 drug, 6.3% if >1, cf. to 0.9% for those not on AED • Lthium (Epstein’s cardiac anolomy); CPZ & VLP (renal tube defects, thus add folic acid 0.4mg/day) • CPZ: 2.3%, valproate: 7.2%, lamotrigine: 3%; other drugs not known • Ref: NICE. Epilepsy. 2nd Consultation, March 2004http://www.nice.org.uk/page.aspx?o=108913

37. AED & breastfeeding • Woman’s historical response as guidance • Carbamazepine & valproate but not lithium have generally been considered compatible with breastfeeding, but data are scarce • Beware sof sudden withdrawal seizure • Neurotoxic effect: floppy baby, EPS • May increase prevalence of NNJ • A review (Chaudron & Jefferson, 2000, J Clin Psychiat., 61, 79-90) found 11 lithium cases (2 had toxicity in infants), 39 valproate (1 report low PL & RBC), 50 CPZ (2 hepatic dysfunction), 1 gabapentin & 3 lamotrigine use.

38. Psychoeducation is mood stabilizer? • Reduces relapses of both mania or depression • Also reduces burden on family • Should be provided to patients and their carers

39. Conclusion • Early treatment is important • Maintenance is recommended to prevent relapse • Frequent relapse cause enduring brain damage and refractory to treatment • Monotherapy is now steadily replaced by polypharmacy (synergy) • Besides medications, psychosocial therapies are important (including compliance therapy)