Janusz K. Rybakowski Department of Adult Psychiatry Poznan University of Medical Sciences

1. Janusz K. Rybakowski Department of Adult Psychiatry Poznan University of Medical Sciences

2. Lithium and traditional anticonvulsants (valproate, carbamazepine) belong to the first generation mood stabilizers ? Introduced as mood stabilizers in 1960-1980 Second generation started in 1995, with identifying mood-stabilizing properties of clozapine, and subsequently olanzapine, quetiapine, aripiprazole, and new anticonvulsant, lamotrigine Rybakowski, Int J Neuropsychopharmacol, 2007

3. After experiments on guinea pigs and on himself he gave lithium to 10 manic patients obtaining remarkable results. This publication is considered as the beginning of modern psychopharmacology Proposal of Cade’s diseaseas eponym of bipolar I

4. The play „Dr Cade” (2003) Written by Neil Cole, former Victorian Shadow Attorney General, who uses lithium to manage his own condition Presented to participants of ISBD regional symposium in Sydney, 2004

5. The movie - 2004 „Troubled minds: The lithium revolution” Directed by Dennis Smith, interviews with John Cade’s sons and others Received the International Vega Awards for excellence in scientific broadcasting Presented to participants of 6th International Conference on Bipolar Disorder, Pittsburgh, 2005

6. Salvador Luria Nobel Prize 1969 for discovery of bacteriophages „A Slot Machine, a Broken Test Tube: an Autobiography”, 1984 Patty Duke Youngest Oscar awardee,16 years, for Miracle Worker „Call Me Anna”, 1987 Kay Jamison Co-author of „Manic-Depressive Illness”, 1st ed. 1990; 2nd ed. 2007 „Unquiet Mind”, 1995

7. He performed the first placebo-controlled study of lithium in the treatment of mania showing therapeutic effect of the drug. He also did the firstsystematic measurements of serum lithium concentration

8. One of the founders of the International Group for Study of Lithium Patients (IGSLI), in 1988 IGSLI study demonstrated antisuicidal effect of lithium Honorary President of the International Society of Bipolar Disorder (1999-2005) Mogens Schou ISBD awards for research, education and alliance in bipolar illness, since 2001

9. Antimanic action (Cade, 1949) Recurrence-preventive action (Hartigan, 1963) Antidepressant action monotherapy (Mendels, 1976) augmentation of antidepressants (De Montigny et al. 1981)best evidence for augmentation so far Lithium meets 2x2 criteria for mood stabilizer (therapy of acute episode, recurrence prevention; mania, depression) (Bauer & Mitchner, 2004)

10. Reduction of suicidal behavior in the course of lithium prophylaxis by approximately 80%, during treatment for an average 18 months(Baldessarini et al., 2006) Anti-suicidal effect is not associated with a quality of the prevention of affective recurrence(Muller-Oerlinghausen et al., 1992)

12. Excellent lithium responders: people whose lives have been changed by lithium prophylaxis (Paul Grof, 1999) The term applies to about 1/3 of lithium-treated patients Cessation of the illness expression throughout the period of lithium administration Beneficial effect of lithium monotherapy for up to 30 years or more

13. Patients entering1970s (79) No of completers: 77 No of excellent lithium responders: 26 Percentage: 33.8% Patients entering1980s (79) No of completers: 69 No of excellentlithium responders: 22 Percentage: 31.9%

14. Clinical characteristics: classic form of illness distinct asymptomatic interepisode intervals moderate frequency of episodes Endophenotype of bipolar illness Association of lithium response with polymorphism of a number of genes Offspring of excellent lithium responders similar characteristics of the illness course

15. Valproate introduced as an anticonvulsant in mid-1960 (potential anticonvulsant effects of the drug were recognized serendipituously) Therapeutic effect of valproic acid amide (dipropylacetamide - Depamide) in a group of patients with acute manic statesLambert PA, Cavaz G, Borselli S, Carrel S: Action neuropsychotrope d’un novel antiepileptique: Le Depamide. Ann Med Psychol 1966, 1, 707-710

16. Suggestion for a mood-stabilizing effect of valproate (thymoregulatrice) Lambert PA, Borselli S, Marcou G, Bouchardy M, Cabrol G: Action thymoregulatrice a long terme du Depamide dans la psychose maniaco-depressive. Ann Med. Psychol 1971, 2, 442-448

17. Randomized, double-blind, parallel group trialof 3 weeks Premature termination: Val 30%, Li 33%, Pla 51% Improvement>50%: Val 48%, Li 49%, Pla 25% Superiority of Val over Li in patients with mixed mania and with patients with multiple episodes prior to treatment Bowden C et al: Efficacy of divalproex vs lithium and placebo in the treatment of mania. JAMA 1994, 271, 918-924

18. Randomized, double-blind, parallel group trialof 12 months Drop-out after 3 months – 43%, 6 months – 57%, 12 months – 69% Premature termination: Val 62%, Li 76%, Pla 75% Time to 50% relapse to any mood episode (days) Val 275, Li 189, Pla 173 Bowden C et al: A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Arch Gen Psychiatry 2000, 57, 481-489.

19. A twelve-week, open, randomised trial comparing Sodium Valproate Chronosphere® to lithium in Bipolar I patients suffering from a manic episode Remission rates after 3 months: 74.5% lithium; 81.8% valproate Subjective satisfaction: 75.8% lithium; 74.3% valproate  Bowden C et al. Int Clin Psychopharmacol 2008, 23, 254

20. Intracellular signaling Phosphatidyl inositol pathway Protein kinase C Neuroprotective Brain- derived neurotrophic factor Antiapoptotic protein bcl-2 Glycogen synthase kinase-3 Antiviral Lithium: herpes viruses Valproate: HIV (adjunctive therapy)

21. Antimanic action (Takezaki i Hanaoka,1971) Recurrence-preventive action (Okuma et al., 1973) Antidepressant action Monotherapy (Post et al., 1986) Potentiation of antidepressants (Rybakowski et al., Neuropsychobiology, 1999)

22. Multicentre study of long-term treatment of affective and schizoaffective psychoses 261 patients, 2.5 years of observation Bipolar illness (Kleindienst & Greil, 2000) Type I: CBZ < Li Type II: CBZ = Li With atypical features: CBZ > Li Schizoaffective illness (Greil et al., 1997) Overall efficacy: CBZ = Li Schizophreniform symptoms / chronic depression: CBZ > Li

23. Li, VPA, and CBZ inhibit the inositol-dependent collapse of sensory neuron growth cones(Williams et al., Nature 2002) A genome-wide association study implicates diacylglycerol kinase eta (DGKH), the enzyme of phosphatidyl inositol pathway, in the etiology of bipolar disorder(Baum et al., Molecular Psychiatry 2008)

24. Both valproate and carbamazepine are more effective in mania and in prophylaxis when combined with lithium than as monotherapy(Denicoff et al., 1997) Tolerability of such combination is equivalent or even better (e.g. Li + CBZ) than for single drug The adherence to combination of 1st generation mood stabilizers is better than to single drug (Sajatovic et al., 2007)

25. Atypical antipsychotic drugs are more effective in mania and in prophylaxis when combined with lithium or valproate than as monotherapy (e.g. Tohen et al., 2004) Good tolerability of combination of 1st and 2nd generation mood stabilizers Enzyme-inducing properties of carbamazepine make a limitation for the drug use in combination

26. Lithium and traditional anticonvulsants – 1st generation mood stabilizing drugs (introduced in 1960-1980) Overwhelming evidence of mood-stabilizing efficacy In 1/3 of patients – effective monotherapy with lithium for 30 years or more In > 50% of patients – combination of 1st generation or 1st and 2nd generation mood stabilizing drugs required for optimal therapeutic results