Pharmacotherapy of depression in women: Ethical, conceptual and practical considerations

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illness. Hormones also have interactions at neurotransmitter receptors, and the synergy between the interactions of hormones and antidepressant drugs at serotonin receptor subtypes can be exploited to design effective antidepressant treatment for women with mood disorders unresponsive to antidepressant therapy alone. That is, down regulation of serotonin 2 receptors is enhanced by both thyroid and estrogen, and this may contribute to the usefulness of these agents as adjuncts to the treatment of mood disorders in women.

18-35-51 Pharmacotherapy of Depression in Women: Ethical, Conceptual andPractical Considerations Uriel Halbreich. State University of New York at Buffalo Higher prevalence of some depressions in women is well documented. A gender difference in response to some antidepressants is plausible but not definitely clear yet. Until recently pharmacotherapeutic trials in women of reproduction age were not sufficiently pursued due to the unknown risks of teratogenic effect. It is obvious and well accepted that effects of medications in women should be studied. The methodological issues of inclusion of women in clinical trails are presented and discussed. They include detection of ovulation, adequate use of mechanical contraception and early detection of pregnancy and its timing. The risk periods for teratogenic effects are quite well determined and their avoidance is practical. On a clinical as well as research level the influence of pregnancy, breast feeding, interaction with contraceptive hormones and menstruallyrelated variables and menopause should all be taken into account when antidepressants are prescribed. Gender difference in antidepressant therapeutic response and side effects might also serve for elucidation of the mechanisms of action of these medications. Interaction with different levels of gonodal hormones might also shed some light on underlying mechanisms of affective disorders and might have practical consequence for future development of antidepressant medications.

I5-361 New Antiepileptic Drugs and Psychopharmacology

I8-36-1 I Adenosine Receptors as a Target for

Carbamazepine's Action in the Brain D. Van Calker, K. Biber, J. Walden, M. Berger. Departmentof Psychiatry, University of Freiburg, Germany

Carbamazepine (CBl) is an alternative to lithium in the treatment of manic-depressive disorders. Since lithium is thought to act by modulating the activity of the inositol phosphate (IP) Ca2+ second messenger system in neural pathways, effects of CBZ on this system are of particular interest. Previous work from this laboratory has shown that CBZ acts as a selective antagonist of adenosine A I -receptors. The neuromodulator adenosine acting via A I-receptors can both inhibit and potentiate the activation by neurotransmitters of the IP/Ca 2+ -system. The impact of these two opposite actions varies depending on the brain region and the neurotransmitter involved. We have analysed the effects of CBl on these modulating activities of adenosine-agonists on the IP/-Ca 2+ system in astrocytes cultured from various brain regions. Chronic treatment with CBl leads in these cultures via antagonism and consequent upregulation of A I-receptors to an increase of the modulating action of adenosine, which is, in the further presence of CBl, only evident at concentrations of adenosine high enough to totally override the antagonistic effect of CBl. Such high concentrations of adenosine are likely to accumulate extracellularly only under conditions of neuronal overactivity, Thus, CBl's prophylactic action in affective disorders might be due to a reinforcement of adenosine's modulating effect on the IP/Ca 2+ system in a manner selective for overactive neural pathways.

I

8-36-2 Calciumantagonism as a Common Mode of Action 1

of Some Antiepileptic Drugs in the Treatment of Epilepsies andAffective Disorders J. Walden, J. von Wegerer, B. HeBlinger, M. Berger. Univ. Freiburg, Dept. Psychiatry & Psychotherapy, Freiburg, FRG Antiepileptic drugs (e.g. carbamazepine) are used in the acute treatment of mania and in the prophylaxis of affective and schizoaffective disorders. In the search for basic mechanisms in the pathophysiology of affective disorders a disturbed intracellular calcium ion homeostasis is discussed. Therefore, the following experimental and clinical studies were performed: (l) In animal experimental studies calcium dependent potentials in the hippocampal slice preparation of guinea pigs were blocked by the antiepileptic drugs carbamazepine and lamotrigine. The drugs showed additice effects with organic calcium channel blockers. (2) In an open clinical study with depressed patients the calcium channel blocker nimodipine showed a prominent action in dosages of 180-360 mg/die in a monotherapy of about 6 weeks. (3) Single patients with bipolar affective disorders were treated with the new antiepileptic drug lamotrigine, partly in coadministration with other antiepileptic drugs. A positive effect concerning manic and depressive episodes were registered in dependence on the plasma level. In conclusion, it can be assumed that besides other elementary actions of carbamazepine and lamotrigine (e.g. block of high-frequency action potentials) these drugs have calcium antagonistic properties which are of relevance for its effect in the treaternent of patients with bipolar affective disorders.

IS-36:3[

New Concepts in Mood Stabilization: Evidence for the Effectiveness of Valproate and Lamotrigine

Cd., Bowden. Departmentof Psychiatry, University of Texas Health

Science Center, San Antonio, Tx 78284 The term mood stabilizer has been largely unaddressed. A proposed working definition is a drug which alleviates the frequency and/or intensity of manic, hypomanic, depressive or mixed episodes in patients with bipolar disorder, and which does not increase frequency or severity of any of the subtypes of bipolar disorder. Recent randomized, double-blind, placebo controlled studies of valproate as divalproex, coupled with earlier open and controlled studies, establish valproate as a safe and effective mood stabilizer, with greater benefits on the manic side of the illness. The spectrum of clinical conditions benefited by valproate appears to be broader than that for lithium or carbamazepine. Many of the disorders with preliminary, although not conclusive evidence of benefit from valproate are significantly comorbidly associated with bipolar disorder. The recently introduced antiepileptic lamotrigine was noted to improve mood in patients with epilepsy. Based on these clinical observations, an open trial of lamotrigine has been initiated. Preliminary analyses suggest a prompt beneficial effect on depressed and mixed states and possibly manic states, including amongst patients with rapid cycling courses. Because of the open, add-on design and the multiple types of episodes allowed for enrollment, the study serves largely for hypothesis generation. No evidence of switching or increased cycling frequency has emerged over the 48 week study. Lamotrigine therefore represents a third antiepileptic drug with putative mood stabilization and good tolerability. For all mood stabilizers it is methodologically easier to establish acute episode effectiveness than maintenance effectiveness. Clinical and research strategies to enhance assessment of long term efficacy will be presented.

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8-36-4 1 Lamotrigine in Treatment Refractory Manic Depression

C. Calabrese. Case Western Reserve University, Cleveland, Ohio, USA Lamotrigine (LTG) is believed to possess mood stabilizing properties. To evaluate this possibility, 67 patients with treatment refractory bipolar disorder underwent an open prospective 6 month trial of either LTG add-on or monotherapy (mean exposure, 72 d). The 31-item Hamilton Depression Rating Scale (HAM-D), the SADS-C Mania Rating Scale