LITHIUM AND SECOND MESSENGER ACTIVITY. Arne Mark, Department of Pharmacology, University of Copenhagen, 20 Juliane Maries Vej, DK- 2100 Copenhagen 0, Denmark.

The search for the mechanims of action of lithium has concentrated on effects of lithium on various neurotransmitter functions. Recent research demonstrating lithium-induced changes in the adenylate cyclase activity and phosphoinositide metabolism suggests that second messenger systems could be targets of the lithium action. Lithium may affect neurotransmitter function by altering pre- and/or postsynaptic signals generated in response to various neurotransmitters.

It has recently been observed that cerebral cortex Gs cr-subunits are elevated in manic-depressive illness.' Some studies indicate that lithium reduces the coupling between receptors and G proteins (Gs, Gi, G,, GJ, prevents receptor-induced stimulation of G proteins or alters the levels of G proteins. These actions and the fact that lithium attenuates second messenger activities by affecting the myo-inositol metabolism, the generation of CAMP and cGMP, cation-transport and several Ca2'- dependent processes indicate that multiple interacting mechanisms might be involved in the therapeutic actions of lithium.

Lithium may'exert its therapeutic effects in both manic and depressive phases by dampening overactivated systems potentially relevant to either mania or depression. Various actions of lithium on second messenger activity will be discussed.

1. Young LT et al. Brain Res 1991, 553: 323-326.

BEHAVIORAL MODELS OF LITHIUM AU-ON OF IMIPRAMIPE RH Eelmaker, Y u l i Bersudskey, Arsen Rev-, J o ~ t h a n E!en]amh, O r a Kofman BeersheM Mental H e a l t h Center, Division of Psychiatry, and Department of Behavioral Sciences, m i o n University, BeersheM, Israel.

Recently Li has been shown t o p e r f u l l y augment hiipramine effects in depressed patients after three w e e k s of non-response t o Xpramine. W e treated four groups of rats (10 per group) w i t h (1) saline i p daily for five w e e k s , ( 2 ) saline ip for five w e e k s d lithium chloride 0.2% m food fo r the last two w e e k s , ( 3 ) imipramine 10 q / k g daily ip for 5 weeks and ( 4 ) Xpramine 10 mg/kq daily ip for 5 w e e k s with l i t h i u m chloride 0.2% in food for the last 2 weeks . Activity was measured in an autamated activity mni tor before starting drug treatment, a f te r 3 w e e k s of treatment (before lithium) and a t the end of the f i f t h week. There w a s no augmentation by Li of any behavioral act ivi ty measure in the presence or absence of imipramine.

Normal volunteers were solicited t o take imipramine 75 mg per day for three w e e k s and then l i t h i u m d n a t e 900 n q daily in addition t o Li for a further t en days. subjects rated Profile of Mood States (FWS) weekly for three w e e k s and then twice weekly a f t e r Li addition. So f a r no subjects have reported mood elevation after Li addition.

114

DEPRESSION, PLATELET SEROTONIN (5-HT) UPTAKE AND CALCIUM. IMPLICATIONS FOR EFFECTS OF FLUNARIZINE. Jensen PN, Smith DF, Poulsen JH, Rosenberg R, Institute of Biological Psychiatry, Department of Psychopharmacology, DK-8240 Risskov, Den- mark. The present project aimed at studying possible mechanisms involved in the therapeutic action and side effects of the calcium antagonist flunarizine. Severe depression is a rather common side effect of long-term flunari- zine treatment for migraine. In both migraine and depression, 5-HT has been implicated. Blood platelet 5-HT uptake has been widely used as a model system for studying presynaptic 5-HT reuptake. In order to prevent blood platelets from releasing 5-HT, uptake is usually measured in media devoid of calcium. As extracellular calcium has to be present if inferences are to be made concerning the mode of action of a calcium antagonist, we developed a method for measuring 5- HT uptake in blood platelets under such conditions. By using this method we found that flunarizine inhibits 5-HT uptake in a concentration-dependent manner. The inhibition was independent of whether calcium was present or not. This indicates that flunarizine exerts a direct action on the 5-HT uptake site.

CALCIUM ANTAGONISTIC EFFECTS OF CARBAMAZEPINE AS A COMMON MECHANISM IN EPILEPSY AND YANIC-DEPRESSIVE DISORDERS J.WALDEN (1 1 , H.GRUNZE ( 1 1 , D.BINGMANN (21, R.DUSING (31, H.Olbrich ( 1 ) , M.BERGER (1 ) ( 1 ) P s y c h i a t r . K l i n i k , U n i v . F r e i b u r g , F R G ; (2)Inst.Pysiol.,Univ.EssenrFRG (3)Desitin GmbH, Hamburg,FRG

Besides its application in neurological disorders carbamazepine (CBZ) is used in psychiatry in the acute treatment of manic syndromes as well as in prophylaxis of affective and schizoaffective psychoses. Since increased transmembraneous calcium fluxes might be a common mechanism in epilepsies and affective psychoses the hypothesis of calcium antagonistic actions of CBZ was tested. Intra- and extracellular recordinus were carried out from area CA1 and CA3 of the hippocampal slice2preparation of guinea pigs. Penicillin-, caf5:ine- and low MU -induced epileptic discharges served as a model of Ca -dependent potentials. CBZ was systemically administered. (1) CBZ (20-100 pmol/l) reduced frequency of occurrence and amplitude of penicillin (2000-3000 IU/l) or caffeine (200-1000 pmol/l) induced paroxysmal depola.rization shifts (PDS) and abolished PDS eventually. Time course of reduction and abolition of PDS resembled that observed after exposureto the organic calcium antaaoaists verapamil and flunarizine. (2) CBZ (20-100 pmol/l) reduced frequency of occurrence of low Mg induced synchronized extracellular field potentials. In summary, the results suggest calciumantagonistic properties of CBZ which might be a common mechanism in epilepsies and affective psychoses.

2 +

115

TESTING FOR LINKAGE BETWEEN BIPOLAR DISORDER AND DOPAMINE RECEPTOR GENES

Mitchell. P. School of Psychiatry, University of New South Wales, Sydney, Australia.

A potential role of dopamine in bipolar disorder has been suggested by several strands of evidence, namely the ability of dopaminergic agonists to induce mania and the effects of lithium, carbamazepine and the antipsychotics on central dopamine receptors and/or turnover. We therefore aimed to determine if bipolar disorder in two large bipolar pedigrees was linked to the recently cloned dopamine D1 ( D R D l ) , D 2 ( D R D P ) , D g (DRD3) and D 4 (DRD4) receptors. (These have been mapped to chromosomal regions 5q35.1, l lq22 .3-q23, 3q13.3 and l l p t e r respectively). Linkage of bipolar disorder and recurrent depression to these markers was tested using a series of genetic models with varying penetrance levels. Additionally, linkage was examined using a series of levels of definitions to affective s ta tus (ranging from bipolar I alone to all affective illnesses). Close linkage of D R D l and DRD2 w a s strongly excluded using each model and definition. range of rates of 'sporadic' (non-genetic) presentations of illness were incorporated in the analysis, but the DRD:! results did not remain statistically significant a t high sporadic rates. The exclusion of linkage to DRDZ is consistent with other recent reports. DRD4 was not informative in these pedigrees. DRD3 results will be completed by the time of presentation.

The findings for D R D l also persisted when a wide

MECHANISMS OF THE PSYCHOTROPIC ACTIONS OF LITHIUM AND CARBAMAZEPINE Rybakowski J . : Depar tmen t of P s y c h i a t r y . Medical Academy. Bydgoszcz. P o l a n d

W i t h i n t h e i r t h e r a p e u t i c spec t ra . l i t h i u m ( L i ) a n d ca rba rnazep ine (CBZ) s h a r e normothvmic p r o p e r t i e s i . e t h e y ac t t h e r a p e u t i c a l l y a n d p r o p h y l a c t i c a l l y a g a i n s t b o t h P s Y c h o P a t h o l o s i c a l poles i n a f f e c t i v e d i sorders . Few s i m i l a r i t i e s be tween l i t h i u m and carbamazepine o n b i o c h e m i c a l and p h a r m a c o l o g i c a l level i n c l u d e enhancement of G A B A - e r s i c t r a n s m i s s i o n . t r y p t o p h a n t r a n s p o r t a n d ATP-ase a c t i v i t y as w e l l as a n i n h i b i t i o n of DA a n d NA-mediated a c c u m u l a t i o n of c y c l i c AMP. These may c o n s t i t u t e a common Pathway f o r normothymic a c t i o n of b o t h d r u g s i n a f f e c t i v e i l l n e s s . The d i f f e r e n c e s be tween Li and CBZ c o v e r m o s t of t h e i r o t h e r b i o l o g i c a l e f f e c t s . Among s p e c i f i c p r o p e r t i e s of L i and CBZ, a b e n e f i c i a l immunomodulatory a c t i o n of L i and a n t i k i n d l i n g a c t i v i t y i n limbic system of CBZ s h o u l d be m e n t i o n e d . They may a c c o u n t f o r some o f t h e a p p l i c a t i o n s of these d r u g s i n s p e c i a l t ypes of a f f e c t i v e i l l n e s s and o t h e r c o n d i t i o n s . However. i n a f r a c t i o n of a f f e c t i v e p a t i e n t s . c o n c o m i t a n t a d m i n i s t r a t i o n of L i a n d CBZ m i g h t be the o p t i m a l t h e r a p e u t i c o p t i o n . where p s y c h o t r o p i c e f f e c t s of b o t h d r u g s are augmented and somatic s i d e - e f f e c t s compensa ted .

116

LITHIUM INDUCED DISRUPTION OF PHOSPHOINOSITIDE SIGNALLING IN BRAIN: RELATIONSHIP TO TEERAPEUTIC ACTION? Stefan R . Nahorski, Stephen Jenkinson & R.A. John Challiss, Department of Pharmacology and Therapeutics, University of Leicester, P.O. Box 138, Medical Sciences Building, University Road, LEICESTER. LE1 9HN, U.K.

One of the most compelling hypotheses concerning the action of lithium in the central nervous system relates to inhibition of the enzyme inositol monophosphatase by the therapeutic concentrations of this monovalent ion. The inhibition is uncompetitive in nature and this can provide a stimulus-dependent disruption of inositol recycling which might be expected to reduce polyphosphoinositide synthesis that is crucial in the signalling of several receptor systems. Recent experimental developments have allowed this hypothesis to be tested. In rat cerebral slices assays of inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate mass and detection of cytidine monophosphate-phosphatidate as a sensitive indicator of inositol depletion has provided strong evidence for this action of lithium. Data on muscarinic receptor, alpha, adrenoceptor and glutamate metabotropic-stimulated phosphoinositide metabolism in different cerebral regions will be presented. Recent information on a particularly sensitive action of lithium (EC, < 1 O O p M ) on the accumulation of the unusual inositol 4,5-bispkosphate in brain will also be described.

S.R. Nahorski, C.I. Ragan, R.A.J. Challiss (1991) TIPS, 12, 297-303.

USE OF A CELL LINE TO INVESTIGATE THE INTERACTION OF LITHIUM IONS WITH SECOND MESSENGER SYSTEMS. M. A. Varney & S. P. Watson, Department of Pharmacology, University of Oxford, Mansfield Road. Oxford, UK

The mechanism of action of Li+ in the treatment of manic-depression remains unclear. However, Li+ uncompetitively inhibits a key enzyme in the phosphoinositide pathway preventing the recycling of inositol into inositol-containing phospholipids, which may be sufficient to attenuate phosphoinositide signalling. This interaction of Li+ has received much attention, not least because it provides an explanation for its selectivity to the CNS. The effect of therapeutic concentrations of Li+ was investigated on the phosphoinositide pathway in the rat pituitary GH3 cell line. Chronic treatment of the cells with 1 mM Li+ in low inositol-containing medium reduced mass levels of Ins( 1,4,5)P3 under basal conditions, and following stimulation with TRH. This reduction occurred after 4-7 days of treatment, and remained attenuated for at least 21 days. This effect of Li+ was prevented in medium supplemented with 10 mM myo-inositol. Furthermore, intracellular myo- inositol levels were reduced to a greater extent in GH3 cells treated with Li+ than in control cells. Levels of the second messengers cyclic AMP and cyclic GMP were unaffected by chronic Li+ treatment. Isotopic radiolabelling experiments with [3H]inositol and [3H]cytidine were used to look at the activity of phosphoinositide pathway and the levels of CDP-DG, respectively. Taken together. results from mass levels of inositol. Ins( 1,4,5)P3, and radiolabelling experiments indicate that Li+ can selectively downregulate the phosphoinositide pathway, an action that may be of therapeutic significance. This work is supported by Bristol-Mvers Squibb

117

EFFECT OF LITHIUM IONS ON FUXCTIONAL RESPONSES IN THE RAT PITUITARY GH3 CELL LINE. M. A. Varney & S. P. Watson, Department of Pharmacology, University of Oxford. Mansfield road, Oxford, UK

To further understand the mode of action of Li+ in the treatment of manic depression we have treated rat pituitary GH3 cells chronically with therapeutic concentrations of Li+. When cells are grown in low inositol-containing medium in the presence of 1 mM Li+ a reduced activity of the phosphoinositide pathway becomes evident following chronic treatment (see accompanying abstract). The functional consequence of a reduced signalling pathway was investigated bfmeasuring inuacellular Ca2+ in fura- 2-loaded cells, and prolactin secretion by radioimmunoassay. Following chronic treatment with Li+, both basal and TRH-stimulated Ca:+ levels were reduced, but K+-stimulated entry of Ca2+ was not affected. Furthermore, a reduction in both the basal and TRH-stimulated prolactin secretion occurred following chronic exposure of the cells to 1 mM Li+. The reduction of inaacellular Ca2+ and prolactin secretion by Li+ could be prevented by growing cells in the presence of 10 mM myo-inositol, suggesting that Li+ attenuates functional responses in these cells through a reduced phosphoinositide signalling, brought about by a depletion of inositol. This work is supported by Bristol Myers-Squibb.

MODULATION OF THE PHOSPHOINOSITIDE CYCLE IN VITRO AND IN VIVO BY LITHIUM AND L-690,330, A SPECIFIC INHIBITOR OF INOSITOL MONOPHOSPHATASE. C.I. Ragan, S. Cook, A.P. Watt, S.R. Fletcher and J.R. Atack. (Merck, Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terllngs Park, Eastwlck Road, Harlow, Essex CM20 2QR).

The ability of lithium to modulate phosphoinositide (PI) signalling through uncompetitlve inhlbltlon of inositol monophosphatase may underlie its utility in the treatment of manic depression. It Is clear that lithium, at therapeutically relevant plasma levels, elevates inositol monophosphates in rat brain, and in vitro, causes decreased ability of the cell to generate Ins(l,4,5)P3 through depletion of the inositol, and presumably, the phosphoinositide pools. Whether all the effects of lithiurn on the PI cycle and other signalling pathways can be explained through this mechanism Is less clear, and specific Inhibitors of inositol monophosphatase would obviously help answer such questions. We have described the synthesis and properties of a series of aromatic bisphosphonates which are potent competitive inhibitors of the enzyme. L-690,330 (4-hydroxyphenoxyethanebisphosphonic acid) inhibits the enzyme from various mammalian sources with Ki values of approx. 1 pM. Although about 1,000-times more potent in vitro than lithium, in muscarinic M1 receptor-transfected Chinese hamster ovary cells prelabelled with [3H]-inositol, L-690,330 only produced 40% of the accumulation of [3H]-inositol monophosphates achieved by lithium at the same concentration (1 OmM), suggesting that the ability of the compound to cross the cell membrane is limited. Nevertheless, L-690,330 was able to cause a 3-4 fold Increase in mouse brain inositol( 1 )phosphate (Ins(1 )P) under conditions of cholinergic stimulation with pilocarpine. This effect was dose dependent (ED,,=0.3mmol/kg s.c.) and was maximal after 1 h. In peripheral tissues, the effects of L-690,330 on Ins(1)P levels mimicked those of lithiurn both qualitatively and quantitatively. However, in the brain the effects of L-690,330 were much less than seen with lithiurn, consistent with the blood-brain barrier further restricting access of the polar L-690,330 into brain cells.

118

SEFlOTONlN RECEF7OR RjNC73N M D 5 PRC)TEINS: IMPLICATIONS FOR DEPRESSION

6. Peter LGSC~, Charanjit S. Aulakh. Dennis L. Murphy Laboratory cf Ciinical Science. National institute of Mental Health. Bethesda, MD 20892, USA

There 4 now molecular and functional evidence for the existence of multiple 5-HT receptors, designatad 5-HT1 A-0, 5-HT2, S-hT3 and 5-HT4; in addition, there is increasingly

mnpeiiing data indicative cf a zornplex associatlon of 5-HT receptor subtypes with distinct G pro:nins and eifector systems. While s!udies of the multiple 5-HT receptor subtypes and their siand transductim mechanisms have dominated many recent investigations of this neurat:sr;smitter sysrem. there nave also been substantial advances in the development of selective recegtor subtype agonists and antagonists with therapeutic potential in depression.

This review provides a swey of !he pharmacology and molecular biology of

5-PIT roceptor-G prorain-sffecror complexes and of the evidence for a 5-HT receptor subtype-

relatea dysfunction in depressicn. It specifically emphasizes those receptor subtypes and components a: signal transduction pathways which are potential targets for antidepressant drug- induced neuroadaptatjon.

Serotonin, Carbohydrates, and Atypical Depression

Msller S.E., Institute of Biological Psychiatry, St. Hans Hospital, Roskilde, Denmark.

A t least three categories of atypical depression have been described. The hysteroid dysphoria is characterized by repeated episodes o f depressed modd in response t o feeling rejected, and a craving for sweets and chocolate. T w o other issues are characterized by a cycliCa1 occurrence o f changes o f mood and appetite, i.e., the late luteal phase dysphoric disorder (DSM-III-R, appendix), or "the premenstrual syndrome" (PMS), and the major depression with seasonal pattern (DSM-III-R), or seasonal affective disorder (SAD). The reactive mood changes are frequently accompanied by features as hypersomnia, lethargy and increased appetite, particularly with a preference for carbohydrates.

behavioural impulsivity, and modulate eating patterns qualitatively and quantita- tively. Depressives wi th PMS or SAD benefit, in general, f rom treatments with serotonin potentiating drugs, suggesting that brain serotonin plays a role in the pathophysiology. Ingestion of carbohydrates increases the plasma ratio o f tryp- tophan to other large neutral amino acids in man and animal, and the serotonin synthesis in the rat brain. Based on these findings i t has been suggested that the excessive carbohydrate intake by patients wi th PMS and SAD reflects a self- medication that temporarily relieves the vegetative symptoms via an increased central serotonergic activity.

Central serotonin pathways participate in the regulation o f mood and

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Are 5-HT3 receptor antagonists likely to be clinically effective in mania?

PH Silverstone & PJ Cowen

Psychopharmacology Research Unit. Littlemore Hospital. Oxford OX4 4XN,

U.K.

The biochemical changes underlying mania are at present uncertain, but it

appears likely that dopaminergic overactivity may play a role in the clinical

symptomotology. In keeping with this suggestion is the finding that amphetamine

5 oiven acutely to human volunteers is a good model of mania. an effect which is

at least partly due to the dopamine releasing action of amphetamine. Preclinical

studies in animals have shown both that 5-HT3 receptor antagonists inhibit

dopamine release from the nucleus accumbens. and that they attenuate

amphetamine-induced behavioural changes. It is therefore possible that 5-HT3

receptor antagonists might have a beneficial therapeutic role in mania. Here we

have examined the effect of ondansetron. a specific 5-HT3 receptor antagonist.

on the psychological and psychomotor effects of amphetamine. Nine healthy

volunteers received either placebo/placebo. placebo/amphetamine ( 15 mg), or

ondansetron (4 mg)/amphetamine ( 15 mg) orally in a double-blind placebo-

controlled balanced-crossover study. The results showed that whilst ondansetron

attenuated the psychological effects of amphetamine. in particular anorexia and

change in subjective state. i t did not attenuate amphetamine-induced changes in

performance on psychomotor tests or systolic blood pressure. These preliminary

findings support suggestions firstly that 5-HT3 receptor antagonists act to

attenuate dopaminergic neurotransmission within the limbic system. and

secondly. therefore. that these drugs may be of clinical benefit in the treatment

of mania. At present we are repeating this study using another 5-HT3 receptor

antagonist. and hope to be able to present the preliminary findings from this

second study at this meeting.

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NON-ENDOGENOUS DEPRESSION, CHRONIC PAIN, ALCOHOLISM AND SEROTONERGIC DYSFUNCTION. E.T. Mellerup and P. Plenge, Institute of Neuropsychiatry, Rigshospitalet-6102, Copenhagen.

An association between non-endogenous depression and increased platelet imipramine or paroxetine binding has been obtained in three studies.

Firstly, endogenously depressed patients were compared with non-endogenously depressed patients; the latter group had significantly higher platelet imipramine binding.

Secondly, chronic pain patients were compared with control persons; the pain patients, who in addition to their pain showed symptoms of depression of the non-endogenous type, had higher platelet paroxetine binding than the controls.

Thirdly, alcoholics had significantly more paroxetine binding sites than the control persons, and the alcoholics with a low Newcastle score had higher platelet paroxetine binding than alcoholics with a higher Newcastle score

The connection between depressive symptoms o f the non-endogenous type and high platelet paroxetine binding in depressed patients, in chronic pain patients and in alcoholics may indicate that these patients have a common dysfunction in their serotonergic system, making them vulnerable in more than one way. Thus impairment of impulse control could also be a serotonergic dependent contribution to the symptoms of these patients.

TEE ACTIONS OF ANTIDEPRESSANTS ON WPAXILJKRGIC RECEPTORS. GIN0 SERRA. DEPARTME" OF NEUROSCIENCE, UNIVERSITY OF CAGLIARI VIA FORCELL 4, 1-09124, ITALY.

In 1919/80 we suggested that chronic treatment with different antidepressants (ADS) potentiates dopamine (DA) transmission in the central nervous system (CNS) by inducing a subsensitivity of DA autoreceptors. This hypothesis was formulated on the basis of the observation that chronic ADS not only potentiated the motor stimulant effect of apomorphine, a DA receptor agonist, but also prevented the hypomotility and inhibition of DA synthesis produced by small doses of the drug. Further support to our hypothesis of "DA autoreceptor subsensitivity" was provided by the electrophysiologica! studies of Chiodo and Antelman. These authors observed that repeated treatment with typical and atypical ADS or electroconvulsive shock prevented the inhibitory effect of apomorphine on the firing rate of DAergic neurons in the substantia nigra. Subsequently, while some authors were able to replicate our biochemical and behavioral findings, others confirmed the potentiating effect of chronic ADS on the stimulatory effect of DA agonists, but failed to observe prevention of the inhibitory effect of apomorphine on motor activity, DA synthesis and the firing rate of DA neurons. On the basis of these latter observations it was suggested that AD-induced potentiation of DAergic transmission is due to a supersensitivity of postsynaptic receptors. However, the "supereensitivity" hypothesis contrasts with the results of DA receptor binding, showing that the D2 receptor number, as measured by (3H]spiperone binding, is unchanged whereae that of D, receptors measured by [3H]SCH 23390 binding is decreased after long term treatment with ADS. More recently, we have suggested that chronic ADS selectively increase the sensitivity of D2 - D3 receptors in the mesolimbic system by 'enhancing neurotransmiesion at the D, receptor level, which has a permissive role for the expression of the D2-D3 mediated behavioral stimulant responses.

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P-ADRENOCEPTORS IN BRAIN AND PINEAL GLAND FROM DEPRESSED SUICIDE VICTIMS.

DE PAERMENTIER F. I, CROMPTON M.R. 2, KATONA C.L.E. and HORTON R.W. IDepartments of Pharmacology and C1 inical Pharmacology and 2Forensic Medicine, St George I s Hospital Medical School, LONDON SW17 ORE and 3Department of Psychiatry, University College and Middlesex School of Medicine, LONDON W1A 8AA.

P-Adrenoceptors were measured by saturation binding of [ 3H] CGP 12177 in nine brain regions and pineal from suicides, with a firm retrospective diagnosis of depression, and age- and sex-matched controls. Twenty one suicides had not recently received antidepressant (AD) drugs, 13 had been receiving AD drugs prior to death. In AD drug- free suicides, the Bmax of p-adrenoceptors was significantly lower in temporal and occipital cortex (non-violent deaths) and in frontal cortex (vio1er.t deaths) than in controls. In AD drug-treated suicides, significantly lower P-adrenoceptor Bmax were found in thalamus and temporal cortex than in controls. In pineal, no significant differences in Bmax were found in AD drug-free or AD drug-treated suicides and matched controls. Depression in suicide victims is associated with deficits in cortical P-adrenoceptors. The lower number of P-adrenoceptors in thalamus appeared to be related to drug treatment.

We thank the Sir Jules Thorn Charitable Trust for financial support.

LYMPHOCYTE INTERLEUKIN-2 RECEPTOR FUNCTION IN DEPRESSION

Kanba, S. , Shintani, F., Shima, S., Miyaoka, H., Nibuya, M., Suzuki, E., Kinoshita, F., Yagi, G., and Asai, M.

Department of Neuro-psychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160 JAPAN

The interleukin-2 (IL-2) receptor-mediated lymphocyte response was examined in depressed patients.

The subjects were 11 depressed patients (5 males) who gave informed consent to this project. The age was 55 & 10 years old (mean & S.D.). The severity of depression assessed by the Hamilton scores was 31 & 7 (mean & S.D.). There was a statistically significant correlation between the IL-2 receptor-mediated response (0.5 U/ml, 72 hr) and the seventy of depression at the time of entry ( ~ ~ 0 . 0 5 ) . The mean & S. D. of [3H]thymidine incorporated (0.5 uCi, 7 hr) at the time of depression was 33000 & 21400 cpm, while 54500 & 22600 cpm in remission. The difference was statistically significant (p< 0.05, paired t test). Thus, when depression improved, the IL-2 receptor-mediated response became higher.

patients were depressed, but increased in remission. This study indicated that the IL-2 receptor-mediated response was decreased when

I22

MOCLOBEMIDE IN DEPRESSION . Kirs t en Behnke.

The existing treatment for depression is not completely satisfactory. Pharmacological therapies are associated with a variety of problems: troublesome side effects, drugs toxicity and limited efficacy. Therefore, there is a need for development of improved antidepressant therapies. Moclobemide is a reversible inhibitor of monoamine oxidase-A (Rima) with a predominant effect upon the A-form of the enzyme. It is relatively transient in its pharmacological action. It has a short elimination half-life in plasma, it is promptly degraded in the tissues and most important the action is reversible i.e. in contrast to older MAOIs.

Controlled studies have documented the efficiacy of Moclobemide in endogenous depression and in a variety of clinical subgroups. A Danish study did not show any difference between Moclobemide and Clompramin in treatment of reactive depression.

Larsen J.K. et al. Moclobemide and Clomipramin in reactive depression. Acta Psychiatr. Scand. 1989:79:530-536.

Angst J. Stab1 M. Efficiay of Moclobemide in different patient groups: a meta-analysis of studies. Psychopharmacology 1992:106:109-113.

COMBINING NORTRIPTYLINE AND LITHIUM IN ELDERLY DEPRESSED PATIENTS: A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY.

Jensen HV', Olafsson K', Lykke-Olesen L', Mark A*, Geisler A', Arup P'.

'Psychogeriatric Department , Frederiksberg Hospital and 'Department of Pharmacology , University of Copenhagen , Denmark.

The antidepressant effect of nortriptyline and lithium carbonate in combination from the beginning of treatment versus nortriptyline alone was compared in a double-blind, placebo-controlled study of 4 4 depressed elderly patients. The patients had a DSM-I11 diagnosis of major depressive disorder, a Newcastle (11) Depression Rating Scale score c -19, a Hamilton Rating Scale for Depression (HRSD) score 2 15 and were aged 2 65 years. The serum nortriptyline levels were in the range of 206 to 570 nmol/l, and the standard 12-h serum lithium concentrations were between 0.5 - 0.7 mmol/l; duration of treatment was 6 weeks. Within treatments, the median HRSD scores decreased significantly, whereas, between treatments, the median changes in HRSD scores did not differ significantly. In conclusion, the study does not support the hypothesis that nortriptyline and lithium carbonate in combination from the beginning of treatment is more efficacious than nortriptyline alone in alleviating depressions in elderly patients, neither as regard rate nor degree of antidepressant effect.

123

LIGHT THERAPY OF DEPRESSION; BASAL AND CLINICAL ASPECTS L. Wetterberg, Karolinska institute, Department of Psychiatry, St. Goran's Hospital, S - 112 81 Stockholm, Sweden

Sunlight strongly influences circadian rhythms of most living bein s. The light

are also important for health and well-being. The resentation will review present research

suppression of the ineal hormone melatonin by light and treatment outcome. Light treatment in mood isorders hypothetically rests on the assumption that changes in li ht- darkness regulate biological rh hms. The system that Benerates different diurnal rhyt ms

upper cervical ganglion to the pineal body. According to an alternative hypothesis light therapy results in a general increase in receptor sensitivity in the central nervous system which results in an antidepressant effect. There is a potential use of hormones such as melatonin as biological markers in depression and specially of endocrine parameters which are dependent on both noradrenergic and serotinergic transmission for its regulation. Sleep disorders which are often found in mood disorders may also be related to disturbances in endocrine functions. Some studies have proposed melatonm as a trait marker and hypothesized a "low melatonin syndrome" characterized by low nocturnal melatonin levels, an abnormal dexamethasone suppression test (DST), a disturbed 24 hour rhythm of cortisol, and a less pronounced daily and annual cyclic variation in depressive symptomatology. The therapeutic response to light therapy ma be predicted from the pretreatment serum melatonin levels showing a more

test in non-improved patients. The study of the regulation of e g the pineal gland hormone melatonin offers a natural link between soma and mind for exploration of mood disorders. Experimental studies describe a complex biological oscillator of circadian rhythms which may provide a basis for explaining many of the abnormalities in both phase and amplitude found in mood disorders. Results of phototherapy from several recent studies will be reviewed.

which enters the eye affects man visually as well as non-visually. The nonvisual e B fects of light

about light treatment of depression and seasona P affective disorders (SAD), the use of

includes signal transmission of 1y' ight impulses via the retina to the hypothalamus and via the i B

pathologica r melatonin rhythm with higher levels in the morning and less response to the light

DRUG-INDUCED DEPRESSION. R.Klysner, Dept.of Psychiatry, Rigshospitalet, Copenhagen, Denmark.

Drugs of many kinds may occasionally induce organic mood disorder, not infrequently in the form of a depressive state. There is, however, apparently much difference in the frequency with which such a state is induced by different drugs, and difference in the proposed mechanisms of drug-induced depression. There also seems to be difference in the reaction to some drugs depending on the presence of prior psychiatric history, while in others there is apparently no such association. An overview of these suggestions and association with psychiatric illness, and their proposed effects on neurotransmitter systems will be presented.

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PROSPECTIVE STUDY OF THE INFLUENCE OF DIFFERENT LITHIUM REGIMENS

ON BIPOLAR PATIENTS' KIDNEY FUNCTION AND COMPLIANCE. M. K u s a l i c .

Depar tment o f P s y c h i a t r y , S t . M a r y ' s H o s p i t a l Cen t re , M c G i l l

U n i v e r s i t y , 3830 Lacombe Avenue, M o n t r e a l , Quebec, Canada, H3T 1M5.

A p p r o x i m a t e l y 1 7 2 b i p o l a r p a t i e n t s a r e t r e a t e d w i t h l i t h i u m

c a r b o n a t e i n o u r A f f e c t i v e D i s o r d e r C l i n i c . D u r i n g t h e p a s t t h r e e

t o four yea rs , t h e m u l t i p l e d a i l y reg imen was r e p l a c e d by a once

a day a t bed t ime reg imen. P r i o r t o t h a t , a n a l y s e s o f u r i n e

c r e a t i n i n e c lea rance , u r i na ry volume, l i t h i u m d a i l y p o s o l o g y i n

m i l l i g r a m and serum l e v e l were done. The same a n a l y s e s were

r e p e a t e d one yea r l a t e r . The advantages of s i n g l e p o s o l o g y w i l l

be assessed and p r e s e n t e d . The e f f e c t o f a d j u n c t i v e a n t i p s y c h o t i c

t r e a t m e n t on k i d n e y function w i l l a l s o be p r e s e n t e d .

INFLUENCE OF ANTIDEPRESSANTS ON CROSS-TALK BETWEEN a- AND a-ADRENOCEPTORS. I. ACUTE I N VITRO EFFECTS. I rena Nalepa, Jerzy Vetulani. Inst i tute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krakbw, Poland

Most of the biochemical effects characteristic for antidepressant treatments appear only i n a chronic situation and are of adaptive character, those adaptation result from the direct action of treatments on cellular structures, that might be observed in in vi t ro experiments. Changes in cyclic AMP (CAMP) formation induced by noradrenaline are believed t o be one of the important characteristics of antidepressant action. Generation of cAMP depends critically on stimulation of R-adrenoceptors, but the efficacy of th is response i s controlled by a-adrenoceptors. One of the causes of the phenomenon of a-potentiation of D-adrenocep- tor response may be activation of protein kinase C (PKC) result ing from stimulation of a,- adrenoceptor. We investigated how imipramine, ,a drug producing 8-downregulation (when given chronically), rnianserin, whose R-downregulatory action was questioned, and citalopram, which dces not produces R-downregulation, affect the cAMP generation i n cerebral cortical slices from rats, The slices were treated with noradrenaline o r isoprotere- no1 in the absence or presence of a phorbol ester, TPA, which activates PKC. No one of the druss bound to B-adrenoceptors, while imipramine showed high aff ini ty to a,-, and mianserin - to a,-adrenoceptors. Imipramine and mianserin i n high concentrations (10 and 100 UM, resp.) inhibited noradrenaline-induced cAMP accumulation, while citalopram was ineffective in this respect. No one of the drugs affected the cAMP response to isoprotere- nol. Direct activation of PKC by TPA potentiated the cAMP responses to isoproterenol and noradrenaline by aDprox. 100 and 50%, resp. This TPA-induced potentiation o f response to noradrenaline and isoproterenol was inhibited by imipramine and mianserin, bu t not by citaloprarn. The results suggest that R-downregulation is caused by chronic administration of those antidepressants that affect acutely the cross-tal k bet'ween a- and R-adrenoceptors, e.g., by acute blockade of a-adrenoceptors.

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INFLUENCE OF ANTICEPRESSANTS ON CROSS-TALK BETWEEN a- AND R-ADRENOCEPTORS. 11. STUDIES IN CHRONICALLY-TREATED RATS. Jerzy Vetulani, I rena Nalepa. Inst i tute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krakdw, Foland

One o f the effects of chronic antidepressant treatments believed to be characteristic for th is class of drugs (and ECT) is B-downregulation, reflected by depression of the eventual response from R-adrenoceptors. This effect may result from reduction in the R-adrenoceptor density or decrease in the efficacy of generation of the second messenger. The latter may be related to a decline in a-R-adrenoceptor coupling. We investigated the effect of three antidepressants of different chemical structure and pharmacological properties, irnipramine, mianserin and citalopram. They were given two daily doses of 10 rng/kg each fo r 14 days, and the responses of cyclic AMP (CAMP) to a mixed a- and R-adrenoceptor agonist noradrenaline and a specific 0-adrenoceptor agonist isoproterenol (both 10 PM) were measured in cerebral cortical slices in the absence of presence of a protein kinase C (PKC) activator. TPA. Only imipramine treatment resulted in significant reduction of cAMP response to noradrenaline (but not isoproterenol) i n the absence of TPA; under conditions of PKC stimulation responses both to noradrenaline and isoproterenol were reduced by approx. 50%. Mianserin treatment dia not result in a significant depression of cAMP response to either noradrenaline or isoproterenol, but in the presence of TPA the response to both agonists were down regulated si gnificantl y. Citalopram treatment produced a significant increase in responses of cAMP to noradrenaline both i n the absence and presence of TPA (by 130 and 52%, resp.), while the responses to isoproterenol were only insignificantly augmented (by 23 and 37% in the absence and presence of TPA, resp.). The resuits indicate :hat imipramine treatment results in more pronounced R-downregulation than chronic administration of mianserin, which results i n depression of responses only in the presence of TPA. Both imipramine and rnianseri.n inhibi t the potentiation of 8- adrenoceptor response b y TPA. The upregulatory effect of chronic treatment with citaloprarn seems to be independent on PKC.