P-2 Antidepressants: basic and clinical stu&es 291

Exclusion crltena are: n~story o f active osychoorganic diseases, cur rent treatment with psvchotroplcs (Lu neuroleptics), pregnant and tactatmg women.

Results. Among 244 enrolled patients, 46 were prematurely withdrawn The mean (+std) decrease of HAD-S total score vanes from 63 {-F6.62) after 2 weeks of treatment to 16.2 (±8 96) after 8 weeks of treatment (p < 0.0001 ) A statistically significant Improvement is observed in all dimensions of the SCL-90 scale with a maximal decrease achieved on the depressive symptoms (highest baseline mean)(p < 0 0001) and a minimal decrease on the psychoticism symptoms (lowest baseline mean). The evolution of each cluster of symptoms is discussed. This improvement is also corroborated through the QOL scores evolution Chnicians and patients agree with the satisfaction of the treatment (CGI: PGI) Frequency of somatic complaints as well as frequency of patients reporting somatic complaints decrease during therapy, leading to a clear decrease of concomitant medications. This open label study in general practice confirms the efficacy o{ Prozac in popu!ations suffering from other forms of depression than those classically described in psychiatric settings or enrolled in sophisttcated trial patterns Finally these results reinforce the efficacy of SSRI's and especially of fluoxetine for managing anxiety symptomatology

References Lydiard, R B , {1991) Coexistmg depresmon and an×iety spec,al diagnosbc and treat

ment Bsues J Clin Psychiatry 52: b {suppl ) Benfield, P, Heel, R C , Lewis, P (1986) Fluoxetme A rev!ew of its pharmacodynarmc

and pharmacokinetic properties, and therapeutic efficacy m depressive Illness Drugs 32:451 508

Stokes, RE, (1993) Fluoxetine Alive years review Chn Ther Vol 15, n 2. 216 243

Onset of action of fluoxetine 20 mg (Prozac) among ambulatory patients suffering from depressive disorders

R M e s t e r s l , M Sangeleerl G. Bussiosl M BoJrgec~s2 1El/L,,//y Benelux S.A., Rue de/'Etuve 52/t, 1000 Brussels, Belg,u, rn, 2 IPHIB, Dreve des Dommicains 24, 6280 LovervaL Belg.,urn

It is generally assumed that a delay of 2 to :3 weeks is r'ecessary before an antidepressant produces any Improvement ,n the symptomatoiogy of tne depressive patient

This delay is related to toe t ime needed te reac~ appropqate concentra tions at the target site and to the modu atlon of :be mcqoar>inerglc system (down regulation process).

In order to address this phenomenon a naturahstic study has been pe" formed as to evaluate the precise onset of act,on of Prozac 20 mg m the treatment of ambulatory depression.

Study characteristics." Mukicentre open StUdy wtth 4 visits on a 4 wee~ period.

Fprstv is l t {day0):demographlccharacterst ics psychlatnchistory, current diagnostic according to DSM Iii R critena, HRS D. Visit 2 (day 71 3 (day 14) and 4 (day 28): HRS D DGI (patler't global impression), date of first improvement according to oatent 's appreciation ned;cations and report of side effects

Results 943 patients have been enrolled Mean age is of 43 years and sex repartition F/M 64%. Un~polar deoress~o~" is the most reported diagnosis (56%}

All efficacy measures (PGi and HRS-D] show an arrlp-ovement as for visit 2 in comparison to the first evaluation I~'provement mcreases reguladyat each of the fol lowing visits

The frequency distribution of tqe delay necessary to feel an imorovement f o r t h e f i r s t t i m e mentioned by the pat ienthtmself show'sabimodal~a: tem after 6 and 11 days of t reatment

These results address the issue of the complexity of the parameters in~. plicated in the clinical response to an anudepressant therapy (drug eft cacy psycho~ogical effect due to the m e d c a l f o l l o w u p etc]

The several aspects invo ved in the efficacy process are d scussec

References Salzman C et al (1992) Predic:ors ol se~oloperg.: antidepressant 'espouse Chn Neu-

ropharm Vol 15 SupDI 1 Pt B Brier, P et al (1994) Current advances and tlends m the trealmem 3f depress,on Trends

Pharmacol Sci ~5(7) 220 226

i P-2-50 } Up-regulation of 5-HT2c receptors by citalopram ' and fluoxetine in rat brain E KG Swalahti, A. Laakso. E-R P~lvimaki, M. Kuoppamaki, J. Hietala. Department of Pharmacology, University of Turku, F/N-20520 Turku, Finland

A subtype of 5-HT (serotonin) receptors, the 5-HT2c receptor has been suggested to play a role in many emotmnal, behavioural and neuroendocrine responses. The 5-HT2c receptor belongs to the 5-HT 2 receptor family which consrsts of three known G-protein coupled receptors that regulate the phospholipase C-coupled phosphoinositide hydrolysis. There is increasing evidence that 5-HT2c receptors may play a role in the actions of many psychoactive agents, including hallucinogenic drugs, some antipsychotics and some antidepressants, but there are no published radioligand binding studies concerning the effects of chronic or acute treatment with SSRIs on 5-HT2c receptor binding sites that would have used binding conditions selective for the 5-HT2c receptor subtype.

In the present study, the effects of chronic (for 14 days) citalopram and fiuoxetine treatments with three doses (2.5, 10 and 20 mg/kg} and with drawal times (24 hours, 68 hours and 14 days) on 5-HT2c (formerly 5-HTIc) receptors m the rat brain choroid plexus were studied with quantitative receptor autoradiography in two separate experiments.

Chronic citalopram treatment caused a consistent and dose-related mcrease in the denstty of 5 HT2c receptors (up to 90%). This effect was shghtly more pronounced when measured with an antagonist lig- and ([3H]mesulergine} compared to measurements with an agonist ligand ([1251]DOI) The up-regulation was most evident 24 hours after the last dose and disappeared thereafter rather rapidly. Chronic f luoxetme treatment also mcreased the density of 5-HT2c receptors 24 hours from the last dose, but the increase was accompanied by a reduced affinity and was less marked than that observed with ci talopram The changes in receptor characteris- tics were not observed consistently after the 68 hours withdrawal from f luoxet ine Furthermore, the up-regulation of f luoxetine appeared not to be dose-related, not reflected by an increase in agonist binding.

In conclusion, the results show that chronic citalopram and fluoxetine treatments reduce an up-regulation of choroid plexus 5-HT2c receptors, but the effect ~s more marked with citalopram. The data also suggest that 5-HT2c receptors are significantly occupied qunng chronic f luoxetine treat- ment (by fluoxetine or more likely by an active metabolite, norfluoxetine), proposmg that the actions of chronic fluoxetine treatment may not reside only m serotonin uptake inhibition. This direct interaction by fluoxetine may trigger additional regulatory mechanisms of the 5-HT2c receptor leading to pharmacodynamic differences between chronic citalopram and fluoxetine treatments

References

clozapine treatment down-regulates serotonin 5-HT-lc receptors in rat brain. Progress m Neuropsychepharmacotogy and Biological Psychiatry 16,727

Hoyer, D, Clarke. D E, Fozard, P R. et al. (1994). VII International Union of Pharmacol- ogy Classification of Receptors for 5-Hydroxytryptamine (Serotonin} Pharmacological Reviews 46, 157

Jenck, F, Moreau J L , Mutel, V, Martin, J R and Haefel¥. W E (1993) Evidence for a role of 5-HT1c receptors in the antiserotonergic properties of some antidepressant drugs Eurooean Journal of Pharmacology 231. 223

The effects of fluoxetine in patients receiving nutritional counselling for bulimia nervosa

Janice Russell, Peter Beumont, Stephen Touyz, Cathy Buckley. Kitty Lowinger, Peter Talbot. Lisa Dowton, Robert Hasky, Helen Allars, Gordon Johnson Sydney University Centre for Eating Disorders (Northside Clinic, Greenwich NSW, Lynton Private Hospital, Chatswood NSW, Royal Prince Alfred Hospital, Camperdown NSW and Westmead Hospital, Westrnead NSW) and Eh L/fly Australia.

A number of studies have reported benefit from the use of f luoxetine in the management of bulimia nervosa. However this effect was not apparent m patients who were also receiving psychotherapy (Fichter et al 1991). The aim of this study was to examme the effect of f luoxetine when given in con- iunct~on with nJtritional counselling to patients meeting DSM-IIIR criteria for bulimia nervosa. Sixty seven female patients aged from 18 to 35 and of normal body weight (BMI 20-25)were studied in a randomised double blind placebo-controlled trial using a daily dose of 60 mg fluoxetine for 8 weeks. All participants received nutritional counselling from the same nutritionist durmg the 8 weeks of the active phase and at each of 2 fo l low up visits at 4 and 8 weeks +ollowing cessation of medication or placebo. Assessment. chn~cally and by a number of instruments which included HAMD, EAT, EDI

292 P-2 Antidepressants." basic and clinical studies

and BSQ was made weekly on all patients after a 2 week washout pe- riod and at both follow up visits The Eating Disorders Examination (EDE) (Fairburn and Cooper 1993) was administered by the study nutntlonlst at visits 2 (at commencement of medication or placebo), 10 (at completion of the active phase), and at each o ~the 2 follow up visits Comprehensive assessment of nutritional intake and wepght losing behaviours was also made throughout the study Treatment with fluoxetine was shown to be associated with significant reductions in binge frequency, body weight, en- ergy intake and in EDE scales for dietary restraint and weight and shape concern. Clinical Global Impression scores indicated greater improvement in the fluoxetine treated group throughout the active phase. Thus fluoxetme administered in coniunction with nutritional therapy, was shown to exert an additional beneficial effect in bulimia nervosa when compared to placebo

References M M Fichter, K Llebl, W ~{ief et al 11991) Fluoxetme versus placebo: a double-bhnd

study with bulimic inpat~ents undergomg mtenswe psychotherapy Pbarmacopsychl atry: 24:1 7

Falrburn CG and Cooper PJ {1993) The Eating Disorder Examination (12th Edition) In CG Fairburn and G Terence Wilson (Eds) Binge Eating Nature, Assessment aqd Treatment New York The Guilford Press, 317 332

Clinical differences in response to mianserin and fluoxetine in depressive patients

F Lavergne 1, I. Berlin 2, C Payan 2, G Besanqon 3 10rganon France B P 144-93204 Sarnt Denis Codex 01, 2 Sen/ice de Pharmaco/ogle C/imque, HSpltal PItiO, Sa/p#tr/ere, 75013 Parrs, 3 H6pzta/ Saint Jacques, 44035 Nantes

Patients aged !8 to 65 yearswitb DSM II crqteria ;ora depressive episode the episode being less than 2 months' duration and wrth a mmmlum score of 25 on the Montgomery-Asberg Dep,ession Rating Scale (MADRS) were included.

Design. Double blind trial mianserm versus fluoxetine with fixed dosage from day 1 to day 14 (mianserin: 60 mgr'd, f luoxetme 20 mgid) and flexible dosage from day 15 to day 56 (mianserin 60 or g0 mg/d; fluoxetine: 20 or 40 rag/d). Co administration of prazeoam up to 40 mgid was allowed

Assessments.- The depression was assessed at day0, 14, 28 56 bythe MADRS and the "Mood-Anxiety-Retardation-Danger" diagram (HARD} I1]

Statlstica/ana/ysis. Between group analysis was performed by chi 2 test for qualitative variables. Quantitative variables were analysed with ANOVA ~or repeated measures and time by time compar,sons were done by one way ANOVA. Inside each group, multiple linear regressLon (stepwlse [Yo cedure) was used to ~dentifv factors ip < 005) contributing to the clinical improvement.

Resu/ts. The 2 groupsfmlansenr ~ n 32: fluoxetine n : 33 iwere compa rable it' respect of the ciinlcal status d'agnosls, history and duration of the depressive illness, MADRS scoreslmlansenn 3 2 3 i 46: f luoxetine 31 9 ±38) ,HARDscores lm~anser in : 3 5 9 ± 5 6 : f i u o x e t i n e : 3 5 1 2: 57) and for the individual items of the MADRS and HARD scales at baseline

- - Global MADRS and HARD scores were comparable at day 14, 28 56 for both groups, However some items showed significant between group differences irl the MADRS "reduced sleep" (13 < 00001)"concer'trat~op c i f f icu l t ies"(p - 0027) and"wearmess' {~ 002) improved better m the mnanserm group than in the fluoxetine group in the HARD scale"inso~'n,a ' (p < 00001), "weariness" (p 0003), "'anxiety factor" (p - 0023) anc "retardation factor" {p 0.0! 7)improved more in tqe miansenn group tna: in the fluoxetine grou9

- - :ndividual items of the MADRS at day 0, and differences, day 0-day 14 were identified to predict the final score of the HARD scale, and inversely, individual items of the HARD scale at day 0 and differences (day 0-day 14) were identified to predict the final score of the MADRS scale.

The ~tems from the MADRS at day 0 which oositively correlated :o t,le final HARD score we'e "incapac ty 10 feel, sadness reported, and suicidal thoughts" in the mlanserin group and "suicidal thoughts"in the fluoxet ne group. Items f-ore HARD at day 0 wh~clq positively correlated to trle f hal MADRS score were "danger factor" and "suicidal thoughts" in both mianserin ano fuoxe t i neg roups

Day 0-day 14 differences in the MADRS which corrtributed slgPificaritly (40%) to the flnat HA~,D score m the mlansenn croup were "tuner :enslor" and reduced s leeo" and in the fluoxetlne group "Desslmlstlc thoughts" {23%)

Day 0-day 14 differences m "retardation factor" of the HARD rl the Glanserln group contribute for 41%. ir" "psychic anxiety, and delbslor~al ~deas" contribute for 57% to the hnai MADRS score In thef luoxetmegrouo

"mood factor" contributes for 19%, "desmterest and suicidal thoughts" contribute for 38% to the final MADRS score

Conctus/on: Ln the fluoxetine group, the improvement in mood by day 14 contributes from 19 to 38% to the final clinical outcome.

The clinical differences between the two treatment groups involve anxiety and retardation. The inter group analysis reveals that anxiety (insomnia, reduced sleep, anxiety-factor) and retardation {concentration difficulties, weariness, retardation factor} are more improved in the mianserin than the fiuoxetine group. They contribute highly to the improvement of the final clintcal outcome (40 to 57%). This result shows that improvement in anxiety and retardation with mianserin is part of its antidepressant effect.

References I1] Ferreri, M ; Rufln JC: Le diagramme HARD-Pratique Med. 1984, 33 : 39~46.

Combined treatment with serotonin reuptake selective inhibitors in depression (I). Evaluation of therapeutic efficacy

JI Franch Valverde. A.A. Soto Loza, M.J. Roddguez Montes, M.L. Dorado Martinez, J L Viafia Caballero. Hospita/Chnico Universitario, Val/ado/id, Espaf~a

Due to the extensive use of the serotonin reuptake selective inhibitors (SSRI) for the treatment of the depressed patient during the past five years, the therapeutic management alternatives of resistant depressive disorder have been moved.

Nowadays, combined treatment with several antidepressant drugs, being one of them a SSRI. is an often used therapeutic strategic for the resistant mood disorders This issue has raised again two important questions con- cerning the approach to the resistant depression:

• ,- The possibility of reducing the necessary time to obtain a clinical im- provement.

-- The rat~o of risks to advantages that these combined treatments have established.

Accord ng to the positive demonstrated results with the previously men- tioned aqt~depressant association that has been employed in our outpa- tients, taking account of their clinical and epidemiological characteristics, we have analysed retrospectively the different kinds of antidepressant as- sociations paying special attention to ~asues referring to their therapeutic efficacy and the necessary time to obtain a positive response.

References Franch Valverde. J , Soto Loza, A, Medina Merino. C , D~ez Martin. J., Viafia Caballero,

J Pslcofarmacos y trastornos afectivos(ll) Dwersificaci6n de tratamiento en tunei6n del trastorno depresivo(TD ) t.Mito o realidad? 5 ° Congreso Mundial de Psiquiatr[a B~ol6glca FIorencia, Junio 1991

Joffe, R T aPd Baklsh. [3 Combined treatment with SSRI and Moclobemide in psychiatric disorders Journal of Clinical Psychiatry 1994;55, no 1,24-25.

Montgomery, S A Anxiety and depression Petersfleld England, Hampshire: Wrightson Biomeaical; 1990

Rosenthal JS , Kaswan, MJ.. Hemlock, C, Winston, A Potenciaci6n de los antidepre- sivos heterociclicos con Fluoxetina Amsterdam JD, editores Depresi6n refractaria Barcelona: JqMS S A , 1993;115-118

Soto Loza, A, Franch Valverde, J, Merino Andros, C , Barbudo Antolin, E, Viafia Caballero, J Psieof&rmacos y trastornos afectivos (Y) Manei o en la elinica de los antidepresivos de tercera generacl6n 5: Congreso Mundial de Psiquiatria Biol6gica, Florencia, Junio 1991

Weilburg, ~ B, Rosenbabm, JE, Biederman, J, Sachs, G.S, Pollack, MH, Kelly, K Flu oxetine added to non-MAgi antidepressants converts nonresponders in responders: a preimTinary report J Clin Psychiatry, 1989;50:447-449

Combined treatment with serotonin reuptake selective inhibitors in depression (11). Aspects concerning tolerance and toxicity in clinical practice

A A Sore Loza, J I FranchValverde, M.J. RodriguezMontes, M .L Dorado Mart[nez, J_. Viafia Caballero. E. Quintana Docio. Hospita/C/inico Unlversitario, Val/ado#d, Espafta

Several therapeutics alternatives have been employed for the approach to resistant mood disorders: lithium, hormones, carbamacepine, etc., and combining two or more antidepressant drugs. The pharmacological inter- actions between the different antidepressant agents that have been used, nave caused very serious side effects, even letal ones. This issue has con- cerned the osychiatrists, who are involved in a great insecurity referring to these associations