304 ['-2 Antidepressants: basic and clinical studies

References Katz, I. R 11993) Drug treatment of depression m the frad elderly: discussion of the NIH

consensus development conference on the diagnosis and treatment of depression in late life Psychopharmacology Bulletin 29, 101-108

Wagner, W, Zaborny, B A and Gray. T E (1994) Fluvoxamme A review of its safety profile in world-wide studies International Clinical Psychopharmacology 9,222 226

I P-2-87 i Comparison of the safety and tolerance of fluvoxamine and sertraline in depressed outpatients

CB. Nemeroff 1, PT. Ninan 1, J.C. Ballenger 2, j . Feighner 3, JH. Greist 4, W M Patterson 5 1 Empty University School of Medicine, Atlanta, GA, 2 Medical University of South Carolina, Charleston, SC, 3 Feighner Research Institute, San Diego, CA; 4 Dean Foundation for Health Research Education, Madison, WI, 5 Birmingham Research Group, Birmingham, AL

Because of the improved safety profile relative to older antidepressants (eg tricyclics), selective serotonin reuptake inhibitors (SSRIs) have become the drugs of choice in the treatment of major depressive disorder However, few trials have been conducted which compare SSRIs directly

The comparative safety, tolerance and efficacy of LUVOX'" (fluvoxamine maleate} Tablets, 50-150 mg daily versus Zoloft ® (sertraline HC]), 50-200 mg daily, were stud~ed m outpatients with DSM-IIFR-defined Major De- pressive Disorder in a randomizea, double bhnd, parallel-group, multicenter study After s one- to two week placebo runin, patients were random- ized to double-blind treatment for seven weeks. Efficacy was evaluated primarily by the Hamilton Psychiatric Rating Scale for Depression (HAM-D) Secondary and supportive measures of efficacy included HAM-D factors scores, the Clinical Global Impression Scale (CGI), the Hamilton Psychiatnc Rating Scale for Anxiety (HAM-A), the Raskin-Cow Scale and the SCL-55 Safety evaluations included vital s~gns, clinical laboratory tests (hematol ogy and biochemistry}, the Sexual Symptoms Distress Index, monitoring of adverse events and concomitant medicat ions

Of 114 patients screened for the study, 97 patients were randomized: 49 to f luvoxamine and 48 to sertrahne. The majority of patients had no other Axis I disorder nor had they been on treatment with psychotropic medicine m the past three months The mean total daily dose after titration was 123.75 mg for f luvoxamine and 137.10 mg for sertraline. Mean HAM D 21-item total scores decreased by 13.03 points for f luvoxamine and by 11.61 points for sertraline (vislt-w~se analysis) over the 7-week period There were no statistically significant differences between groups at any visit and at end-point for the primary efficacy variable (HAM-D 21-item total score) Secondary and supportive measures confirmed the results obtained wi:h the HAM-D

Neither treatment was associated with any clinically important changes in laboratory values or vital s~gns. There were more overall complaints as- sociated with sertraline than with f luvoxamine (93.5% of sertraline patients reported adverse events versus 85.7% with f luvoxamme) Although more fluvoxamine-treated patients discontinued owing to adverse events (nine f luvoxamine vs. one sertraline, p 0.016). there was no clear pattern to the reasons. In evaluating overall reports of adverse events, there was little difference between the two treatments with the majority occurring in the body as a whole (e.g, headache, asthenia), digestive (e.g., nausea, diar rhea), and nervous (eg., insomnia, somnolence) systems. Sertraline was associated with more sexual dysfunction complaints (libido decrease, ser traline 19.57% vs. f luvoxamine 6.12% p = 0.049: ejaculatory abnormality, ser t ra l ine22.22%vs f luvoxamine5.26%)thanf luvoxamine. No patient was rated as worse in suicidal ideation at the end of the study.

References Wilde, M, PIosker, G L , Benfield, R Fluvoxamme: an updated review of its pharm acologv

and therapeutic use in depressive illness (!993) Drugs 46 (5), 895 924 Delgado PL, Price, LH, Charney, D S, Henlnger, GR Efficacy of fluvoxamme m

treatment-refractory depression (1988) J Affective Dis 15.55~60

Comparison of fluvoxamine and fluoxetine in major depression

M. Rapaport 1. E Coccaro 2,Y.Shel ine 3, P Holland 4 . T Perse 5 . L Fabre 6 1 UmversJty of California, San Diego, CA, 2 Medical College of Pennsylvania, Philadelphia, PA, 3 Washington Universi~, St. Louis, MO, 4 Boca Raton Psychiatry Group, Boca Raton, FL, 5 NFPC, Edmonds, WA, 6 Research Testing, Inc., Houston, TX

Fluvoxamine maleate (LUVOX'") is a potent and specdic inhibitor of sere

tonm reuptake with demonstrated antidepressant activity in a number of clinical trials This is a report from a randomized, double-blind, parallel group study of the efficacy and safety of f iuvoxamine and fluoxetine (Prozae ®) in major depressive disorder. Based on previous studies, we postulated that: (1) f luvoxamine and fluoxetine would have comparable efficacy; and (2) flu- voxamme would be associated with fewer treatment emergent signs and symptoms (TESS) than fiuoxetine, in particular, less problems with insom- nia, agitation, nervousness, restlessness, and anxiety.

After a one-to-two week placebo run-in, patients received double-blind treatment with either f luvoxamine (50-150 mg/day) or f luoxetine (20-80 rag/day) for seven weeks. The Hamilton Depression Rating Scale (HAM-D) was the primary efficacy measure and secondary efficacy measures in- cluded HAM-D factor scores, the Clinical Global Impression Scale (CGI), the Hamilton Psychiatric Rating Scale for Anxiety (HAM-A), the Raskin- Covi Scale and the SCL-56 Vital signs, clinical hematology and biochem- istry tests, adverse events, concomitant medication, and scales for suici- dal ideation (Modified Scale for Suicidal Ideation). and akathisia (Barnes Akathisia Scale) comprised the safety evaluations.

One hundred fifteen patients were screened for the study, with 100 patients randomized: 51 to LUVOX'" and 49 to Prezac ®. The patient charac- tenstics bid not differ between groups and represented a sample of a typical depressed outpatient population. The mean age and gender for f luvoxamine and fluoxetine were 40 and 38.6 years and 60 and 63.8% female, respec- tively. The mean decrease in HAM-D 21-item total score from baseline to week 7 was 15.52 for f luvoxamine (2515 to 9.63) and 15.85 for f luoxetine (25.57 to 972) (p = 0.641 ). There were no statistically significant differences between groups at any visit, including end-point, for the primary efficacy variable (HAM-D 21-item total score). Secondary and supportive measures confirmed the results obtained with the HAM-D.

Sixteen patients did not complete the study (eight in each group), how- ever, only 4 patients discontinued due to adverse events. Clinical laboratory results and vital signs did not reveal any clinically significant changes. In spite of a rather high incidence of treatment emergent adverse events, (100% of fluoxetine patients and 94% of f luvoxamine patients reported at least one adverse event) treatments were well-tolerated, with few drop-outs due to adverse events, The most common adverse events for the fluoxe- tine treated group were headache (53%), nausea (43%). insomnia (28%), diarrhea (28%). and nervousness (23%). The most common adverse events for the f luvoxamine treated group were headache (50%). insomnia (36%}, and nausea (22%). Patients treated with fluoxetine experienced significantly more problems with nausea (p = 0.03). Very few patients were rated as hav- ing measurable suicidal ideation at baseline, and there was no significant change in suicidal ideation at endpoint.

As postulated, f luvoxamine and fluoxetine were equally efficacious for the management of outpatients with major depression. Although we did not find that fluoxetine caused statistically more agitation by rating scale, subjects did report more feelings of nervousness and had significantly more problems with nausea. This suggests that f luvoxamine may afford some benefit in terms of a slightly more favorable side effect profile.

References Lapierre. J et al Treatment of major affective disorder with fluvoxamine (1987). J Clin

Psychiatry, 48, 65~8 Cohn, J B, Wilcox, C. A comparison of fluoxetine, imipramine, and placebo patients with

major affective disorder (1985) J Clin Psychiatry. 45, 26-31.

Safety and tolerability of fluvoxamine in adolescent depression

M Alfonso 1, R. Ferrer 1 , R Such 2. 1 Department of PsychJatm/ Hospita/ de San Rafael, Vail d'Hebrdn, 107, 08035 Barcelona, Spain," 2 Medical Department, So/vay Duphar, Diagonal, 507, 08029 Barcelona, Spain

The study was planned as a double blind pilot study to evaluate the safety and tolerability of two different doses of f luvoxamine (50 mg and 100 rag) during eight weeks of treatment (1 week wash-out period, 7 weeks active treatmentl. Patients of both sexes, with ages between 12 and 18 years diagnosed of major depression, dysthymia, or adaptive disorder with depressed mood according to DSM-III-R were included in the study. Patients in treatment with MAOIs or other SSRIs during the previous two weeks, or lithium during the previous week, and those with systemic disease of clinical relevance were excluded. The patients selected for the study fol lowed a single blind phase of 3 weeks, receiving placebo in the first week (wash- out period), f luvoxamine 25 mg in the second week and f luvoxamine 50 mg m the third week. After this period the patients were allocated in the 50 mg or 100 mg group, receiving this doses for the next 5 weeks. The

P-2 Antidepressants." basic and clinical studies

t r e a t m e n t w a s a d m i n i s t e r e d a s a d a i l y s m g l e d o s e a t m g h t Clinlcalcontrols were performed on inclusion, day 7. 14. 21. 35 and 56. All patients were rated on Clinical Global Impression Scale (CGI} in every control and on Children's Depression inventory (CDI) on inclusion and days 35 and 56 Routine blood tests, urine tests and hormonal tests (growth hormone and prolactin in all patients, testosterone in male patients and estrogen and follicle stimulant hormone ~n female patients) were performed in days 7, 35 and 56. in all the controls, all new signs and symptoms were carefully assessed. The protocol was approved by the local ethics committee and the Spanish Health Authorities, and all patients gave their informed consent to participate in the study.

Twenty patients (10 male, 10 female) were included in the study. The distribution of age. sex and diagnosis were the same ~n both groups The evolution of the ratings on CGI and CDI are shown on the table.

Day

0 7 14 21 35 56

CGI Fluvoxamine 50 mg 41 4 1 Fluvoxamlne 100 mg 4 3 4 4

CDI Fiuvoxamine 50 mg 14 9 Fluvoxamine 100 mg 173

40 33 26 20 43 35 27 24

90 73 130 121

The side effects (2 patients in the 50 mg group, 4 patients in the 100 mg group) were mild and disappeared without any additional t reatment There were no significant changes in the hormonal determinations during the treatment.

Fluvoxamine appears to be a safe and effectwe treatment in adolescent depressed patients

Antidepressant actions on peripheral visual detection mechanisms in humans

Aviv Weinstein, Sue Wilson, Jayne Bailey, David Nutt. Psychopharmaeology Unit, University of Bristol, School of Medicat Sciences, University Walk, Bristol BS8 1 TD, UK, Tel: ~Z K 0177-9253066 Fax U. K 011~9277057

The safety of sedative antidepressants ~s a topical issue in the treatment of depression with driving ~mqairment being of particular concern. We have recently completed a study with normal male volunteers comparing the actions of dothiepin (a traditional, sedating antidepressant) with those of f luvoxamine (one of the selective serotonm reuptake inhibiting SSRI class of newer antidepressants) on psychomotor functions relevant to driving We set out to investigate whether these drugs ~mpair visual selective at- tention (focused and divided) by employing the 'odd-balr task. Subjects were required to respond to letters of the alphabet (T for target and other letters for non-targets) that were presented at the centre and/or periphery of the computer screen Results show that dothiepin delayed responses to single peripheral targets compared w~th f luvoxamine and placebo (table l i but it did not affect response t imes to central targets or response rate. Fur thermore, both drugs delayed responses to central targets compared with placebo on the divided attention trials (table 2). Finally, response accuracy in detecting peripheral targets was greater under placebo compared with f luvoxamine and dothiepin (table 3)

Table 1 : Averaged reaction time {seconds) in all subjects in {doused attention

Centre Penphery

T non T T non-T

Fluvoxamine 0 707 0744 0 686 0 910 Dothiepln 0 787 0 603 1 001" O 984 Placebo O 687 0587 0 715 O 690 W = 2 1 ; p - 0 0 3 6

Table 2: Averaged reaction time {seconds) m all sublects in dwlded attenbon

Centre Per,phery T T

Fluvoxamine 1 063' 0 987 Dothiepin 1 071" 1 139 Placebo 0729 0866

W - 21 ; p = 0036

305

Table 3: Averaged percentage (%) of correct responses an all subjects in divided atten- tion

Centre Periphery T T

Fluvoxamine 86 87 Dothepm 93 91 P!acebo 92 96 F(2 60)=1311 ;p=0 .00

The impairment produced by dothiepin is presumably a consequence of the central blockade of cholinergic muscannic or histaminergic H1 recep- tors It couid contribute to the reported association between the tricyclic class of antidepressants and road traffic accidents, and would be worth ;urther investigation in depressed patients taking both classes of drug.

~-2-91 [ A multicentre study of nefazodone and sertraline ;

in depressed outpatients

T Burns 1, N Kosky 1, K. Balasubramaniam 2. j . D'Souza 3. G. Andrews 4. C Freeman 5 ,s Buckingham 6 , E. Hawkings 6, K, Mellors 6 ,A .Aseher 6, ! St George's Hospital, London," 2 Bedford Genera/Hospital, Bedford," 3 V/ctona Hospital, B/ackpool," 4 The Ridgewood Centre, Frim/ey," 5 Royal Edinburgh Hospital, Edinburgh," 6 BnstoAMyers Squibb Company, 141-14,9 Staines Road, Houns/ow, Middlesex, TW3 3JA, UK

Nefazodone is an antidepressant drug with a dual mechanism on the sero- tonerg~c system, giving it a ~3harmacologic profile distinct from that of most other antidepressants including the serotonin reuptake inhibitors (SSRI) e.g. sertraline, fluoxetine and paroxetine (Eison et al., 1990). The objective of tins trial was, therefore, to compare the safety and efficacy of nefazodone aqd the seroton~n selective re-uptake inhibitor, sertraline, in the treatment of outpatients with moderate to severe non-psychotic depression.

[he study was a multicentre, randomized, double*blind, parallel group comparison of the two compounds in outpatients who met DSM-IIIR criteria for non-psychotic major depressive episode or bipolar disorder (depressed). Following a one to four week baseline phase (designed to ensure that there was an adequate drug-free interval), patients were randomized to receive either nefazodone (200 mg) or sertraline (50 mg). Total daily dosage could be titrated to a maximum of 600 mg nefazodone or 200 mg sertraline. The double-blind treatment period was eight weeks.

Efficacy evaluations included investigator ratings (the 17 item Hamilton qating Scale for Depression (HAM-D-17), the Clinical Global Impression Scale (CGI), the Hamilton Rating Scale for Anxiety (HAM-A) and the Mont- gcme'yAsberg Depression Rating Scales (MADRS)}, and patient self-ratings (:he Patient Global Assessment Scale (PGA)).

A, total of 2 !0 patents were enrolled at 19 centres in this study. 104 patqents recewed sertraline and 106 received nefazodone. The mean modal da~ly doses of study medication at week 8 were 427 mg in the nefazodone group and 115 mg in the sertraline group Intent-to-treat analysis of the Last Observation Carried Forward (LOCF) data set for the HAMD-17 total score showea that treatment with nefazodone and sertraline resulted in consistent improvement over the eight weeks of therapy. The change from baseline scores were not statistically different between the two treatment groups at any week of the study.

The HAM-D Sleep Disturbance Factor is defined as the sum of items 4 (initial insomnia), 5 (middle insomnia), and 6 (delayed insomnia) of the ~AM-Dscale The LOCF analysis showed a reduction in the HAM-D Sleep Disturbance Factor in both groups, however there were significant differ- encestP _< 0 01 ) between the two treatment groups in favour of nefazodone at weeks 1. 2 and 3,

Analysis of the CGI. PGA, MADRS and HAM-A total scores, showed con- tlnuous ~mprovement over the eight study weeks, however the differences were not statistically signif icant

One hundred and sixty-seven of the 210 patients reported an adverse event during the study; 87 (82%) nefazodone treated patients and 80 (77%) sertraline treated patients. The most frequently occurring adverse events {reported ~n >10%) in the nefazodone group were asthenia, headache, nausea, dry mouth, dizziness and somnolence, and in the sertraline group were asthenia, headache, nausea, diarrhea and somnolence.

The results provide evidence that nefazodone and sertraline both have antidepressant activity. There was improvement for both treatments with no statmtically significant differences noted at week 8 on any of the efficacy outcome measures Both study drugs were found to be safe and well tolerated by the patients.