HIIV-infected - Europe PMC

Research

Paper

Article de recherche

Treatm-ent

epression

of

Pedrazzoli, MD; Marco Cusini,

Laura

Professor Emeritus,

Neurology

Psychiatry, University

and

Schizophrenia, Milan, Italy; Bessone, Bertrando,

Pedrazzoli

Centre, Ospedale Maggiore, Milan, Italy; Cusini

Background: Pharmacological

treatment

efficacy

study

assessed the

drug

the

least 16 and who received

at

depression

feasibility

mg/d

Contexte:: On est

la fluox6tine

et

On

improvement

du sexe,

tard.

pression

prevalence

qui

qui

ont

6t soulag6e

a

plus vient

a

16

patients

ont

requ

obtenu

resultat

20

the many

to

Correspondence

to:

in the

mg/j

Scale for were

Depression

scores

studied. Results:

of

at

Depression

seropositive patients occurred later. Inter-

treatment

treating depression

people

in

with HIV

particularly suitable, especially

because

etude,

de la d6pression chez les patients infect6s 6value 1'efficacit6 et faisabilit6 d'un traitement m6dicament patients infect6s par le VIH. Me-

et

16

d'au

on

Ia

aux

autres

momns

s6ron6gatifs, jumel6s 6galement 16

A 1'6chelle d'6valuation

de fluox&ine pendant huit semaines.

de

en

fonction de

la d6pression

Resultats

de

d6pres-

La

:

comme

Ia

ce

parce que les personnes

disorders among because of

psychiatric

psychosocial

or

has been ascertained.

be ef-

to

I'am6lioration chez les patients s6ropositifs s'est produite traitement de d&r6sultat confirme 1'efficacit6 de la fluox6tine infect6es par le VIH. Comme il n'a pas d'effet ind6sirable, traitement

illness be-

fore the infection, involvement of the central

fection

patients has been found

Le

:

surtout

neuropsychiatric

system

on

Screening

chez les deux groupes, mais

chez les personnes

underlying predisposition

AIDS

pharmacologique

cette

d'administrer le

un

HIV-infected patients is relatively high', an

Schizophrenia,

to treatment.

s6ropositifs

moms

au

Interpretation

particuli6rement,

of

faqon

meilleure

6tudi6

:

sion

respond

que le traitement

constat

Ia

I'age

et

to

efficace. Dans le cadre de

thodes

Hamilton

The

a

on

with fluoxetine and the best method of

Rating

The results confirm the effectiveness of fluoxetine in

seronegative people take longer

et

in HIV-infected treatment

of fluoxetine for 8 weeks

infection. The lack of adverse effects makes this

par le VIH

of

age and sex, who had Hamilton

least 20

alleviated in both groups. However,

pretation:

of Milan and President, Association for Research

Association for Research

patients with HIV infection. Methods: Sixteen seropositive and 16 seronegative

to

patients, equally matched for

was

of

and

MD

Screening Centre, Ospedale Maggiore, Milan, Italy

AIDS

fective. This

administering

atilents

Cazzullo, MD; Enrico Bessone, MD; Paolo Bertrando, MD;

Carlo L.

Cazzullo

HIIV-infected

in

nervous

factors after HIV in-

Treatment

Prof. Carlo L. Cazzullo,

of

psychiatric

Association for Research

se'ronegatives

con-

prennent plus de temps ~ y

disorders is therefore

important

r6agir.

to

improve

ity of life of HIV-positive patients3 and the

chotropic drugs in clinical

drugs

on

to do this is

practice.4','

Our

the

use

qual-

of psy-

increasingly widespread

study

looked at the effects of

mood disorders, which

occur

at all

stages of

HIV infection.',' on

Schizophrenia,

Via

Tamagno 5,

20124 Milan.

Italy;

fax 0039 2

29402922

Medical

subject headings: antidepressive agents; depression; fluoxetine;

J Psychiatry

Neurosci

HIV infections

1998;23(5):293-7

Submitted Dec. 12, 1997

Revised

May 25,

Accepted June 2,

1998

1998

1998 Canadian Medical Association

Vol. 1998 23, no V6LX 23, no 5,5~1998

Neuroscience of Psychiatry & Journal 6f j6iiiiiiii Psyi.mkq & Neuroscience

29

:t a:::t::: :::::::::: i0:0 ::: ::::.-: :::::::: :: Cazull e1::::L

positive patients met these criteria, therefore 16 seronegative people of the same age, sex and psychiatric diagnosis were recruited for the control group. We excluded patients who had a HAM-D score of more than 16 but whose level of anxiety (a score higher than 15 on the Hamilton Rating Scale for Anxiety [HAM-A]) meant that nonoccasional treatment with a benzodiazepine was required. Patients with other psychiatric disorders, such as psychotic disorders, bipolar disturbances in the manic phase, substance abuse, personality disorders, acute reaction to stress, adjustment disorders, dysthymic disorders, as well as renal, cardiac, hepatic and organic mental disorders, were excluded from the study. All patients, both seropositive and seronegative, completed the study. The subjects were all men; in the HIV-positive group they were between 28 and 52 years of age, and in the in HIV-negative group they were between 27 and 50 years of age. Mean age values were, respectively, 37.50 (± 7.58) and 38.87 (± 7.07) (Student's t-test -0.529; degrees of freedom 30; p = 0.601, NS). The time between diagnosis of HIV infection and enrollment in the study ranged from 12 to 92 months, with an average of 48.37 (± 23.63) months. Subjects underwent further tests: the HAM-D, the HAM-A, the Brief Psychiatric Rating Scale (BPRS) and the Mini-Mental State Examination. Approximately 25% of the subjects (7 who were HIV-positive and 6 who were HIV-negative) had a history of substance abuse. CD4 count and viral load were not measured during the 12 weeks of the study because we enrolled asymptomatic people who were tested every 6 months. None of the people in our study were undergoing any concomitant psychotherapy. All subjects gave their informed consent. Tables 1 and 2 provide detailed characteristics of the 2 groups. For all subjects, the starting dose of fluoxetine was 20 mg/d for 8 weeks; in the event of no response or a partial response, the dose could be increased to 40 mg/d after 4 weeks. At the end of week 4, week 8 and week 12, they underwent further tests: the HAM-D, the Zung Scale for Depression, the Zung Scale for Anxiety and an interview with a psychiatrist.

A previous study3 has been published on the effects of antidepressants on depressive symptoms and syndromes during HIV infection. Doctors have to consider the potential side effects when choosing which antidepressant to use,"' given the debilitated state of the patient, the comorbidity of other illnesses and the concomitant use of other pharmacological treatments with which the antidepressant might react.4 The sensitivity of HIV-positive patients to psychotropic side effects had been theorized and overstated early in the course of the HIV epidemic. The evidence of the increased sensitivity of people who are seropositive, especially during the symptomatic phase, to the anticholinergic effects of tricyclic antidepressants led to studies of the efficacy of selective serotonin reuptake inhibitors (SSRIs).'213 Fluoxetine was found to be effective at considerably low doses and was tolerated well by people who were HIVpositive and people with AIDS because side effects were minimal and infrequent. Overdose was also less dangerous than with earlier antidepressants."'4 In both studies'0'14 treatment dose of fluoxetine was 20 mg/d. Our main objectives in this study were to verify the practicality and efficacy of treatment with fluoxetine for major depression in people who were HIVpositive, and to compare the effects of the same treatment in people who were HIV-negative. We were also interested in assessing the specificity of response of HIV-positive people to fluoxetine in terms of the speed of response and the occurrence of side effects.

Material and methods This study involved HIV-positive patients recruited from HIV-infected people attending the AIDS Screening Centre at the Dermatologic Clinic, Ospedale Maggiore, Milan, and from HIV-negative patients attending the Centre for Diagnosis and Treatment of Sexually Transmitted Diseases at the same hospital, who were treated with fluoxetine. All patients complied with the treatment for the 3 months of the study. To assess the severity of depressive symptoms, we used the clinician-rated, 23-item, Italian version of the Hamilton Rating Scale for Depression (HAM-D).15 On this scale, mild depression is defined by scores ranging from 8 to 15 and major depression by scores over 16. For HIV-positive patients, the eligibility criteria were being asymptomatic for HIV, being male, meeting the DSM-III-R criteria for major depression and having a HAM-D score of more than 16. Sixteen HIV294 w2:

Results The results we obtained should be considered preliminary because of the small size of our sample. Table 3 lists the HAM-D scores for the 2 groups before, dur-

neuroscience de neurosdence et de de psychiatrie it. Revue evue &.Wyp4.atne

..it

t 0

0

0

Vol. 23 nO ~1998

in paent HIV-intd Treating depression ~~~~~~~~~~ :. nS -, S on. ts- :S

X~~ ~~~~~~~~~~~~~~~~

ing and after treatment. The average HAM-D score for HIV-positive patients fell from 26.1 (range from 20 to 35) at baseline to 6.4 (range from 3 to 19) after 8 weeks of fluoxetine treatment. In the control group, the initial mean HAM-D score was 26.5 (range from 22 to 31). The score fell to 6.5 (range from 3 to 18) after 8 weeks of treatment. The difference between the 2 groups was nonsignificant. After 4 weeks of treatment, 25% of the HIV-positive patients (n = 4) and 12% of the HIV-negative controls (n = 2) showed partial or no remission of symptoms (HAM-D score 16); these patients received a higher dose of fluoxetine during the last 4 weeks of the study (40mg/d). At week 8, 2 of the HIV-positive patients and 1 HIV-negative patient showed a benefit from the increase of dosage (HAM-D score < 7); the other 2 HIV-positive patients (12% of the total) and 1 HIV-negative patient had HAM-D scores of > 16 (mean 18.5). A statistical analysis of HAM-D intra- and intergroup values was performed. No significant statistical differences emerged with either the Student's t-test or analysis of variance when pre- and post-treatment values were compared (Student's t-test -0.334, degrees of freedom 30, p = 0.740 v. Student's t-test -0.075, degrees of freedom 30, p = 0.941). After 2 weeks of treatment, a Student's t-test was conducted to compare the 2 groups. The results indicated that symptoms regressed more slowly in those who were HIV-positive than in those who were HIV-negative (t = 2.618, p = 0.014).

.Tabl Age 34 28 31 41 40 32 42 45 38 28 29 43 48 52 29 40

Cha

..ris

Sexual orientation homosexual heterosexual homosexual homosexual homosexual heterosexual homosexual homosexual homosexual heterosexual heterosexual bisexual homosexual homosexual heterosexual heterosexual

cs

of.th .16.H Probable mode of infection sexual needle sexual sexual sexual needle sexual sexual sexual sexual needle sexual needle sexual needle sexual

Three patients (19.6%) experienced undesired side effects (feelings of discomfort in the epigastric region of the abdomen, slight tension and irritability and temporary insomnia), but they were so slight that treatment was not suspended. The hematological and hematochemical parameters before and after treatment (hematochrome, AST, ALT, y GT, creatinine and azotemia) showed no significant changes. Five patients had a high value of y GT at t,, but treatment did not affect this result.

Discussion This study indicated that the treatment of depression with fluoxetine in HIV-positive people is effective and practical. Symptoms were significantly reduced and the effect of fluoxetine was comparable to that in severely depressed seronegative subjects. The absence of specific side effects indicates that this treatment could be prescribed at day clinics without unduly increasing case-management resources. The size of our sample and our method of recruitment limit the impact of the data. Studies with larger sample sizes and, consequently, higher statistical power will need to be conducted to confirm our results. The results also show that, in a small number of cases, the effect of fluoxetine in reducing depressive symptoms was slower in HIV-positive patients. After 2 weeks of treatment, we found a significant statistical

...pat.ents* At-risk behaviour* multiple

sex

partners

former drug addict multiple sex partners multiple sex partners multiple sex partners former drug addict multiple sex partners multiple sex partners, former drug addict multiple sex partners multiple sex partners, former drug addict former drug addict multiple sex partners former drug addict multiple sex partners former drug addict multiple sex partners

Time between diagnosis and study, m 37 30 12 49 92 19 41 62 19 39 61 78 82 68 41 44

Type of depressive episode single episode single episode recurrent recurrent recurrent recurrent

recurrent recurrent

recurrent

single episode single episode recurrent recurrent recurrent

single episode

*People who were infected by needles had not abused drugs for at least 2 years prior to treatment.

Wxe,:: Vol. 23, no :tr5, I1998i 0 66 V6L, ,X .2;n3-J.

Neuroscience Journalwilw. of & weu of Psychiatry & scieme, ..

.*

295

_M

at Czzule :::

difference between the HIV-negative and HIV-positive people. This suggests that the treatment period should be longer for people suffering from depression who are HIV-positive than for those who are HIV-negative. Since none of the HIV-positive people were being treated with anti-HIV medication, we know that the slower response to fluoxetine in the HIV-positive

group was not because of any interaction between fluoxetine and another drug that lowered fluoxetine bioavailability and serum levels. Slower response to fluoxetine cannot be ascribed to a poorer compliance either since no significant compliance differences emerged between the groups. Studies on this difference should be undertaken, be-

Table 2: Characterisitcs of the 16 HIV-negative patients

Age 31 40 42 44 27 39 44 50 50 37 38 29 42 41 40 28

Sexual orientation heterosexual homosexual homosexual homosexual heterosexual heterosexual heterosexual homosexual heterosexual heterosexual heterosexual homosexual heterosexual heterosexual homosexual heterosexual

Type of depressive episode recurrent recurrent recurrent recurrent single episode recurrent single episode recurrent recurrent recurrent recurrent single episode recurrent recurrent recurrent single episode

At-risk behaviour* former drug addict multiple sex partners former drug addict multiple sex partners, former drug addict multiple sex partners none none

multiple sex partners former drug addict multiple sex partners former drug addict multiple sex partners none

former drug addict multiple sex partners none

*Multiple sex partners includes the absence or minimal use of protection during intercourse.

Table 3: HAM-D scores at base:ine, during and .after treatment of the 16 HIV-pos.itive and 16 HIV-negative study partic.i.pants Week 4

Baseline

Mean SD

HIV+

HIV-

HIV+

HIV-

HIV+

28 24 27 30 22 23 29 29 20 35 24 27 24 31 23 21 26.06 4.11

27 24 22 22 29 30 28 22 24 31 26 30 28 27 31 23 26.50 3.29

10

8 12 6 7 4

4 6 4 18 5 3 6 5 4 6 19 6 4 3 4 5 6.38 4.84

12 8 27* 7

13* 19*

12 24* 10 16 25* 23* 10 6 8 13 13.87 6.96

6 8 8 4 l 6 9 10 8 8.69 3.77

Week 12

Week 8 HIV-

HIV+

HIV-

5

4 5 3 20 4 3 5 8 4 5 14 5 4 4 3 4 5.94 4.61

4 14 4 5 3 4 20 5 5 3

I

4 6 4 7 18 5 4 6 4 7 4 6 7 6 6.50 3.56

6 4 4 6 5 6.06 4.49

*People who required a higher dose of fluoxetine by the fourth week of treatment.

296

neuroscience Revue de di Ineuroselence ne"i. di psychiatrie psy6tatne etit de 0

e

0

Vol. 23l n° S, 19908

Vol. 23,

n0

5,

1998

Tratkf iLin.s

cause clinical implications concerning compliance to antidepressant treatment have not been extensivley covered. It seems necessary, especially-in cases where initial response to the drug is minimal, to increase the dosage and to provide the patient with psychological support. Compliance may improve if motivation is provided. In conclusion, treatment of major depression in HIV-positive patients with fluoxetine is feasible. Results also indicate that such treatment is as effective as it is in HIV-negative patients. The high degree of tolerance and the absence of side effects, which are important in both clinical and hematological terms, make fluoxetine a first-line treatment for HIV-positive patients with major depression.

Acknowledgement Translation of this manuscript was supported by Eli-Lilly s.p.a., Via Gramsci 733, Sesto Fiorentino, Florence, Italy.

References 1. Maj M, Satz P, Janssen R, Zaudig M, Starace F, Delia L, et al.

WHO neuropsychiatric AIDS study, cross-sectional phase I. Study design and psychiatric findings. Arch Gen Psychiatry 1994;51:39-49. 2. Maj M, Janssen R, Starace F, Zaudig M, Satz P, Sughonhabirom B, et al. WHO neuropsychiatric AIDS study, crosssectional phase II. Neuropsychological and neurological findings. Arch Gen Psychiatry 1994;51:51-61.

3. Cazzullo CL, Bessone E, Cusini M. Depressione in soggetti HIV positivi: sintomi e trattamento. Istituto Lombardo Accademia di Scienze e Lettere (Rend Sc) B 1994;128:57-62. 4. Ayuso JL. Use of psychotropic drugs in patients with HIV in-

fection. Drugs 1994;47(4):599-610.

Vot23,no$. I.%

5. Vitiello B, Stover ES. Psychopharmacology in HIV-positive patients: research perspectives. Psychopharmacol Bull 1996;32(3): 293-7. 6. Lyketsos CG, Hoover DR, Guccione M, Drew MA, Wesch J, Bing EC, et al. Depressive symptoms over the course of HIV infection before AIDS. Soc Psychiatry Psychiatr Epidemiol 1996;31:212-9. 7. Maj M. Depressive syndromes and symptoms in subjects with human immunodeficiency virus (HIV) infection. Br J Psychiatry 1996:168(30):117-22.

8. Fernandez F, Levy J. Psychopharmacology in HIV spectrum disorders. Psychiatr Clin North Am 1994;17(1):135-48. 9. Rabkin JG, Rabkin R, Harrison W, Wagner G. Effect of imipramine on mood and enumerative measures of immune status in depressed patients with HIV illness. Am J Psychiatry 1994;151:516-23 10. Rabkin JG, Rabkin R, Wagner G. Effects of fluoxetine on mood and immune status in depressed patients with HIV illness. J

Clin Psychiatry 1994;55:92-97. 11. Rabkin JG, Wagner G, Rabkin R. Effects of sertraline on mood and immune status in patients with major depression and HIV illness: an open trial. J Clin Psychiatry 1994;55:433-9.

12. Fernandez F, Levy J. Psychopharmacotherapy of psychiatric syndromes in asymptomatic and symptomatic HIV infection. Psychiatr Med 1991;9:377-93.

13. Storch DD. Caution with use of tricyclics in patients with AIDS. Am J Psychiatry 1991:147:495-7. 14. Judd FK, Mijch AM, Cockram A. Fluoxetine treatment of depressed patients with HIV infection. Aust N Z J Psychiatry

1995;29:433-6. 15. Bech P, Kastrup M, Rafaelsen SJ. Minicompendio delle scale di valutazione di stati di ansia, depressione, mania, schizofrenia con le corripsondenti sindromi del DSM III. Acta Psychiatr Scand 1986;73(Suppl 326):1-39.

297