the potential side effects when choosing which antide- pressant to ... ment in people who were HIV-negative. We were ... giore, Milan, and from HIV-negative patients attending ..... RabkinJG, Wagner G, Rabkin R. Effects of sertraline on mood.
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
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Vol. 23l n° S, 19908
Vol. 23,
n0
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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.
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