Feasibility of pharmacotherapy in HIV-related affective spectrum disorders: an open trial with fluvoxamine

Eur Psychiatry 1996; 11:40-45 Q Elsevier, Paris

40

Original article

Feasibility of pharmacotherapy in HIV-related affective spectrum disorders: an open trial with fluvoxamine P Perrettal,

3Professor

C Nisital, E Zaccagnini I, C Lorenzetti l, A Nuccorini2, GB Cassano l*, DM McNair3, HS Akiska14

I Psychiatric Clinic I, University of Pisa Via Roma 56, 56100 Pisa, Italy; 2Cenrer for AIDS Surveillance of Pisa, Spedali Riuniti S Chiara, Pisa. Italy; Emerirus, Boston University, Boston. MA; ‘University of California at San Diego, San Diego, (Received

22 March

1995; accepted

CA, USA

26 June 1995)

Summary - Among HIV patients treated for AIDS-related adjustment, major depressive disorders and other affective disorders, we assessed in an open study the feasibility of using a serotonergic antidepressant (fluvoxamine). Thirty-five seropositive patients with the above conditions (22 men and 13 women) were followed over a minimum period of four weeks. At the end of the treatment, a large number of patients (77%) showed marked improvement. “Nuclear” depressive and anxiety symptoms remitted, while the “somatic” ones seemed less sensitive to treatment. Treatment had to be terminated prematurely due to side effects in only two patients (6%) . fluvoxamine

I treatment

I HIV

patients

/ affective

spectrum

disorders

INTRODUCTION Depressive disorders are widely associated with human immunodeficiency virus (HIV) infection and represent one of the common reasons for psychiatric consultation during the illness progression (Colon, 1988; Goodkin, 1988; Seth et al, 1991; Wolkott et al, 1986; Maj, 1990a; Derix et al, 1990). However, different methodological approaches in psychiatric data collection do not actually permit correct estimates of the real incidence of psychiatric disorders during the course of HIV infection (Faulstich, 1987). The neurotropism of HIV itself (with prevalent limbic involvement) (Levy et al, 1985; Gazbuda et al, 1986) can explain the high rate of psychiatric disorders, particularly depressive, and chronic psychological distress due to the psychosocial implications of the illness, representing a significant risk factor for the development of anxious or

l

Correspondence

and reprints.

/ organic

mood

disorder

depressive reactions (Maj, 1990b; Abrams et al, 1986; Wolkott, 1986). Moreover, it is well known that some treatments (Interferon, anticancer drugs) can cause severe depression that is indistinguishable from the syndrome of major depression (McDonald et al, 1987; Buhrich and Cooper, 1987). Despite the occurrence of depressive symptomatology, efficacy of antidepressants in HIV seropositive-patients has rarely been considered. However, anxiolytics or hypnotics are currently widely prescribed as psychoactive drugs in the care of AIDS patients (Ochitill et al, 1991). Efficacy and side effects of imipramine in the treatment of major depression in HIV patients has been reported in a sample of eleven patients (Rabkin and Harrison, 199 1); central and peripheral anticholinergic effects facilitating sedation, confusion, cognitive disturbances, urinary retention, and xerostomia suggest caution in the prescription of tricyclics

Feasibility of pbarmacotherapy in HIV-related affective spectrum disorders

(Curran et al, 1988; Starch et al, 1991, Femandez et al, 1989). Recently depression in some HIV patients was also found responsive to treatment with a specific antiviral agent, zidovudine (Rosenstein et al, 1991). However, in our experience, this drug is more effective in those with cognitive impairment; it may actually induce depression-like states in some patients. Psychostimulant medication, as the treatment of choice of depressive syndromes with organic features or mild cognitive impairment, was sometimes associated with excitement and/or agitation (Femandez et al, 1988). Among the serotonin-uptake inhibitors (SSRI), fluoxetine has been shown to be tolerated by AIDS patients (Levine et al, 1990). Fluvoxamine is a SSRI, utilized in several countries for the treatment of depression and obsessive compulsive disorder. Some authors advocate its effectiveness in treating elderly patients, because of its shorter half-life when compared to fluoxetine, and its side effect profile which includes minimal cognitive impairment (Lapierre and Browne, 1987). We evaluated, in an open study, the effectiveness of fluvoxamine as an antidepressant medication for the treatment of AIDS-related affective spectrum disorders: mood disorders, adjustment disorders and organic mood disorders according to DSM-III-R criteria (APA, 1987). SUBJECTS AND METHODS Subjects Among patientsat different stagesof HIV infection presenting depressive symptoms at the Pisa Center for AIDS

Surveillance,

35 (18 outpatients

and 17 inpa-

tients) were treated with fluvoxamine. Evidence of depressive

symptoms

(guilt

feelings,

depressed

mood,

Table I. Immunological voxamine treatment

41

and act features

before

Negative

%

I

(27)

pz microglobuline < 4mcg/ml > 4mcg/ml CD4 count 2 5OO/mmc < .500~200/mmc c 200 mmc Stage I Stage II Stage III CAT findings Positive Negative

19

flu-

Ajk?r

Before n HIV-l Ag Positive

and after

n

8

5

(73)

21

g::;

20 6

g;;

19 7

(73) (27)

5 5 16 1 15 10

(19.2) (19.2) (61.5) (3.8) (57.7) (38.5)

1: 14

(42.3) (53.9)

2 24

(7.7) (92.3)

1;

$:T;

(15.4) 1: 12

g;

(3.8)

Italian National Statistics on AIDS (GIAIDS, 1993), intravenous drug users (IVDU) were the largest category. There were 18 IVDU patients (51%); 7 homosexuals (20%); 1 IVDU and bisexual (3%); 4 promiscuous heterosexuals (1 l%), and 4 partners of HIV seropositives (11%). By the US Center for Disease Control criteria (1986), one patient (3.8%) was at stageI, 15 patients (57.7%) were at stage II, and 10 (38.5%) were at stage III (table I). DSM-III-R Axis I diagnoses prior to treatment were the following: adjustment disorder, n = 15 (43%), about equally divided into depressive, anxious and mixed subtypes; major depressive episode, n = 18 (51%), seven of which had past hypomanic features and would qualify for bipolar not otherwise specified; and organic mood disorder, n = 2 (6%). Nearly half the patients (48.5%) had a lifetime history of at least one psychiatric disorder other than drug

difficulty in concentration, insomnia, etc) represented

addiction antedating many years their seropositive

the basic criteria for psychiatric evaluation and treatment. Among somatic symptoms (loss of weight, gastrointestinal and genitourinary symptoms, headache, muscular and sensory anxiety symptoms, etc) only those not justified by HIV illness were considered as psychopathological features. Patients affected by CAT

status, for which they had received treatment. Mean age at first treatment was 26.5 f 8.3 years. That these patients suffered from legitimate psychiatric disorders was further testified by the fact that 68.7% had positive family history for psychiatric disorders, principally for mood and alcohol use disorders. A detailed report on the psychopathology of these patients is in preparation and

detectablebrain damagewere also treated if seriously depressed (2 patients presenting suicide feelings and a lifetime history of suicide attempts had mild cerebral

will bepublishedindependently.

atrophy).

Treatment protocol

The patient sample consisted of 22 men and 13 women. The mean age was 34 years (range, 20-68 years ). On the basis of at-risk behavior, in conformity with

Three groups of patients were defined on the basis of clinical, and immunological features :

42

P Perretta et al

Group Z Asymptomatic HIV seropositive patients or those with soft signs and non-specific physical symptoms, according to the classification of the Centers for Disease Con-

Major blood parameters (CD4 count, HIV-l antigen, and P,-microglobulin) and a neurological workup, including CT scan, were fixed before and after psychotropic treatment.

trol (Atlanta) (CDC, 1986);

Group ZZ Asymptomatic HIV seropositive subjects that satisfied the following criteria: a) CD4 T-lymphocyte count < 500; b) abnormal serum level of &-microglobulin (> 4 rig/L); c) HIV-Ag positivity; no anti-~24. Symptomatic HIV seropositive that satisfied the criteria for the diagnosis of ARC. Specifically, each patient had one or more of the following clinical symptoms for at least three months: a) fever with a temperature of more than 38°C; b) weight loss of more 10% of body weight or 7 kg; c) persistent lymphadenopathy involving two or more extrainguinal chains with at least one lymph node equal to or greater than 10 mm in diameter in each chain; d) diarrhea; e) fatigue interfering significantly with work; and f) night sweats. Laboratory abnormalities included a depressed absolute T lymphocyte cell number of less than 0.5 x 109/L; at least one of the following cytopenias: leukopenia; thrombocytopenia; anemia with hematocrit < 0.40; or absolute lymphopenia with a total lymphocyte count cO.OO1xlOa/L; or no response to skin testing with six antigens (purified protein derivative, candida, coccidioidin, mumps, tetanus and trichophyton).

Group ZZZ Patients satisfying criteria for the diagnosis of AIDS. All patients were treated with fluvoxamine over a minimum period of four weeks (mean 5.9 f 2) on a flexible tid dose schedule, beginning with 50 mg/d and increasing to 200 mg/d by 50 mg increments every three days (mean 124 + 50 mg/d). Clinical judgment was the basic guideline to adjust dosage day by day. Other psychotropic drugs were associated if needed: diazepam for benzodiazepine dependent patients and valproic acid (200-800 mg/d, mean 436.3 & 172.3) to prevent seizures or for treating major depressives with hypomanic features.

The global treatment responsewas assessed by the Clinical Global Impression Scale (CGI): responders were defined as patients rated 1 or 2 (very much or much improved), and non-responders were those rated 3 or 4 (minimally improved or no change). The psychopathological status was evaluated by the Hamilton Rating Scale for Depression (HAM-D), the Hamilton Rating Scale for Anxiety (HAM-A) and the Brief Psychiatric Rating Scale (BPRS). Cognitive impairment was assessed by the Mini Mental Status Examination (MMSE).

Statistical procedure Statistical analyses were performed using Student’s r-test for paired data, with the significance level set at

P = .05. RESULTS Twenty-six patients completed the trial. Seven patients were lost at follow-up, four of which were IVUDs. Pluvoxamine was prematurely terminated in two cases: one patient showed prominent signs and symptoms of multifocal leucoencephalopathy, another patient suffered from gastric pain and tremor of hands, which resolved after discontinuation of the treatment. Although two additional patients developed de novo organic features, this did not preclude an antidepressant response to fluvoxamine which was, therefore, continued. The two patients who at baseline were diagnosed as suffering from organic mood disorder were also among the fluvoxamine responders and tolerated the antidepressant without significant side effects. On the basis of CGI scores of one or two (very much improved or much improved) at the fourth week, 20 (77%) patients were defined as responders; six (23%) showed a mild improvement and were defined as non-responders. Table II shows that after a period of at least four weeks (mean 5.9 f 2) of fluvoxamine treatment the BPRS mean total score decreasedfrom 34.2 + 5.9 to 25.1 + 5.2 (df= 25; t-value = -26,371; P = .OOl). The HRSD total score decreasedfrom 18.1 f 6.8 to 9.2 r 5.8 (df= 25; t-value = -12,629; P = .OOOl) (table III). The HRSA total score decreased from 17.3 f 6.1 to 10.8 f 6.2 (u’f= 25; t-value = -13,527; P = .OOOl) (table IV). Perusal of tables II, III and IV indicates that most depressive and anxiety symptoms improved significantly, with the exception of somatic complaints. The MMSE mean total scores showed no statistically significant differences (mean 29 + 2, range 7 vs 30 + 2; range 8; df = 25; P = .422). No statistically significant differences were found in the immunological parameters @,-microglobulin, CD4 and CD8 count) at the end of the trial (table I).

Feasibility Table

II. BPRS

ratings

before

of pharmacotherapy

and after fluvoxamine Before X (SD)

After X (SD)

in HIV-related

treatment.

III.

spectrum

I-IRS-D

ratings

P

Somatic concern Anxiety Emotional withdrawal Conceptual disorganization Guilt feelings Tension Manyerism Grandiosity Depressive mood Hostility Suspiciousness Hallucinatory behaviour Motor retardation Uncooperativeness Unusual thought content Blunted affect Excitement Disorientation

3.5 3.7 1.5 1.0 3.0 2.7 1.1 1.9 4.2 1.4 1.6 2.2 1.2 1.1 1.5 1.1 -

(1.2) (1.5) (1.0) (0.0) (1.3) (1.4) (0.6) (0.4) (1.4) (1.1) (1.2) (6) (1.5) (0.6) (0.6) (1.2) (0.4) (-)

2.7 (1.4) 3.0 (1.3) 1.1 (0.4) 1.0 (0.2) 1.9 (1.3) 1.6 (0.9) 1.0 (0.5) 0.9 (0.2) 2.6 (1.0) 1.9 (0.4) 1.2(0.7) - (-) 1.5 (0.8) 1 .o (0.2) l.O(O.0) 1.0 (0.0) 1.0 (0.2) - (6)

.05 .02 .03 .3 .009 .005 .6 .2 .OOOl .l .l

Factors Anxiety/depression Anergia Thought disturbance Activation Hostility/suspiciousness

3.6 1.6 1.0 1.6 1.4

(0.9) (0.7) (0.3) (0.6) (0.8)

2.5 1.1 1 .o 1.2 1.1

.OOOl ,008 .4 .02 .06

(0.5) (0.2) (0.5) (0.4) (0.2)

Table ment.

affective

.06 .2 .3 .03 .4 -

DISCUSSION In planning pharmacological treatment for depression in HIV seropositive-patients, it is crucial first to consider the potential side effects or adverse drug reactions in those patients with compromised cerebral and physical function. The occurrence of organic mental changes over time in HIV seropositive-patients suggest that psychiatric diagnosis is likely to shift from mood or adjustment disorders to organic mental disorders as part of natural progression of the disease (Perry, 1990; Egan et al, 1992; Darko et al, 1992). There is a great need for thorough longitudinal evaluations in the diagnosis and treatment planning of HIV-related psychiatric disorders. When we treat depression in HIV patients we must take into consideration that these patients could be developing CNS lesions not currently CAT-detectable (Seth et al, 1991) in the different stages of HIV infection (Wolcott, 1986). At baseline, two of our patients had an organic mood disorder. Three additional patients developed such features during the study. Only one of these had to be prematurely discontinued from fluvoxamine. The other four eorganici patients tolerated this antidepressant without side effects, indeed, they concluded the study with significant improvement.

43

disorders before

and after

Before X (SD)

fluvoxamine

After X W)

P St01 .0009 .008 ,003 .004 .0007 .4 .07 .03 .0002 .03 .07 .Ol .6 .3 .2 .04 .7 .2 .2 .4

Depressive mood Guilt feelings Suicide Early insomnia Central insomnia Late insomnia Work and activities Retardation Agitation Psychic anxiety Somatic anxiety Gastrointestinal symptoms General somatic sensory Genitourinary symptoms Hypocondriasis Loss of weight Insight Diurnal variation Depers. / derealization Paranoid symptoms Obsess/camp. Symptoms

2.4 1.4 0.6 1.2 1.1 0.6 1.5 0.7 0.8 1.4 1.3 0.6 1.1 0.8 1.1 1.4 0.1 0.8 0.3 0.3 0.3

(1.1) (1.0) (1 .O) (0.8) (0.8) (0.7) (1.1) (0.9) (0.3) (0.9) (1.0) (0.7) (0.7) (0.9) (1.0) (1.2) (0.3) (0.8) (0.6) (0.6) (0.7)

1.4 (0.8) 0.5 (0.8) 0.1 (0.3) 0.5 (0.7) 0.5 (0.7) 0.1 (0.3) 1.3 (1.3) 0.3 (0.5) 0.3 (0.7) 0.6 (0.5) 0.7 (0.8) 0.3 (0.7) 0.6 (0.7) 0.7 (0.8) 0.8 (1.1) l.O(l.2) 0 (0.0) 0.7 (0.9) 0.1 (0.4) 0.1 (0.4) 0.2 (0.4)

Factors Anxietylsomatization Weight Cognitive disturbances Diurnal variation Retardation Sleep disturbances

1.5 0.9 2.3 1.1 1.2 1.2

(1.4) (0.4) (1.7) (0.1) (1.1) (0.6)

2.6 1.3 3.0 1 .o 1.6 2.0

Table

IV. HRS-A

treat-

(2.0) (0.5) (1.9) (0.0) (1.1) (1.6)

ratings before and after fluvoxamine

.04 .l .2 .4 2 .004

treatment.

Before X (SD)

After X (SD)

Anxiety Tension Fear Insomnia Intellectual Depressed mood Somatic (muscolar) Somatic (sensory) Cardiovascular symptoms Respiratory symptoms Gastrointestinal symptoms Genitourinary symptoms Autonomic symptoms Behavior at interview

2.0 (0.9) 1.9 (0.8) 0.3 (0.7) 1.8 (1.0) 1.4 (0.8) 2.0 (0.9) 1.4 (1.3) l.O(l.0) 0.8 (1 .O) l.O(l.7) 1.1 (0.9) 0.8 (0.9) 0.9 (0.9) 0.5 (0.8)

1.3 1.2 0.3 1.1

(1.0) (1.0) (0.7) (0.9)

.Ol .009 NA .0006

1.1 1.5 0.9 0.5 0.4 0.4 0.6 0.8 0.3 0.2

(0.8) (0.9) (1.0) (0.8) (0.7) (0.8) (0.8) (1.1) (0.5) (0.6)

.& .08 .08 .l .05 .06 .9 .005 .08

Factors Somatic Psychic

1 .O (0.6) 1.4 (0.9)

0.6 (0.5) 0.9 (0.5)

.007 .0002

anxiety anxiety

NA: not available.

P

44

P Perretta

Relative safety in treating physically compromised patients such as these HIV cases was further shown by the fact that only in one patient treatment was terminated due to gastrointestinal side effects and tremor. Our study demonstrates the feasibility of using this antidepressant in depression with and without eorganici features. Depressive features (depressive mood, feelings of guilt, suicide) and related anxiety symptoms (tension, psychic and somatic anxiety) were significantly less severe at the end of the study. Fluvoxamine appeared particularly effective in reducing sleep disturbances, which represent one of the most frequent and troublesome complaints in HIV patients. In a naturalistic study it is impossible to exclude spontaneous improvement. It is noteworthy that physical symptoms tended to improve least, suggesting perhaps that they might constitute ongoing clinical manifestations of AIDS. As to dosage, our results confirm that HIV seropositive patients, like those with cancer, require lower doses of antidepressants than “pure” psychiatric patients (Goldberg and Mor, 1986; Femandez et al, 1989; Popkin et al, 1985). Moreover, we can confirm the safety of an SSRI, such as fluvoxamine, which has no anticholinergic and convulsant effects and appears well tolerated in the presence of cerebral pathology. Our results show no differences in the immune parameters, including T4 cell count, at the end of the study (table I). However, a follow-up is necessary to confirm if the changes we observed are less than expected with the natural decline of T4 cells in 6 months or one year (Munoz et al, 1988). On the other hand, the data available in the literature of the impact of depression and antidepressants on immunocompetence are inconsistent and call for further study (Burack et al, 1993; Calabrese et al, 1987; Lyketsos et al, 1993; Udelman and Udehnan, 1985).

CONCLUSION AIDS is a chronic illness spreading silently, typically fatal, and evoking various responses in the affected individuals. The progressive course of infection leads to different levels of distress, also associated with multiple depressive episodes which may not meet the full diagnostic criteria for major depression. The results of this study constitute supportive evidence for the use of fluvoxamine in short-term treatment of depression, and its possible use for the prevention of the relapses of depression in HIV-positive patients. In order to evaluate the latter aspect, a follow-up study is now in progress.

et al

ACKNOWLEDGEMENTS research was supported by a grant from the MiniSuperiore di Sanitci, AIDS project, Rome,Italy, and Unione Chimica Medicamenti (UCM) Torino, Italy. This

stero della Sanitci-Istituto

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