BEING ALIVE/Los Angeles (January, 1993)
Judith G. Rabkin, Ph.D., MPH and George Gewirtz, M.D.

DEPRESSION AND HIV

Although clinical depression is the most commonly observed psychiatric disorder among people with HIV illness, rates are no higher in HIV-infected gay men than in the general population. Early reports of psychiatric illness among those with HIV were described up until 1987 as widespread depressive and anxiety symptoms. However, these studies relied primarily on self-report symptom rating scales.

More recent and more extensive studies of community samples and research volunteers have been conducted. These studies used structured diagnostic instruments and trained clinicians as interviewers. They found rates of current depressive disorders among HIV+ gay men to be approximately the same as those found in HIV- gay men and general population samples that had been matched for age and gender.In one study of gay men who had an AIDS defining diagnosis for at least three years ("long-term survivors"), only three of 53 (6%) were depressed.

Similarly low rates for gay men using self-report symptom checklists were reported. The same has been found in nondrug-using women. It should be noted, though, that some investigators have found higher rates in HIV+ men. In general, about 4%-14% of HIV+ men and HIV+ nondrug-using women are found to have current depressive disorders. The prevalence rate in the general population is 5%.

It is important, of course, to recognize that the majority of HIV+ people who do not have clinical depressive disorders are nevertheless likely to experience periods of sadness and distress from time to time. For example, in the "long term survivor" study mentioned above, participants were asked, "How has your mood been recently? Have you felt pretty cheerful or depressed?" Forty-two percent answered "cheerful," and another 42% described transient sad feelings. An additional 11% had some depressive symptoms. These transient states are not routinely reported in epidemiological studies, and therefore no comparison group exists. However, the absence of a current depressive disorder does not necessarily signify a persistently "cheerful" mood or a total absence of distress.

HIV AND SUICIDE

A recent study published in the Journal of the American Medical Association reported on the risk of suicide among persons with AIDS. The study found that while people with AIDS have an increased risk of suicide, a recent trend in rates shows a decline in AIDS-related suicide between 1987-1989. The authors find the declining suicide rates to be encouraging and possibly due to greater optimism among PWAs about both quality of life and long-term survival, emerging potential therapies for HIV, better psychiatric care, and a perceived lessened social stigma about people with HIV disease. Health care providers, nonetheless, should consider assessment of suicide risk as an integral part of standard HIV care.

CAUSES OF DEPRESSION

It has been suggested but not demonstrated that HIV itself causes mood changes and that AIDS related dementia induces depression. There is, however, little evidence to support either of these hypotheses. Depressed mood also does not appear to be associated with early, subtle cognitive changes in HIV+ men. Apathy rather than sadness appears to be the predominant effect in AIDS-related dementia.

Another important question is whether HIV drugs such as AZT induce mood changes. Isolated cases of AZT-associated mania have been reported in the literature. Some patients report feeling depressed after starting to take AZT, but there is little systematic documentation of such effects, if indeed they exist.

In an interview of 15 leading AIDS specialists in 1992, each of whom had a current caseload of an average of 500 HIV+ patients, one study found none who had observed consistent mood effects from HIV medication. In practice, it is extremely difficult to distinguish between the symbolic effects of starting antiretroviral treatment with its direct chemical effects. In later stages of HIV illness it becomes even more difficult to identify effects of any one medication on mood (such as alpha interferon and INH), since as a rule many are taken simultaneously. Overall, while individual patients may experience mood changes in association with an HIV medication, no major impact on mood has been documented to date.

DIAGNOSIS

The diagnosis of major depression, as defined in current psychiatry, requires the presence of at least five of nine specific symptoms during the same two-week period. These must include either the first or second of the following:

- Depressed mood;

- Markedly diminished interest/pleasure in almost all activities;

- Significant unintentional weight gain or loss;

- Insomnia or oversleeping;

- Fidgetiness or slowed movement or speech;

- Fatigue or loss of energy;

- Feelings of worthlessness or excessive/inappropriate guilt;

- Diminished ability to think or concentrate;

- Recurrent suicidal thoughts.

The task of diagnosis is complicated, since several of the above symptoms could be caused by HIV itself, specific HIV-related conditions, or even HIV medications. Furthermore, the diagnosis is not made if the disturbance is "a normal reaction" to the death of a loved one. However, if focused queries are employed by a clinician with experience in depression and HIV illness, it is possible to obtain a reliable diagnosis in the context of HIV.

CLINICAL TRIALS

Published information on antidepressant treatments for HIV illness is extremely limited. Virtually no data have been released on the use of psychostimulants for depression. To our knowledge, in fact, only three controlled clinical trials of antidepressant medication have been conducted to date. No results have been published.

Manning and colleagues at Cornell University conducted a randomized double-blind comparison of imipramine (brand name Tofranil) and placebo for 40 HIV+ men and women with major depression. Standard medication doses (up to 250 mg/day of imipramine) were prescribed, with a mean peak dose of 225 mg/day. Response rates were 67% for imipramine-treated patients and 47% for participants taking placebo. The response rate to imipramine was as expected, but the placebo response in this study was unusually high.

Rabkin and colleagues reported results for the first 63 patients randomized in a study of the same design and with the same drug as described above. Upon entry, 33% of participants had T4 counts under 200. Response rate to imipramine was 69%, for placebo 23%, making a statistically significant difference. The same rate was found in patients with entry T4 counts under 200 as in those over 200. Thus the degree of immune suppression in participants was not found to be a factor in response to antidepressant medication.

Zisook and colleagues in San Diego are conducting a double-blind trial of fluoxetine (Prozac) and placebo. All patients are invited to a weekly support group. Of the 35 patients studied to date, high rates of response have been found in both treatment groups. In another study, Rabkin and colleagues treated with Prozac 31 patients who had failed imipramine or placebo. Twenty-eight patients responded, about half with additional low doses of Dexedrine after partial response of Prozac alone.

Fernandez and colleagues are conducting a study in which depressed HIV+ patients are randomized to either methylphenidate (Ritalin) or desipramine (Norpramin) in a six-week trial. There is no placebo-control group in this study. So far both treatments appear to be effective.

Finally, Rabkin and Rabkin are conducting an open pilot study of dextroamphetamine (Dexedrine) as an initial treatment for people with AIDS defining conditions who are depressed, have low T4 counts, and manifest lethargy as a major problem. Of the seven patients treated to date, who at entry had an average of 10 T4 cells, six responded with excellent results. The seventh patient discontinued medication because he felt "wired." Dexedrine to treat depression has to be used selectively, and patients with history of psychostimulant abuse should be excluded. The study needs extension and replication, but appears to offer a promising strategy for a select group of late-stage HIV+ people.

TOLERANCE OF ANTIDEPRESSANTS

The available research literature indicates that HIV+ depressed patients can tolerate standard doses of antidepressant medications. These are up to 250-300 mg/day of imipramine, 40 or 60 mg/day of Prozac, and up to 200 mg/day of sertraline, if insufficient clinical effect is obtained at lower doses.

Tests of the medication should last at least six weeks (eight weeks for Prozac) before a decision is made that the drug is not effective. Many "treatment" failures are due to inadequate dose and duration of medication.

Prozac is safer to use because danger of overdose is limited. Its long half-life is a clear advantage for a patient who is ill or hospitalized. Additionally, discontinuation of the drug seldom causes problems, except for patients taking unusually high doses, in which case five weeks are needed to clear the drug from the system.

Several AIDS specialists are prescribing Prozac at 20 mg/day when patients complain of depression. This is often helpful and sufficient. Some patients may need a lower dose initially (10 mg/day). During the first four to six weeks, clinical improvement may not be noticeable, and patients also need encouragement and support during this time. Higher doses (up to 60 mg/day) are sometimes in order. Adding another medication, such as a low dose of a tricyclic or psychostimulant, may be helpful.

PSYCHOSTIMULANTS

In clinical practice methylphenidate (Ritalin) is more often prescribed than Dexedrine because it is a more "acceptable" treatment to both physicians and patients. Starting doses of Dexedrine, which is more potent, are 2.5 to 5 mg/day, taken at least eight hours before bedtime. Occasionally, 30 or 40 mg/day is necessary to affect energy and mood. Cautioning patients not to discontinue medication abruptly is necessary for people taking doses in this higher range. Dexedrine has a very rapid action, and a ten-day trial is often sufficient to assess efficacy. Ritalin is usually started at 15 mg/day, increasing as needed up to 60 mg/day in three divided doses.

SIDE EFFECTS

In the available research literature and our own clinical experience, depressed HIV+ patients respond well to tricyclic antidepressants. The most common side effects include dry mouth, constipation, postural hypotension, and drowsiness. Additionally, drugs like Prozac and Zoloft that inhibit a neurotransmitter called serotonin are effective and often preferred because the side effects are milder. Side effects to these drugs include overstimulation, upset stomach, and headache.

PSYCHOTHERAPY

Several clinical studies report that therapy and group therapy can be of benefit to patients with depression. An encouraging pilot study by Markowitz and Perry observed that 20 of 23 HIV+ patients improved after an average of four months of interpersonal psychotherapy. The authors are conducting a comparative clinical trial with two forms of structured psychotherapy: cognitive behavioral therapy and interpersonal psychotherapy, each of which comes with a detailed training manual for therapists. In the study, imipramine and additional clinical management are used. It is the impression of the authors that psychotherapeutic methods are effective in alleviating clinical depression and general distress.

TESTOSTERONE REPLACEMENT THERAPY

Hormones originate in the thyroid, adrenal, testes, or ovaries and travel by the bloodstream to places in the body in order to regulate various functions. Testosterone is the naturally occurring male hormone that is produced in the testicles and adrenal glands. Its function is to build muscles and masculinize. Synthetic versions of the hormone have been used to stimulate the bone marrow to produce red and white cells in certain autoimmune diseases in men and women.

Some HIV+ men have been found to have low levels of testosterone at a wide range of T-cell levels. The condition is associated with sexual dysfunction in men, muscle loss, and a lack of energy, including mild depression. Some doctors have begun to offer patients testosterone in monthly injections. The effect of testosterone replacement has not been documented in HIV+ people. It is not being offered to or tested in women. But to date there have been no reports of adverse effects in HIV+ men from injections of testosterone.

CONCLUSION

The limited experience to date indicates that people with HIV illness respond like anyone else to standard treatment, and treating depression has been one of psychiatry's success stories. The overall message has two components: first, most people with HIV disease are not depressed. Second, those who have clinical depressive disorders respond well to treatment.

(This article is reprinted, with slight abridgment, from Treatment Issues, December 1992.)
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