Important note: Information in this article was accurate in January 1997. The state of the art may have changed since the publication date.With the advent of protease inhibitors for the treatment of HIV infection, the media has asked, "How will the AIDS culture...deal with...a chronic manageable disease?" Is it a chronic manageable disease? Certainly, the presence and availability of protease inhibitors has and will change the face of HIV infection now and in the next few years. Thus, changes in the treatment of HIV/AIDS can affect one's outlook and life perspective. With respect to these new treatments, one faces many questions. Should I take them, and at what point in the course of infection? Are they available to me? What will they do to my life? Will I feel better, and what happens if I feel much better? Should I go off disability? Or will I be unable to tolerate them and then...feel worse?
While these are only a few questions that may arise with new treatments, they may evoke a myriad of feelings including helplessness, loss of control, rejection, hopelessness, isolation, withdrawal, anger, sadness and fear. These feelings may precede or become what is known as depression, or in clinical terms, a major depressive episode. With changes in treatment, many people may experience these feelings with the multiple losses of control that occur in the context of HIV infection. One might naturally assume that HIV-infected individuals would 'naturally' become depressed upon learning of their infection or upon the realization that they are unable to tolerate a protease inhibitor. Studies have investigated this, and although there have been no large-scale epidemiological studies, as with many chronic illnesses, this is not the case.
The diagnosis of depression is based on a minimal duration of certain groups of symptoms. A major depressive disorder is diagnosed when one has several of the symptoms in Table 1 (see end of article) which last for at least 2 weeks and include the presence of 1 or 2 symptoms (or both). An untreated episode typically remits within 6-12 months. Chronic mood depression (for most of the day, more days than not) that persists for at least two years and is accompanied by the symptoms above is diagnosed as dysthymia. Some individuals have chronic depression (dysthymia) with episodes of depression superimposed on top of it. This is called "double" depression.
Cross-sectional and prospective studies in both HIV+ and at-risk HIV populations estimate lifetime prevalence of depressive disorders to range from 22.1 - 61.0% with 6 - 12 month (current) prevalence ranging from 0 - 18.4% in HIV positive and 0 - 9.1% in HIV seronegative populations. These rates are all elevated when compared to estimates of lifetime (5% and 17%) and current (3% and 10%) diagnoses of major depression in community samples. Depression appears to be the most common psychiatric disorder found among HIV-infected individuals.
Depression has a significant effect on quality of life, progression of disability and ability to receive good medical care. With the advent of protease inhibitors, which have the potential to control HIV infection and prolong life, treatment of a major depressive disorder is even more critical, since untreated depression could both compromise medication adherence and potentiate the disabling effects of the illness. Preliminary evidence also suggest that chronic depressive symptoms may be associated with increased mortality in HIV positive patients.
It has been suggested that HIV itself causes depression, that HIV associated neurocognitive changes (now referred to as Minor Cognitive Motor Disorder and HIV Associated Dementia) may be a cause of depression, or that HIV associated medications (including AZT) may cause mood changes. There are a few case reports which address these issues, but there is little evidence to support these hypotheses.
Many depressive symptoms are difficult to assess in HIV/AIDS population. This is often related to clusters of physical symptoms that are associated with HIV-related medical illness or psychological symptoms such as anxiety or loss of interest in activities when the person has been bedridden, housebound, or unable to participate in social and recreational activities. In early stages of HIV infection, these symptoms rarely coexist with depression. However, as HIV infection progresses, physical symptoms can be clearly attributable to HIV itself, thus making it difficult to separate from a depressive disorder. In these cases, it is important to rule out causes of physical illness. The provider should then review the symptoms present, rule out other causes, and consider the prominent symptoms. When other causes have been ruled out, depressed mood is most often the prominent symptom.
Many treatment options are available. Individuals who are experiencing any or some of the symptoms listed in Table 1 should consider seeking further evaluation and treatment via their primary care provider. Two recent studies looked at depressive symptoms over time and noted an association with progression of illness. This has yet to be substantiated, but suggests that treatment of depressive symptoms may affect survival.
The most effective methods of treating depression include a combination of counseling (psychotherapy) and medication. Psychiatrists, psychologists, nurse practitioners, and social workers all provide different forms of treatment for depressive disorders.
Psychotherapy or counseling in HIV+individuals has been approached from several models including supportive, cognitive behavioral therapy (CBT), interpersonal therapy (IPT) and group therapy. Common themes for clients during therapy are loss of relationships and autonomy, employment, physical well-being and appearance, fear of neurologic problems, spirituality as well as stigma and discrimination.
All forms of therapy involve supportive elements that play a role in the success of the therapies, but supportive and insight-oriented therapy define support as paramount. Not only is the supportive relationship between therapist and client a vehicle for exchange of information between client and therapist, but the relationship itself is of therapeutic benefit in a variety of ways.
IPT has been studied in outpatient HIV+ individuals with Major Depression. In these people, it helped relate changes in mood to changes in their environment or in role changes. The therapist engages the client in their emotional life issues, conceptualizing difficulties within one of four interpersonal problem areas: grief, role dispute, role transition, or interpersonal deficits. The therapist then uses specific strategies to deal with the problem areas, focusing on the here and now, on what the client wants to achieve, and on what options exist to achieve it.
In contrast, CBT is based on the philosophy that depressed people distort reality in a particularly negative way. CBT involves setting goals, defining target symptoms, problem solving, investigating relationships between thoughts and emotions and their underlying assumptions. As well, in the context of CBT, self-defeating behaviors and interpersonal and coping skills are often addressed. For example, a CBT therapist would challenge a HIV+ person's view that their life is hopeless, believing that people have the capacity to construct a positive sense of the future. The CBT therapist would engage the client in an effort to identify hypotheses which would support or reject their beliefs.
Group therapy has been used extensively with HIV+ individuals in a variety of contexts and is highly efficient. It provides psychoeducation, confrontation regarding mispercetions about the illness, and shared experiences, all of which help to improve peoples' mood and quality of life.
The approach to pharmacotherapy for HIV+ individuals with a major depressive disorder may be slightly different than for the general adult population. HIV+ individuals often respond differently to medications, often being more sensitive, and may need a "start low and go slow" approach. As well, individuals with advanced HIV infection are often on multiple medications which increase the probability of drug-drug interactions. Additionally, side effects may occur differently, with some being helpful and some aggravating current symptoms of HIV infection itself or HIV-related illnesses. There are few controlled studies which have evaluated the efficacy of antidepressant medications in HIV+ individuals. Several open trials have looked at efficacy of a few other antidepressant medications, however, their data is confounded by the complicating effects of medical illness as well as separation of drug-placebo differences. And, more recent studies have alluded to the important relationship between tolerability and efficacy in this population.
Major depressive disorder in people with HIV infection has been effectively treated in open trials with fluoxetine, imipramine, sertraline, fluvoxamine, methylphenidate, desipramine and testosterone. Of these, only two (imipramine and paroxetine) have been investigated in randomized placebo-controlled trials. Imipramine demonstrated an effective antidepressant response that was similar to that seen in medically healthy depressed people and unrelated to the severity of immunosuppression. A high rate of imipramine discontinuation in this trial, coupled with open trial reports of mild and infrequent side effects for fluoxetine and sertraline (although not fluvoxamine) was found in depressed HIV positive people. This suggests that fluoxetine and sertraline (both known as selective serotonin re-uptake inhibitors), although not more efficacious, may be more tolerable and have increased overall effectiveness in this population (a higher proportion of treated who benefit). Paroxetine was subsequently compared to imipramine in a double-blind placebo-controlled trial and found to validate what was previously hypothesized: SSRIs (fluoxetine, paroxetine, sertraline) are more tolerable with fewer side effects and thus may be more tolerable leading to an increased overall effectiveness.
Testosterone replacement has been shown to improve depressive symptoms in individuals with low testosterone levels, especially for those with decreased libido or sexual dysfunction. Before administered, a clients' testosterone levels should be checked.
Additionally, stimulants have been shown to improve mood, energy and alertness and to be effective in medically ill populations. There have been several open trials which used stimulants and have suggested that people benefit from stimulants with decrease in depression and cognitive deficits. It is important to note that stimulants have side effects which include insomnia, agitation, weight loss, and paranoid ideation. In addition, tolerance may develop after initial benefit. There have yet to be significant randomized, placebo-controlled trials which more thoroughly evaluate stimulants against other antidepressants with respect to tolerability and overall efficacy.
Side effects and tolerability are important aspects to treatment in the HIV+ client. People may have many concerns including loss of control, the focus on identifying somatic symptoms which may indicate physical illness and sexual dysfunction which all effect how they tolerate a medication. The provider initiating antidepressant treatment should consider their client's HIV-related symptoms when selecting an antidepressant. TCAs may be more sedating, and may be helpful for insomnia. Their anticholinergic side effects may be effective for managing chronic diarrhea. On the other hand, TCAs may be more effective in managing a person with concurrent HIV neuropathy to treat neuropathic pain in association with depression. SSRI antidepressants are not usually sedating and can cause nausea and exacerbate chronic diarrhea or may have sexual side effects, but may alleviate chronic constipation. Stimulants may increase cognitive processing, but can cause agitation and weight loss.
The newer antidepressants including, venlafaxine, nefazodone, and mirtazapine have yet to be investigated in open or randomized, double-blind trials. They have different side effect profiles than both the TCA's and SSRIs and may be especially helpful in patients attempting to avoid specific side effects or combat physical symptoms of HIV or HIV-related illnesses. Venlafaxine has properties of both TCAs and SSRIs and may be useful if these side effects are avoided with low doses. Nefazodone has no reported sexual side effects and although it is known to cause dry mouth and dizziness upon initiation of therapy, these are often easily tolerated. Mirtazapine may be useful in people who are experiencing insomnia and could benefit from weight gain, in that it both stimulates appetite and increases weight. These, as with both the TCAs and SSRIS, all need to be evaluated in the context of the individual's current HIV-related symptoms and how they are affecting their quality of life.
SSRI and newer antidepressant medications have several advantages over TCAs for people with HIV illness. They are likely to be better tolerated with fewer side effects, leading to a lower incidence of side effect related dropout and increased compliance with treatment. As a result they are likely to be more effective in treating depression. They are not sedating and lack the anticholinergic side effects seen in TCAs. Therapeutic dosing is easier and often allows management by the primary care provider. Clients should be educated about the length of time it takes for antidepressant response (often 3-4 weeks) and about common side effects one might experience with a particular antidepressant including how this may affect their HIV illness. Finally, it is especially important to reinforce compliance by arranging contact with the client within a brief time after initiation of therapy in order to evaluate side effects, treatment effect, and patient expectations.
Table 1. Symptoms of a Major Depression |
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| Adapted from the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), 4th edition. Washington, DC: American Psychiatric Press 1994:327. |
Table 2: Risk factors for Major Depression in HIV+ or At-Risk Populations |
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Table 3: Common Conditions Mimicking Depression |
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| Pneumocystis | Shortness of breath, lethargy, fever, cough |
| Toxoplasmosis | Headache, depression, social withdrawal |
| Cryptococcal Meningitis | Headache, fever, depression |
| HIV Associated Dementia | Memory loss, social withdrawal, personality change |
| Lymphoma, PML | Withdrawal, depression, focal neurologic changes |
Table 4: Treatment Options |
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Psychotherapy
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Pharmacotherapy
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Combination Therapy
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Table 5: Types/Classes of Antidepressant Medications |
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| Tricyclics | Amitriptyline, Nortriptyline, Desipramine, Imipramine |
| Bicyclic | Venlafaxine |
| SSRI's | Paroxetine, Sertraline, Prozac |
| MAOI's | Parnate, Nardil |
| Other | Wellbutrin, Nefazodone, Mirtazapine, Trazadone |
Table 6: Approach to Pharmacotherapy with Anti-Depressants in HIV+ Infection |
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Of the FDA approved protease inhibitors, ritonivir (Norvir) may be the most potent inhibitor of the drug metabolizing system referred to as the cytochrome P-450 system. It is a collection of enzymes which metabolize many of the natural chemicals and medications in your body. Many HIV-related medications inhibit these enzymes, including ketoconozole and the protease inhibitors. The protease inhibitors are known to inhibit specific groups of enzymes referred to as the 3A group. While ritonivir and indinavir are known to potently inhibit the 3A system, not all protease inhibitors have the same specificity for these systems. Several antidepressants are metabolized through one or more of the cytochrome P-450 enzymes including fluoxetine, fluvoxamine, paroxetine, nefazodone, and tricyclic antidepressants. Levels of those antidepressants which are metabolized by the 3A system may be increased when protease inhibitors are administered concurrently, which in turn are experienced by the client as side effects and may be misinterpreted as a change in medical illness state leading to medical evaluation or hospitalization. People at increased risk of drug interactions include: those who are on multiple medications, and have multiple medical illnesses; those with deficiencies in one or more cytochrome P-450 enzyme system; people with renal and hepatic disease; those who are elderly and or physically debilitated; or those people who are on single potent enzyme inhibitors such as the protease inhibitors. Prescribing providers should carefully evaluate clients on protease inhibitors for possible drug interactions and side effects.
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