The way that treatment is provided changes the way that people experience chronic illness. In 1997, more effective antiretroviral therapies now called highly active antiretroviral therapy (HAART) became the standard of care for HIV affected individuals. This therapy has changed the face of HIV, becoming part of the language of HIV infection, its care and treatment. And yet, not all individuals choose or are able to take HAART. When one isn't able to tolerate, manage or choose HAART, he or she may become angry, resentful, or have feelings of failure, helplessness, hopelessness and even depression. Individuals may fail or not be able to take HAART for many reasons including those associated with having few resources, difficulty with adherence, and or mental illness. Because of the way the media has described antiviral therapy for HIV infection, individuals living with HIV are constantly re-evaluating what "treatment" means to them. Thus, changes in the treatment of HIV/AIDS can affect one's outlook and life perspective. With respect to these new and constantly evolving 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? What will they do to my body? How will I look to others? Will I feel better, or what happens if I feel much better? What if they affect my ability to work? 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, these thoughts may evoke a myriad of feelings including helplessness, loss of control, rejection, hopelessness, isolation, withdrawal, anger, sadness and fear. These feelings may become what is known as depression or in clinical terms, a major depressive episode. With changes in treatment, many people experience these feelings with the multiple losses of control that occur in the context of HIV infection. One might 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. Depression in HIV infection is similar to depression in other chronic illness such as heart disease or diabetes.

What Is Depression?

The diagnosis of depression is based on a minimal duration of certain symptoms. Major Depressive Disorder (MDD) is diagnosed when one has at least five of the symptoms listed in Table 1 that last for at least 2 weeks. An untreated episode typically gets better within 6 to 12 months. Chronic depression (depressed mood for most of the day, more days than not) that persists for at least 2 years and is not accompanied by the other symptoms listed in Table 1 is diagnosed as dysthymia. Some individuals who have chronic depression (dysthymia) also have intermittent episodes of major depression. This is called "double" depression.

Depression and HIV Infection

Cross-sectional and prospective studies in HIV-positive populations estimate the lifetime prevalence of depressive disorders ranges from 22 percent to 35 percent and the current prevalence (1-2 months) ranges from 6 percent to 10 percent. These rates are all elevated when compared to the estimates of lifetime (9 percent) and current (3 percent) prevalence of major depression in the general community. Depression appears to be the most common psychiatric disorder found among HIV-infected individuals. Similar to HIV infected persons, people who are HIV-negative, but at-risk for HIV infection, have similar increases in rates of depression. In other words, if you are from a population that is at-risk for HIV infection, you are also at increased risk of depression compared to the general population.

Depression has a significant effect on quality of life, progression of disability and ability to receive good medical care. With the development of HAART, which has the potential to manage HIV infection and prolong life, treatment of depression is even more important, since untreated depression could both compromise medication adherence leading to viral resistance and also potentiate the disabling effects of the illness.

It was initially suggested that HIV itself causes depression, that HIV-associated neurocognitive changes (now referred to as HIV-Associated Cognitive Impairment) may be a cause of depression or that HIV associated medications may cause mood changes. There are a few case reports that address these issues, but there is very little evidence to support any of these hypotheses. Depression has a biological and neuro-chemical basis in the context of an individual's social functioning. From the opposite standpoint, many reports have investigated whether depression leads to HIV illness progression with a decline in the CD4 count and increase in the viral load. While viral load studies haven't been reported for large populations, these reports all seem to indicate that depression is not associated with progression of illness. Other lymphocyte markers such as natural killer cells or CD16 cells may be more associated with stress, depression and coping, but these need to be further studied. Recent reports suggest such associations.

Many depressive symptoms are difficult to assess in individuals with chronic illness. Chronic illness may generate symptoms that look like depression and depression can mimic symptoms of a medical illness. Identification of physical symptoms (associated with medical illness) or psychological symptoms (anxiety or loss of interest in activities when bed-ridden, housebound, or unable to participate in social and recreational activities) is important. In the early stages of HIV infection, these symptoms rarely coexist with true depression, however, as HIV infection progresses, physical symptoms attributable to HIV itself are difficult to separate from the symptoms of a depressive disorder. In these cases, it is important to rule out a physical illness first. Then, your healthcare provider should review the symptoms present and consider the most prominent ones. When other causes have been ruled out, depressed mood is most often the prominent symptom.

Treatment of Depression in HIV Infection

Many treatment options are available. If you are experiencing any or some of symptoms listed in Table 1, you should consider seeking further evaluation and treatment via a mental health provider or your primary care provider. 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

Psychotherapy or counseling in HIV-positive individuals has been approached using several models including supportive therapy, interpersonal therapy (IPT), cognitive behavioral therapy (CBT), biofeedback, stress-reduction/relaxation exercises, alternative therapy, and group therapy. Common themes for people during therapy are loss of relationships and autonomy, loss of employment, declining physical well-being and appearance, fear of neurologic problems, loss of spirituality as well as fear of stigma and discrimination.

All forms of therapy involve supportive elements that play a role in the success of the therapy, but supportive and insight-oriented therapy define support as paramount. Not only is the supportive relationship between therapist and patient a vehicle for exchange of information between patient and therapist, but the relationship itself is of therapeutic benefit in a variety of ways.

IPT has been studied in outpatient HIV-positive individuals with MDD. For these people, IPT helped them 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 patient 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, and investigating relationships between thoughts and emotions and their underlying assumptions. 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-positive client's view that their life is hopeless. The goal is to help the client believe 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 that would support or reject their beliefs.

Group therapy has been used extensively with HIV-positive individuals in a variety of contexts and is highly efficient. Sessions provide psychoeducation, confrontation regarding misperceptions about the illness, and shared experiences, all of which help to improve patients' mood and quality of life.

The goal of counseling should be to help individuals to function as well as they can. Therapists should try to adapt the psychotherapy method they are most comfortable with the special needs of the person living with HIV. People living with HIV are not significantly different from other clients. The therapist should provide an objective but empathic environment where the individual can freely express their emotions. Therapy should attempt to engage clients in assessment and mobilization of their resources, including those provided by family, friends, and community. Psychoeducation should be provided about HIV, its course, treatment and effects.

Pharmacotherapy

The approach to pharmacotherapy for HIV-positive individuals with a depressive disorder may be slightly different than for the general adult population. HIV-positive individuals often respond differently to medications, often being more sensitive to them, and may need a "start low and go slow" approach. In addition, individuals with advanced HIV infection are often on multiple medications which increases the probability of drug-drug interactions and the chance of experiencing side effects. More recent studies have called attention to the important relationship between tolerability and efficacy in this population.

MDD in patients with HIV infection has been effectively treated in open trials with almost all antidepressant medications. Of these, only three (imipramine, fluoxetine 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 patients. The efficacy of fluoxetine appears similar to that of desipramine, sertraline and paroxetine. When compared to tricyclic antidepressant, fluoxetine, paroxetine, sertraline, and citalopram (known as "SSRIs") are more tolerable and have fewer side effects, which may lead 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 testosterone is administered, a patient's testosterone levels should be checked.

Additionally, stimulants have been shown to improve mood, energy and alertness and have been shown to be effective in medically ill populations. Several open trials that used stimulants have suggested that people benefit from them with a decrease in depressive symptoms and an improvement in cognitive deficits. It is important to note that stimulants have side effects that include insomnia, agitation, weight loss and paranoid ideation, plus tolerance may develop after initial benefit. There have yet to be significant randomized, placebo-controlled trials that 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-positive person. People may have many concerns about medications including loss of control, the ability to distinguish symptoms that may indicate physical illness, increase or change in weight, sedation, and sexual dysfunction. All of these side effects can affect how a person tolerates a medication. The provider initiating antidepressant treatment should consider the individual's HIV-related symptoms when selecting an antidepressant. Tricyclic antidepressants (TCAs) may be more sedating and therefore may be helpful for insomnia. On the other hand, the anticholinergic side effects (the side effects due to blocking a branch of the nervous system) may actually be helpful for managing chronic diarrhea, concurrent neuropathy or neuropathic pain. SSRI antidepressants are not usually sedating and can cause nausea, exacerbate chronic diarrhea or 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 citalopram, venlafaxine, nefazodone, and mirtazapine have all been investigated in open (non randomized, non blinded) trials. They have different side-effect profiles from the TCA's and SSRIs and may be especially helpful in people who cannot tolerate these other classes of antidepressants. Venlafaxine has properties of both TCAs and SSRIs, but side effects are avoided at 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 symptoms are often easily tolerated and resolve. Mirtazapine may be useful in patients who are experiencing insomnia and need to gain weight. These newer antidepressants, 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.

In general, SSRIs and the newer antidepressant medications have several advantages over TCAs for patients with HIV illness. These drugs 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 and as a result are likely to be more effective in treating depression. They are not sedating and do not have the anticholinergic side effects seen with TCAs. Therapeutic dosing is easier, as well, often allowing management by the primary care provider.

Clients should be educated about the length of time it takes for antidepressant response (often 3 to 4 weeks) and about common side effects they might experience with a particular antidepressant and how this may affect their HIV illness. And finally, it is especially important for individuals to reinforce compliance by arranging contact with their health care provider within a brief time after initiation of therapy in order to evaluate side effects, treatment effect, and expectations.

Protease Inhibitors and Antidepressants

Of the FDA approved protease inhibitors, ritonavir (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 chemical and medications in your body. Many HIV-related medications inhibit these enzymes including ketoconazole, clarithromycin and the protease inhibitors. The protease inhibitors are known to inhibit specific a specific group 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 the these systems. Several antidepressants are metabolized through one or more of the cytochrome P-450 enzymes including fluoxetine, fluvoxamine, paroxetine, citalopram, nefazodone, and tricyclic antidepressants. Levels of the antidepressant which are metabolized by the 3A system may be increased when protease inhibitors are administered concurrently which in turn are experienced by the patient as side effects and may be misinterpreted as a change in medical illness state and lead to medical evaluation or hospitalization. Patients at increased risk of drug interactions include those who are on multiple medications with multiple medical illnesses, those with deficiencies in one or more cytochrome P-450 enzyme systems, those with renal and hepatic disease, those who are elderly and or physically debilitated, and those who are on a single potent enzyme inhibitor such as a protease inhibitor. Prescribing providers should carefully evaluate patients on protease inhibitors for possible drug interactions and side effects.

Andrew Elliott, M.D., M.P.H. works with the Madison Clinic at Harborview Medical Center University of Washington, Department of Psychiatry and Behavioral Sciences.