From The Ashes ...

The Diagnosis and Treatment of Depression in HIV-Infected People

By Ross Slotten, M.D.

Depression is the most common psychiatric disorder in the United States. According to the National Institute of Mental Health, 10% of American adults, or nineteen million people over the age of eighteen, suffers from some sort of depression every year and a third of the adult population will experience a major depressive episode in their lifetimes. The incidence of depression in individuals living with HIV is twice as high. This is not surprising, since depression occurs at higher rates in all groups of people with chronic illnesses. The economic costs of depression in terms of lost time at work and medical care are considerable; but the greatest effects are on health. In patients with HIV disease, severity of depression correlates with rapidity of decline in CD4 counts, suggesting that a failure to treat depression may accelerate HIV disease progression and impact survival. Thus, depression can be as serious as certain co-infections, like hepatitis B and C.

Although there has been considerable progress in our understanding of the brain, the ultimate cause of depression is unknown. Even the role of certain neurotransmitters like serotonin is still unclear, despite intense marketing by the pharmaceutical industry. The hallmark of depression is an alteration in mood, but there are physical symptoms as well. Psychiatrists have identified ten symptoms of depression, which include the following:

• persistent sad, anxious or empty moods;
• feelings of hopelessness or pessimism;
• feelings of guilt, worthlessness or helplessness;
• loss of interest in pleasurable activities like sex or hobbies;
• decreased energy, fatigue or feeling "slowed down";
• difficulty concentrating, remembering or making decisions;
• sleep disturbances (insomnia, frequent awakenings or oversleeping);
• appetite and/or unintentional weight changes;
• thoughts of death or suicide or suicide attempts; and
• restlessness and irritability.

If five or more of these symptoms are present every day for at least two weeks, then a person is suffering from a major depressive episode. If the depressed moods and two or more of the above symptoms persist for at least two years, then the person is diagnosed with a dysthymic disorder (an antiquated term derived from the Greek, meaning diseased mind -- in this case, representing mild, chronic depression). If in addition to one or more major depressive episodes, the person experiences wild mood swings in the opposite direction -- that is, inflated self-esteem, grandiosity, pressured speech and so-called "flight of ideas," and abnormally high energy -- then he or she is said to be bipolar.

Diagnosis

Complicating the diagnosis of any mood disorder is substance abuse, which not only can mask underlying mental illness but can also mimic one mood disorder or another. Crystal methamphetamine, for example, elevates a person's moods to the height of mania, until the person crashes and appears profoundly depressed. Chronic use can lead to depletion of serotonin, which may result in permanent depression unresponsive to antidepressant medications. Crystal methamphetamine attracts depressed individuals because it creates a temporary sense of well-being and high energy, counterbalancing the low self-esteem and other debilitating somatic and cognitive symptoms of depression. After ingestion, this drug can also produce intense anxiety and palpitations or chest pain; patients frequently request antianxiety medications like Xanax or Valium to calm their nerves. Frequent requests for such medication should raise suspicions of substance abuse. In some studies, nearly three quarters of HIV-infected individuals who abuse drugs and alcohol suffers from some sort of psychiatric disorder, including depression.

Despite clear-cut criteria for diagnosing depression, depression is not always easy to diagnose or manage. Patients present with headaches, fatigue and weight loss, just as people do with other illnesses. If depression is suggested as a cause, they may insist that something else is wrong. In HIV-positive patients, the diagnosis of depression is especially tricky because they may indeed have serious underlying disease. But unless a person has end-stage AIDS or is on the downward slope of uncontrolled HIV infection, most HIV-positive people are relatively healthy -- the various nonspecific symptoms that they are suffering from may be due not to a deadly opportunistic infection but to depression. Yet ruling out other causes may be greeted with resistance or skepticism. It is ironic that, because of the stigma attached to mental illness in our country, people would rather be told that they have some dreaded disease than depression.

The public still does not equate psychiatric disorders with organic disease -- diseases of the mind seem less legitimate than pneumonia or lymphoma. A blood test, CT scan, MRI or an X ray will not diagnose depression; it remains a clinical diagnosis, after other diseases have been ruled out. And treatment is no easier. The prevailing belief is that depression can be solved by a change in attitude, finding a new job, moving to a new city, or ending a relationship -- all of which may happen without improvement in symptoms before the true problem is addressed. In the meantime, the patient is lonely, unhappy and living in strange surroundings without adequate emotional support. Moreover, the notion of psychotherapy or antidepressants repels most people, even though depression is a treatable condition, unlike the dreaded disease the patient thinks he or she has.

As mentioned, other diseases should be ruled out before diagnosing depression. First and foremost is advancing HIV infection. Patients with declining CD4 counts and rising viral loads may exhibit a few of the characteristics of depression, such as fatigue and weight loss. If the patient has never been treated for his or her HIV infection, or the patient with resistant disease has remaining treatment options, then highly active antiretroviral therapy (HAART) should improve symptoms in a few weeks. AIDS-dementia, now rare, may also present as a depression-like illness. In more subtle cases, neuropsychiatric testing -- a battery of written and oral testing by a specially trained psychologist -- must be conducted in order to distinguish between organic brain diseases like HIV encephalopathy and a mood disorder. Unlike depression, dementia progresses over time, with profound impairment of mental processes, radical personality changes, and eventual alterations in levels of consciousness before death.

Two other medical conditions should be considered before treating depression: hypogonadism and hypo- or hyperthyroidism. Hypogonadism, or abnormally low testosterone levels, may cause fatigue, weight loss and depressed moods. For reasons that are unclear, impairment of testosterone production is common in HIV-infected men. Testosterone deficiency is defined as a total serum testosterone

Finally, a number of anti-HIV medications have so-called neuropsychiatric side effects. The most infamous in the category of antiretroviral agents is efavirenz (Sustiva in the U.S. and Stocrin in some other countries), which can cause an array of symptoms, from vivid dreams to mood-altering states mimicking depression. AZT (Retrovir) and abacavir (Ziagen) can produce extreme fatigue, loss of energy, and depression. Cause and effect are usually obvious, occurring within days or weeks of initiation of therapy. When the patient finds these side effects intolerable, stopping the medication resolves the problem; persistence suggests another reason for alterations in mood. Many other agents used to treat a variety of non-HIV related problems can also depress mood or induce somatic complaints, but the list is too long to enumerate in this article.

The management of depression in HIV infection is usually multidisciplinary, involving psychologists, social workers and psychiatrists. The primary health care provider rarely has the time or expertise to provide the full scope of services to the depressed person. When substance abuse is a problem, access to a good treatment program with sensitivity to issues unique to HIV like sexuality is essential. In addition to restoring emotional health, major goals of psychotherapy are the prevention of the transmission of HIV to uninfected individuals or reinfection with a resistant strain of HIV, and adherence to the HIV-treatment regimen.

Most of the DHHS recommendations are common sense. Implementation of these recommendations, however, can be a challenge. The clinician must overcome a number of barriers to ensure proper therapy -- social, psychological and medical. Some of these barriers have nothing to do with the patient but everything to do with our health care system, which is fragmentary and driven by third-party payers. Yet until the creation of a comprehensive health care system in this country -- whether in the form of a single-payer, government-managed system, or one resembling the mix of government and private payers cobbled together by the Clinton administration -- certain barriers, such as access to affordable health care for the working poor, will be impossible to overcome.

First, the patient must be convinced that he or she is depressed, which, as already noted, is not always easy. Second, the patient must agree to see a psychotherapist, at least for an evaluation. For those who lack or have insufficient mental health benefits, access to less expensive or free mental health care varies from community to community. In communities offering such services, quality is not always consistent. Psychotherapy may span weeks or years, which is a significant time commitment; out-of-pocket expenses can be considerable, even for those having the most extensive insurance coverage. Gay patients often prefer to see a gay therapist, which HMOs and other managed health care plans may not be able to guarantee, though insurers have become increasingly sensitive to sexual orientation in recent years. In some parts of the developing world, psychotherapists do not exist; patients who emigrate from those countries may not be amenable to psychotherapy because they do not accept the Freudian or post-Freudian model of the mind. Thus, there may be cultural barriers that prevent patients from obtaining psychotherapy. Third, the primary care physician or psychiatrist may recommend prescription medication that patients are reluctant to take. Patients often resent the addition of yet another medication to an already burdensome regimen, or they may fear antidepressants, which they equate with mind-altering substances like LSD. They may also worry about side effects, especially the impact on sexual function.

Treatment

The pharmacological treatment of people with HIV and depression has been studied extensively, though not every drug available has been examined. The oldest class of antidepressants, the tricyclics (amitryptilline, imipramine, desipramine and nortryptilline), were the first drugs subjected to a scientific evaluation. Approximately three-quarters of patients given imipramine, for example, responded favorably as compared to 30% on placebo. However, almost a third of the patients stopped imipramine because of side effects, which include constipation, dry mouth, drowsiness, headaches, cognitive problems and sexual dysfunction. This is unfortunate, because tricyclics are inexpensive. Today, their role is limited mainly to the treatment of pain from peripheral neuropathy, which improves with a dose lower than that for depression. More expensive medications, like fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa) and a derivative of citalopram, Lexipro, which belong to the SSRI class (selective serotonin uptake inhibitors), have produced response rates as high as 90% in some studies. Side effects are relatively few, though sexual dysfunction, which is the most common complaint, occurs at rates higher than the pharmaceutical companies like to admit. Rarely are erections a problem; most aggravating is time to ejaculation. In this setting, Viagra, Levitra and Cialis are of no use, since these agents help only those men who have difficulty obtaining or maintaining an erection and do nothing to speed up ejaculation. Venlafaxine (Effexor), nefazodone (Serzone), buproprion (Wellbutrin) and mirtazapine (Remeron) -- the non SSRI antidepressants -- seem to cause less sexual dysfunction. In fact, bupropion is sometimes added to an SSRI-containing regimen to improve sexual function. Few studies with these agents have been conducted in HIV infected patients -- which does not mean they are not effective in this population. Moreover, there may be a significant interaction between these non-SSRI agents and antiretroviral regimens containing Norvir (ritonavir). These drugs should therefore be used with caution in patients on Norvir boosted PIs or Kaletra.

Psychostimulants, like methylphenidate (Ritalin), can also help patients who are suffering from depressed mood, fatigue and cognitive impairment. Their onset of action is more rapid than that of the tricyclics, SSRIs, and other antidepressants, which may take four to six weeks before maximal benefit is observed. Ritalin works in a matter of hours; but its abuse potential is high and tolerance to its effects typical. Annoying side effects include overstimulation and insomnia; and for those who are concerned about maintaining weight or lipodystrophy, amphetamines suppress appetite. This class of drugs works best in patients with end-stage disease or in those whom the clinician suspects adult attention deficit disorder, a syndrome whose symptoms are difficult to distinguish from chronic anxiety disorder as well as depression. Finally, St. John's wort should be mentioned. Although shown to be effective for mild depression, St. John's wort negatively interacts with indinavir (Crixivan), making regimens containing indinavir less effective. Its interactions with other protease inhibitors are unknown. St. John's wort should not be used in patients taking HIV medications until further studies support its safety and efficacy.

In conclusion, depression is a common, treatable problem in people with HIV infection. It may be due to a condition long preceding HIV infection or to substance abuse; or it may arise in the course of infection, either as a result of HIV medications, illnesses, or the overwhelming emotional response to HIV itself. If not treated or recognized, it can profoundly affect quality of life and life expectancy. Clinicians, patients, their families and significant others should suspect depression when there is no other explanation for depressed mood, fatigue, or other vague somatic complaints that impair social functioning. Psychotherapy and the appropriate use of antidepressant medications can restore such individuals to normal emotional health, which, by curtailing self-destructive behavior and improving adherence to antiretroviral regimens, will help ensure a long, productive life.