Mental illness complicates the management of HIV infection in several ways. First, studies have shown that mental illnesses, especially depression, contribute to treatment non-adherence and poor HIV outcomes.3 Second, patients with mental illness are less likely to be prescribed certain treatments including hepatitis C virus (HCV) therapy and highly-active antiretroviral therapy (HAART) in many settings,4 despite new data suggesting that patients with mental illness who receive treatment for the mental illness achieve HIV clinical outcomes equal to or better than HIV-infected control patients without mental illness.5 Lastly, mental illness, when sub-optimally treated, has been associated with behaviors that risk transmission of HIV.6-8
A key to improving outcomes in HIV-infected populations is adequate detection and treatment of mental illnesses. At the very minimum, HIV providers should be familiar with the screening and management of the most common mental illness among HIV-infected patients -- depression. Reviews on the management of depression, including in HIV-infected patients, have been recently published.6,9 In this article we highlight diagnostic and therapeutic approaches to depression among HIV-infected incarcerated persons.
Depression may manifest predominantly as somatic complaints. Although readily ascribed to underlying HIV disease, symptoms such as abdominal pain, fatigue, insomnia, inexplicable muscle or visceral pain and atypical cardiac symptoms have been found to be more likely due to depression than advancing HIV disease, especially in patients with relatively high CD4 T-cell counts.10 Data among non-incarcerated individuals suggest men and women with depression present with similar complaints, though women are more likely to report anxiety, somatization, increased appetite, increased weight, increased sleep and hostility.11
In the setting of HIV infection, screening for depression can be aided by the use of standardized scales. We have validated two screening tools -- the General Hospital Questionnaire (GHQ) and the Beck Depression Inventory (BDI) in HIV-infected individuals. In a study of outpatients with HIV infection, any patient who scored above six points on the GHQ and above 14 points on the BDI was found to have a high likelihood of major depression when evaluated by a psychiatrist.1 Thus, a patient who breaches these thresholds on both instruments should be evaluated thoroughly to determine the type of depressive illness he or she is experiencing.
Patients with a complaint of depression usually suffer from either endogenous depression (also known as major depression), or reactive depression (also known as adjustment disorder or demoralization). A third diagnosis, dysthymia, is less common. Patients with major depression are less able to experience pleasure from pleasurable stimuli, a state known as anhedonia, and in any given setting the patient will be less able or unable to feel pleasure. A simple analogy is that for patients with major depression, the experience is as if the electrical outlet is not connected to the wires carrying the current -- no matter what you plug in or when you try it, there is no power. In contrast, patients with a reactive-type depression are depressed about something, and therefore can experience pleasure when distracted from the circumstance or event that is upsetting. In this instance, it is as if the electrical outlet is controlled by a switch -- when the switch is off because the patient is in the depressing setting (e.g., at home, in jail or prison, in the HIV clinic, etc.), there is no power, but when the switch is on because the patient is distracted from the depressing setting, the power flows normally.
In a very simple categorization, major depression is a brain disease in which the ability to feel pleasure is broken in a pervasive and persistent manner, while adjustment disorders are psychological impairments in which the patient's meaningful experiences of life's events and circumstances cause an understandable bad mood.
Understanding this basic premise of major depression allows for a greater understanding of the experience of life by a depressed person. One may try to imagine a life in which nothing felt good. Food does not have much flavor, sleep is not restful, friends and family bring no joy, sex is not pleasurable and one's usual enjoyable activities are no longer fun. Further, without pleasurable inputs allowing one to interpret one's actions as successful and uplifting, one quickly comes to expect that every action will lead to either numbness or pain. Hopelessness ensues. Major depression driven suicide kills thousands of people who have fallen to despair and have begun to believe that nothing will ever go right again. Of course, things do go right all the time, but the depressed person cannot experience the pleasure that other people and life have to offer -- to return to the analogy, it is as if the outlet has been disconnected from the electricity.
When assessing a patient with a complaint of depression, it is therefore important to ask about pleasurable experiences. In a correctional setting, pleasurable experiences may be limited, but an interviewer open to exploring a patient's daily routines may discover several activities that result in good feelings if the patient does not have anhedonia (e.g., playing ball, talking with friends, watching television, playing cards, visiting with relatives/friends, reading, etc.). Furthermore, it is often very useful to obtain input from an outside observer, when possible. If a patient will consent, the interviewer could contact a family member or friend to determine how the patient appears to feel when interacting with him or her (e.g., on the phone, during a visit, etc.).
It is likewise important to explore any of the patient's interpretations of his or her depression fully, without allowing the interviewer's attitudes about the complaint to interfere. Such is the case, for example, when a patient reports depression about having HIV infection. Just because the interviewer might feel it would be devastating to have HIV, one cannot assume the patient shares those feelings exactly. For many incarcerated individuals, being diagnosed with HIV was not the most devastating life experience that they have endured. He or she may be reacting to an entirely different aspect of the illness, or may be reporting he or she is upset about the illness when nothing, in fact, has changed. By saying the cause of the depression is HIV-related, the patient may be trying to explain depressive symptoms in an understandable way. Likewise, inmates may attribute a host of depressive symptoms to being incarcerated -- restriction of activities resulting in less pleasure, other inmates' activities interrupting sleep, cafeteria food taste causing loss of appetite, etc. In this way, a major depressive episode could be missed if the questions do not inquire deeply enough about the experiences to which negative feelings are attributed.
When major depression is diagnosed, assessment should be made for suicidal ideation (see Case #1 in this month's Case Series). Assessment includes past mental health history including prior suicide attempts, symptoms of psychosis (voices commanding the patient harm him/herself), plans for suicide (patients with specific plan for how to accomplish suicide are at greater risk), beliefs regarding HIV disease progression and current life stressors.
Infectious and opportunistic conditions can be assessed as is appropriate given the clinical stage of the patient and other suggestive symptoms and signs. In all patients with depressive symptoms it is crucial to examine for abnormalities of the thyroid axis in men and women and testosterone levels in men. Patients should be queried for symptoms of these conditions and basic laboratory studies should be done at least annually to detect sub-clinical abnormalities. Correction of hypothyroidism and hypotestosteronemia is often necessary to achieve remission from major depression.12,13
In any case where major depression is suspected, probing for symptoms of bipolar disease, specifically symptoms of mania, should be performed given differences in the management of these disorders.
There is some evidence that HIV infection itself directly causes major depression. First, there is a higher prevalence of major depression in HIV-infected patients than in the general population, as previously stated. Second, there is a correlation between progression of HIV disease and development of major depression. This, taken in concert with models for depression caused by chronic CNS inflammation (likely mediated by both pro- and anti-inflammatory cytokine action in CNS glial cells),14 demonstrates a possible causal relationship for HIV infection and major depression.
In addition to the direct effects of HIV and inflammation on the brain causing major depression, medications can cause or worsen depression. Two medications in particular, efavirenz and alpha-interferon15-17 (the latter used to treat HCV, frequently comorbid with HIV -- particularly in correctional settings) can cause depressive symptomatology. In general, depressive symptoms that begin after these medications are started should raise suspicion for a causal relationship. This may be overlooked, however, since the depressive symptoms often take some time to develop. While the time course for efavirenz is less clear, depressive symptoms develop between one and 24 weeks after starting treatment with alpha-interferon, with a mean of eight to 12 weeks after first dose. Screening for depression prior to initiation of alpha-interferon and regularly during therapy is prudent and should be incorporated into the management of HCV infection.
The cornerstone of effective treatment for major depression is anti-depressant medication. All available standard anti-depressant therapies have a potential efficacy for treatment of major depression co-morbid with HIV and/or alpha-interferon therapy. Selection of an agent is therefore based primarily on tolerability. In general, anti-depressants with few side effects experienced by the patient may promote adherence to the medications, and therefore, may have a good chance at effective treatment. Treatment should be started at low doses and titrated upward to minimize the risk of adverse effects. An algorithm for the management of depression and a listing of variables to consider when prescribing an antidepressant are shown in this month's IDCR-o-gram.
As the efficacy of the various classes of anti-depressants is similar, the search for a good match between the patient and treatment can be informed by the properties of the agents and the patient's medical and psychiatric symptoms. For example, tricyclic anti-depressants, such as nortriptyline, doxepin and desipramine, often curb diarrhea, promote sleep and assist with weight gain -- all of which may be desirable for certain patients. Some selective serotonin-reuptake inhibitors (SSRIs) (e.g., fluoxetine and escitalopram), venlafaxine XR, bupropion SR and XL often cause some activation, thus eliminating fatigue. Bupropion SR may also be useful in combination with smoking cessation programs, since it treats symptoms of nicotine withdrawal. Venlafaxime XR may reduce chronic pain. Matching the side effect profile of the medication to the patient's presenting symptoms can be useful in promoting adherence, thus enhancing the likelihood of a therapeutic effect. An excellent review of the properties of anti-depressants has been recently published.9
An additional consideration when choosing an anti-depressant for an HIV-infected patient are interactions with current medications and those that are likely to be prescribed in the future.6 The IDCR published a review of drug-drug interactions between mental health and HIV medications in January 2005, available at www.IDCRonline.org.19 SSRIs, like many protease inhibitors, are metabolized via the cytochrome P450 system. Ritonavir, in particular, is an extremely potent inhibitor of the P450 enzymes. Nevirapine can induce the P450 system, producing relatively decreased SSRI levels. Therefore, there is a potential for drug interactions that can alter SSRI levels; however, in general, the majority of interactions between SSRIs and antiretroviral fail to be clinically significant, and this information is presented to alert potential prescribers of a mechanism for those rare cases of clinically-significant interactions. Again, starting with lower doses of the anti-depressant will reduce the risk of supratherapeutic plasma drug levels and adverse effects and permit titration to doses that are tolerated and effective.
Following the initiation of anti-depressant therapy, the patient should be assessed every two weeks initially, at first for monitoring of side effects and later for efficacy. It may take six weeks to notice a significant change in depressive symptoms and patients should be counseled not to expect rapid results. Once remission in depression is achieved, the dose of the anti-depressant should not be altered.
Failure to achieve an effect should lead to reassessment of the diagnosis. Suboptimal dosage, drug-drug interactions and/or poor medication adherence may have contributed to the failure. If these are ruled-out, then a switch to another agent can be attempted. Response rates to a second SSRI after failure to respond to a drug in this class are 60-70%.11 In cases where a partial effect is seen during initial anti-depressant therapy, the patient may be a candidate for augmentation with a second agent with a slightly different neuropharmacological profile (e.g., adding venlafaxine or bupropion to an SSRI). There is a fair amount of evidence suggesting that lithium carbonate is an effective augmenting agent which can be monitored by serum levels.20,21 Anti-psychotic medications are also very useful in this regard. In particular, olanzapine22 promotes sleep and weight gain and ziprazidone provides a nice "energy boost" in lower doses (but must be taken with food to be effectively absorbed in the stomach).23 All patients with treatment-resistant depression should be referred to a psychiatrist.
It is important to remember that anti-depressant medications themselves will only affect a person's ability to feel pleasure. Psychotherapy is an integral part of the treatment of major depression and is more effective when combined with pharmacological therapy than when either is used alone.24 Returning to the electric outlet analogy, anti-depressants will turn on the power to the outlet. The patient's attitudes about the use of electric appliances may be unaffected -- he or she may believe that life contains no pleasures or that pleasures are fickle and subject to disappear without notice. This is the reason for combining psychotherapy with anti-depressant medication. Psychotherapy is the process of changing the patient's assumptions, behaviors and feelings about the world through discussion, exploration and practice. In essence, a depressed patient has to gain insight that the experiences he or she had while depressed were inherently biased because of a brain disease disallowing the experience of pleasure, and that new experiences, now that the power is back on, will be different. In this way, trials of behaviors once thought to be unrewarding may result in regained pleasures and thus, generate a sense of hope.
Several clinical studies have demonstrated enhanced efficacy of the treatment of depression in HIV-infected patients with psychotherapy25-27 and correctional systems with access to psychiatric consultation and on-going appropriate counseling services for patients with major depression have a distinct advantage in their ability to treat this disorder. For patients who are about to be released, post-release community counseling and mental health care should be arranged.
In all cases, there needs to be coordination among HIV care providers and those providing psychiatric care to ensure that each is aware of alterations in the status of the patient, modifications in treatment or dosage, potential for drug interactions and the development of relevant treatment-related adverse effects.
Andrew F. Angelino, M.D., is an Assistant Professor in the Department of Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine. He has nothing to disclose.
Glenn J. Treisman, M.D., Ph.D. is an Associate Professor in the Department of Psychiatry and Behavioral Sciences and the Department of Medicine at Johns Hopkins University School of Medicine. Honoraria: Pfizer, Eli Lilly, AstraZeneca, GlaxoSmithKline, Abbott, Agouron, Gilead, Boehringer-Ingelheim, Roche, Shcering-Plough, Janssen, Merck.