Mental illness occurs more frequently among people infected with HIV. In addition, individuals with mental illnesses are at greater risk for contracting HIV. Therefore, psychiatry has a great deal to offer in the management of patients with HIV--whether through proper patient education or safe and effective psychopharmacology.
April Bonus Edition 2005, Vol. XXII, Issue 5
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Dr. Rogers is assistant professor at the Massachusetts College of Pharmacy in Manchester, N.H. His interests are in psychopharmacology, infectious disease and pain management. He is a board-certified pharmacotherapeutic specialist and practices at Elliot Hospital. He has indicated he has nothing to disclose regarding the nature of this article.
The human immunodeficiency virus was identified in 1984 as the organism responsible for the development of the acquired immune deficiency syndrome known as AIDS. This syndrome, identified three years prior, leaves the host's immune system defenseless. As a result, infected individuals become prone to opportunistic infections, which eventually lead to their demise. Although the virus continues to be problematic, great strides have been made in identifying and treating its presence. In 1985 an extremely accurate blood test became commercially available to aid in diagnosing individuals who were infected with HIV and in screening blood-supply products. Two years later the first antiretroviral agent (zidovudine or AZT [Retrovir]) was approved by the U.S. Food and Drug Administration and, since then, over 20 other products have been added to the armamentarium.
In the mid 1990s, the combination of antiretroviral agents began to extend the life expectancy of HIV-infected patients. The combination of such medications has been termed highly active antiretroviral therapy (HAART) and generally consists of at least three agents. The goal of HAART is to keep the virus at bay by minimizing its levels within the bloodstream and thereby decreasing its effects on the immune system. Unfortunately, the immune system and the bloodstream are not the only sites in which the virus resides.
Early in its course, HIV also has the ability to penetrate the central nervous system. As a result, psychiatric and neurological symptoms may be evident despite the absence of an opportunistic infection. In addition, HAART therapy may be associated with certain psychiatric side effects, as may interactions between HAART and psychotropic medications. Therefore, a psychiatric evaluation is recommended at the onset of treatment, with follow-up evaluations as needed. For those patients already presenting with a psychiatric diagnosis, proper monitoring will not only help assess the current therapy, but also watch for the possibility of new ailments.
Furthermore, patients who do not have an initial psychiatric disturbance become vulnerable to developing one, given the presence of HIV. The inclusion of a psychiatric assessment will help to aid in the successful treatment of HIV and improve quality of life.
This piece is designed with the psychiatrist in mind. It will begin with a quick review of HIV that is meant to be informational and to familiarize the reader with basic principles in HIV therapy. The next section will focus on the possible psychiatric components of HIV. These psychiatric disturbances may have resulted as a consequence of the virus or as a contributing risk factor in acquiring the HIV infection. Treatment modalities of the psychiatric component will then be presented with a concentration on pharmacodynamic and pharmacokinetic concerns. At the end, the reader will be left with a more complete understanding of the role psychiatry plays in treating this devastating illness.
HIV Quick Review
The human immunodeficiency virus is a retrovirus. Simply stated, it possesses the ability to make DNA from RNA. Although a complicated organism, HIV carries only three enzymes, which are responsible for its life cycle. These enzymes are reverse transcriptase, protease and integrase (Streicher et al., 2000). Currently, available drug classes target two of these enzymes (reverse transcriptase inhibitors and protease inhibitors). These medications inhibit the life cycle of the virus once it is inside the cell. Enfuvirtide or T20 (Fuzeon), a relatively new agent only available as an injection, actually inhibits the entry of HIV into the host cell (Fung and Guo, 2004). It is the only medication of its kind and is typically reserved for patients with antiretroviral failure.
Table 1 and Table 2 present the antiretroviral medications separated by their respective classes. To help the psychiatrist recognize each agent, trade names, abbreviations and generic names are listed. However, it is strongly recommended that the generic names be used when referring to these agents to avoid confusion and potential errors.
Viral load is a measurement that determines the amount of virus in the blood. The value is expressed as the number of viral copies per unit of blood. There are currently two different methods used in determining viral load, and they differ based on sensitivity. While a viral load of <20 copies is considered undetectable, this does not mean the virus is absent. Rather, it may suggest that the medication regimen is adequate.
Conversely, viral load increases may be indicative of noncompliance or viral resistance. To avoid resistance, a drug regimen containing at least three antiretroviral agents is the basis of HAART therapy (Yeni et al., 2002). It is important to recognize that certain antiretroviral agents are actually combination products. For example, Combivir contains both lamivudine and zidovudine, while Trizivir is a combination of abacavir, lamivudine and zidovudine. Therefore, a patient may only be on one or two prescriptions, but a total of three or more medications. Recognizing the generic name of the medications in combination products will help the psychiatric practitioner in identifying potential concerns regarding drug interactions and/or psychiatric side effects.
As previously mentioned, HIV destroys a person's immune system and renders the host defenseless. A measurement of CD4 T-cells is used as a marker for the extent of immune suppression. Cell counts <200 cells/µL are considered a risk for opportunistic infections (i.e., pneumocystis carinii pneumonia). The lower the CD4 T-cell count, the higher the risk of other opportunistic infections. A CD4 T-cell count of <200 cells/µL or the presence of an opportunistic infection gives the diagnosis of AIDS. Prophylaxis medications (i.e., sulfamethoxazole) are prescribed as CD4 T-cell counts drop below 200 cells/µL (Yeni et al., 2002).
These medications also have the potential for neuropsychiatric implications. The psychiatrist must be particularly cautious of antituberculosis agents such as rifampin (Rifadin, Rimactane) and rifabutin (Mycobutin). Both agents have the potential of increasing the clearance of many psychotropic agents (Yew, 2002).
The virus is spread through blood, semen and breast milk (Streicher et al., 2000). The transmission of HIV from mother to newborn is also possible. Given the potential for substance abuse and risky sexual behavior in individuals who are mentally ill, there is a greater potential for contracting and spreading the virus in this population. Therefore, proper education regarding the sharing of needles and unprotected sexual intercourse should be emphasized frequently.
Mental Illness and HIV
Numerous investigations have been conducted to correlate HIV and mental illness. When reading these studies, it is important to recognize that many of them were completed before the advent of HAART. Therefore, the results may be significantly different than more recent investigations since HAART alone will help lower the viral load and therefore leave less virus available for penetration into the CNS.
Blank and colleagues (2002) examined the prevalence of a concomitant psychiatric disorder and HIV infection in the Philadelphia Medicaid program between 1994 and 1996. Patients were screened for a diagnosis of HIV or serious mental illness.
The researchers found that 4.1% of the HIV-infected patients also had a diagnosis of schizophrenia, approximately twice that of the general population. Patients with a concomitant major affective disorder accounted for 8.8% of the HIV-positive participants, which is also of significance. The overall findings suggested that HIV-infected patients were five times more likely than the general population to suffer from schizophrenia or a major affective disorder (12.9% versus 2.8%).
The investigators speculated that schizophrenia and major affective disorders may actually be risk factors for HIV. They based this assumption on the fact that psychiatric patients are more prone to the major modes of transmission due to lack of judgment. The investigators also discussed the possibility of HIV causing serious mental illness.
Infected individuals appear to be at a higher risk for developing depression, anxiety and/or psychotic features.
Regardless of which diagnosis led to the other, it is evident that psychiatry has much to offer in the realm of HIV. Proper education of the psychiatric patient may prevent the transmission of HIV. On the other hand, psychiatric assessment at the time of diagnosis and throughout the disease may help a nonpsychiatric patient cope with stressors associated with the illness.
In addition to schizophrenia and affective disorders, anxiety disorders have also been reported to be more prevalent in the HIV-infected population. Tsao et al. (2004) estimated the prevalence of posttraumatic stress disorder to be 10.4% in HIV-infected individuals and panic disorder to be 11.2%. In a previous study, Vitiello et al. (2003) found that 16.7% of 1,489 HIV-infected individuals were receiving anxiolytics. It is the consensus that manifestations of anxiety are seen at the time of diagnosis, during new treatment or during periods of acute illness (Goldenberg and Boyle, 2000a). Such times would be ideal for the psychiatric practitioner to become involved.
Human immunodeficiency virus-associated dementia (HAD) encompasses a broad range of both psychiatric and neurologic symptoms. One end of the spectrum presents with minor cognitive and motor disorders (MCMDs), and at the other end is the more severe AIDS dementia complex (ADC), which is a subcortical ailment occurring at the later stages of the disease (i.e., after AIDS has developed). Although studies are less clear about the actual prevalence of dementia and/or delirium, it has been estimated that up to 20% of patients with AIDS will develop ADC and that 30% to 40% of hospitalized patients with AIDS will develop delirium (Goldenberg and Boyle, 2000b).
Realizing the potential for a higher rate of psychiatric disturbances that may accompany HIV, one's attention will now be geared to potential treatment modalities. The following sections will be based on the various psychiatric ailments. Pharmacological agents and possible drug interactions will be reviewed.
Depression is the most prevalent psychiatric ailment among HIV-infected individuals and ranges from 4% to 15% (Ferrando and Wapenyi, 2002). Numerous studies have demonstrated the effectiveness of safely treating depression in HIV-infected patients (Markowitz et al., 1998; Wagner et al., 1996; Zisook et al., 1998). Careful consideration in regard to choice of pharmacological agents is warranted. Antiretrovirals such as didanosine (DDI) (Videx) and zalcitabine (or ddc) (HIVID) have the unpleasant side effect of peripheral neuropathy. A patient presenting with peripheral neuropathy and depression may warrant trial with a tricyclic antidepressant. However, in some HIV-infected patients, TCAs have disadvantages, which will be discussed later. In addition, if diarrhea results from HAART, then an anticholinergic antidepressant may be preferred over an agent with the potential of causing diarrhea (i.e., venlafaxine [Effexor]).
The potential for drug-drug interactions poses significant problems (Tseng and Foisy, 1999). Since many of the agents used in treating HIV depend on the cytochrome P450 (CYP) system, it would be wise to avoid antidepressants that have the potential of inhibiting or inducing these enzymes. The agents of most concern, due to strong inhibitory effects on several of the CYP enzymes (e.g., 2D6, 2C9/19 and 1A2), are paroxetine (Paxil), fluvoxamine (Luvox) and fluoxetine (Prozac) (Tseng and Foisy, 1999). Although case reports may not be available for all these agents, one must still accept the likelihood of an interaction. Increasing the levels of antiretroviral drugs via inhibition would obviously increase the risk of antiretroviral-associated side effects.
On the other hand, certain antiretrovirals (i.e., ritonavir [Norvir], delaviridine [Rescriptor]) also have the potential of inhibiting or inducing various isoenzymes (CYP 3A4, CYP 2D6) and therefore run the risk of exposing the patient to higher levels of various antidepressants. The actions of ritonavir are complicated and will be discussed in the next section. Nevirapine (Viramune), a non-nucleoside reverse transcriptase inhibitor, can induce the CYP system (especially CYP 3A4), which may result in lower levels of psychotropic agents. Therefore, higher levels of some antidepressants may be necessary.
It may be advantageous to utilize agents that have therapeutic levels that can easily be monitored. Treisman and colleagues (2001) rationalized the use of desipramine (Norpramin) in a 41-year-old HIV-infected female with a history of substance abuse (cocaine). They chose desipramine secondary to the availability of serum plasma levels to monitor compliance and potential interactions. In addition, desipramine offered significant improvements in the patient's sleep and appetite. This type of rationale must be employed in all HIV-infected patients. Although temptation may lead one to prescribe newer/safer antidepressants, their choice may not always be the most appropriate. On the other hand, use of TCAs may lead to both peripheral and central anticholinergic side effects, as well as orthostatic hypotension, which may be problematic in some HIV-infected patients.
Like depression, the concomitant treatment of schizophrenia and HIV should focus on potential drug interactions and/or overlapping side effects. The HIV itself may affect the basal ganglia and lead to stiffness and rigidity. When considering long-term therapy with an antipsychotic, an agent with a low chance of causing extrapyramidal side effects may be preferable (Goldenberg and Boyle, 2000a). Treatment with an atypical appears to be the best alternative, but there are other concerns. Clozapine (Clozaril) may not be the best choice given its small risk of causing agranulocytosis in an already immunocompromised patient. In addition, both clozapine and olanzapine (Zyprexa) have a higher association of weight gain, dyslipidemia and glucose dysregulation. These adverse effects are also seen with various protease inhibitors (Rana and Dudley, 1999) and may worsen the medical situation. On the other hand, if the individual is not receiving a protease inhibitor and has experienced significant weight loss, olanzapine may be a viable option given its stronger potential to cause weight gain.
Ritonavir has interesting effects on the CYP system and glucuronosyl transferases. Although this protease inhibitor has been shown to inhibit the clearance of CYP 3A4 and CYP 2D6 substrates, it induces CYP 1A2 and glucuronosyl transferase, both of which are responsible for the metabolism of olanzapine (Penzak et al., 2002). Therefore, higher doses of olanzapine may be necessary in patients receiving ritonavir therapy. On the other hand, therapy with ritonavir in combination with indinavir (Crixivan) has been shown to increase the chance of extrapyramidal symptoms and neuroleptic malignant syndrome in patients receiving risperidone (Risperdal) (Kelly et al., 2002; Lee et al., 2000). This is the result of CYP 2D6 and CYP 3A4 inhibition. Therefore, if an HIV-infected patient is receiving ritonavir in any formulation (i.e., Norvir or Kaletra [lopinavir/ritonavir]), extreme caution should be used in prescribing all antipsychotic agents.
It is also important to rule out psychosis as an adverse effect of the medications used in the treatment of HIV or its sequelae. Efavirenz (Sustiva) has been associated with vivid dreams and psychotic events (de la Garza et al., 2001; Poulsen and Lublin, 2003). It has also been associated with a 13% to 16% rate of depressive side effects. The package insert for this medication recommends dosing at bedtime. However, administering it approximately three hours before retiring may decrease the incidence of vivid dreams and hallucinations.
Ellen et al. (1999) have demonstrated that HIV-infected patients may respond better to antipsychotics than mood stabilizers in the treatment of mania. Interestingly, 17 out of 19 patients were prescribed haloperidol (Haldol), and one patient received lithium (Eskalith, Lithobid). Although they did not discuss why other mood stabilizers (i.e., divalproex [Depakote], olanzapine, risperidone) were not used, the outcomes were favorable, and they suggested that low doses of these agents may be preferred. Nevertheless, other therapeutic options must be considered.
A recent case report brought to light the possibility of severe anemia with the combination of valproic acid and zidovudine (Antoniou et al., 2004). It was suspected that valproic acid inhibited the glucuronidation of zidovudine, thereby raising levels and causing toxicity. It has also been speculated that valproic acid therapy may increase replication of the virus as well (Jennings and Romanelli, 2000).
The atypical antipsychotic agents approved for bipolar disorder (BD) (i.e., aripiprazole [Abilify], olanzapine, risperidone, quetiapine [Seroquel], ziprasidone [Geodon]) could all be used. Again, caution is warranted in those individuals who are receiving ritonavir. In addition, potential lipid, weight and glucose effects must also be considered.
Lithium offers significant advantages over the other agents in this population. It avoids hepatic metabolism and is associated with therapeutic levels, which can be used to assure compliance similar to the TCAs (Tseng and Foisy, 1999). In addition, lithium may be neuroprotective against HIV-associated cognitive effects (Everall et al., 2002). This medication should be considered as a viable agent in HIV-infected patients with BD, as well as dementia, which will be reviewed later.
Finally, one must be extremely careful with the utilization of carbamazepine (Equetro, Tegretol), which was recently approved for the treatment of BD. This medication induces the CYP system and thereby may decrease levels of prescribed antiretrovirals (Tseng and Foisy, 1999). Such actions may contribute to drug resistance (Hugen et al., 2000). Avoidance of this medication is warranted.
Coping with the diagnosis of HIV or AIDS can obviously lead to disturbing feelings of fear, panic, insomnia and various somatic complaints. Appropriate psychotherapy is useful, as in depression, but often pharmacotherapy becomes warranted. Short-acting benzodiazepines, which avoid the CYP pathway, may be preferred (Goldenberg and Boyle, 2000a), and they may be remembered by the acronym LOT (lorazepam [Ativan], oxazapam [Serax] and temazepam [Restoril]). In addition to benzodiazepines, antidepressants are useful in the context of panic disorders, social phobias and/or obsessive-compulsive disorder. Again, one must be cautious with the potential for drug-drug interactions. Buspirone (BuSpar) may be useful in treating generalized anxiety in this population, especially if the individual has a history of substance abuse. This agent may actually increase CD4 T-cell counts (Hofmann et al., 1996); however, caution should be used in the presence of ritonavir since it inhibits CYP 3A4, a major metabolic pathway for buspirone (Clay and Adams, 2003).
Delirium and Dementia
Probably the most useful intervention in treating HAD is the inclusion of antiretroviral agents with CNS permeability. These agents include didanosine, stavudine (Zerit), zidovudine, efavirenz, nevirapine and indinavir (Goldenberg and Boyle, 2000b). Although it is beyond the psychiatrist's scope to prescribe these agents, one should ensure that they have been considered and, if utilized, assess compliance.
In addition to such therapy, concomitant depression and apathy should be treated appropriately. Psychostimulants and stimulating antidepressants may be useful (Goldenberg and Boyle, 2000b). As previously discussed, lithium's potential for neuroprotection should also be considered. Its unique advantages make it an extremely viable option in treating many aspects of dementia. However, patients with underlying dementia may be more sensitive to lithium's CNS side effects and require lower doses/blood levels.
One should be careful not to prescribe highly anticholinergic agents, such as amitriptyline, to patients with HAD, as they may contribute to worsening cognition (Goldenberg and Boyle, 2000b). Acetylcholinesterase inhibitors (e.g., donepezil [Aricept], rivastigmine [Exelon], galantamine [Reminyl]), on the other hand, have a less clear role in treating HAD. Although they would appear beneficial, there are limited data supporting their use. Furthermore, these agents can increase the incidence of gastrointestinal upset and/or diarrhea seen with many of the antiretrovirals.
Delirium generally occurs rapidly and may be the result of multiple etiologies. The psychiatrist needs to rule out metabolic as well as possible medication causes. Corticosteroids, such as prednisone (Deltasone, Prednisone Intensol), are used in the initial treatment of pneumocystis carinii pneumonia. A patient being treated for pneumocystis carinii pneumonia who presents with acute mental status change may be febrile, hypoxic and/or suffering from steroid-induced psychosis. Therefore, before treating the situation with psychotropics, the clinician needs to assess the overall presentation. Pharmacological management relies on the use of antipsychotic agents. Haloperidol is generally preferred because it can be given intravenously, intramuscularly or orally (Goldenberg and Boyle, 2000b). The intramuscular preparations of olanzapine and ziprasidone may also be used, but are significantly more costly. Benzodiazepines and drugs with anticholinergic activity should be avoided in patients with delirium as they may worsen the clinical picture (Breitbart et al., 1996).
This paper has focused on comorbid psychiatric illness in individuals infected with HIV. What has not been discussed is the preventive role the psychiatrist can play in the mentally ill population. If one agrees that mental illness is a risk factor for contracting HIV, based on behavior and poor judgment, then psychiatrists must make every effort to prevent such an occurrence.
Continuous education on transmission of the disease, as well as assuring the provision of condoms for sexually active patients, is imperative. In addition, if substance abuse is unavoidable, the psychiatrist should make an effort to examine the possibility of a needle-exchange program. Many states will allow a limited amount of syringes to be purchased over the counter without a prescription.
The psychiatrist must also learn to recognize and screen for the possibility of HIV. These techniques should not only be employed for those patients presenting medically ill, but in all patients. Walkup and colleagues (2000) found that only 17% of 300 patients with schizophrenia were tested for HIV despite numerous risk factors. Obtaining a complete patient history including HIV risks is mandatory. If risks are identified, an HIV test, as well as others (i.e., hepatitis C), is warranted. Such actions have the potential of preventing further transmission.
It has been demonstrated that mental illness occurs more frequently among individuals infected with HIV. In addition, psychiatric patients are more prone to contracting HIV based on behavior and judgment deficiencies. The treatment of individuals with this comorbid presentation can be complicated and difficult. Based on these premises, one would agree that psychiatry has much to offer for the management of HIV. Whether through proper patient education or safe and effective psychopharmacology, the psychiatrist should be considered the cornerstone of the interdisciplinary team that treats patients with HIV. This article has served as a review for the psychiatric practitioner and will hopefully improve the outcomes in the world of HIV and psychiatry.
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