BETA March 1997.
by Mary Romeyn, MD
In this article, adapted from a February 1997 Grand Rounds presentation at Saint Francis Memorial Hospital in San Francisco, a San Francisco physician with a large AIDS practice speaks to medical professionals about dealing with the unique psychiatric needs of HIV positive men and women.
As with any process that imposes high levels of stress on the body over a long period of time, the spectrum of consequences of HIV infection frequently includes psychiatric manifestations. Recognizing and treating these conditions is only a beginning. The patient and doctor also must consider the potential for drug interactions between psychiatric medications and drugs used to manage HIV disease, and must adjust dosages as needed.
This article will attempt to:
Depression has been reported in 4-14% of people living with HIV. One long-term study evaluating men with HIV disease at 6-month intervals for 8 years reported that over 50% met the criteria for clinical depression at least once during that time. With intensifying depression, the risk of death was found to increase by two-thirds, independent of CD4 cell counts. Thus it makes sense to diagnose depression early, eliminate external causes, and treat this condition.
In the medical literature, depression has been associated with many medications commonly used by people with HIV disease, including AZT (Retrovir), acyclovir (Zovirax), sulfonamide antibiotics, anticonvulsants, narcotics and isoniazid (INH). However, in clinical practice, a clear association between these medications and depression is relatively infrequent. If a drug suspected of causing depression is not critical to the maintenance of health or suppression of viral load and -- if the patient and doctor both agree -- a brief trial discontinuation of the drug may be tried to see if symptoms resolve.
Depression may occur during withdrawal from androgenic steroids. A slow taper schedule may be appropriate if withdrawal from an anabolic steroid is thought to be a factor in depression.
N. Sacktor, MD and colleagues, from Johns Hopkins University School of Medicine, reported on a study of 31 HIV-infected men, 19 of whom were classified with HIV encephalopathy (brain disease). They reported 2 distinct symptom-complex subtypes. Common to both groups were a tendency toward depressed mood, frequent crying and confusion. While physical symptoms and a feeling of being overwhelmed were more common in the group with encephalopathy, the group with a CD4 cell count of greater than 200 cells/mm3 and no evidence of encephalopathy showed more classic symptoms of depression, less self-esteem and more social withdrawal than the group with encephalopathy. The researchers suggest that the difference in patterns of depression between these 2 subtypes may argue for a trial of different medication strategies in each group. A physician experienced with different strategies might explore various treatment options.
The use of recreational drugs must also be considered when depression exists. Effects of multiple substance abuse and/or withdrawal can be difficult to tease out when superimposed on a regimen of multiple therapeutic drugs and their interactions. Treatment decisions must reflect the likelihood and nature of recreational drug use and the potential for additive toxicities.
Treatment must also take into account the potential for drug interactions. The protease inhibitor ritonavir (Norvir), for instance -- by inhibiting the cytochrome P450 enzymes in the liver that process and excrete a wide variety of medications -- can increase tricyclic antidepressant (TCA) drug levels by 1.5-3 times, and increase levels of fluoxetine (Prozac) and paroxetine (Paxil), both selective serotonin reuptake inhibitor (SSRI) antidepressants, by 19% and 150%, respectively. Levels of sertraline (Zoloft) -- another SSRI -- may be increased by more than 300% in the presence of ritonavir, and probably should not be used in this setting. Because of its long half-life, fluoxetine also should be avoided with ritonavir, because high drug levels in the blood that can cause neurologic or cardiac effects decrease slowly.
When SSRI drugs are used in combination with TCA drugs, blood levels of SSRI drugs can rise even higher. Low doses and close observation of people on such regimens are appropriate.
SSRI at therapeutic doses can reduce sexual desire and delay ejaculation. At toxic levels, one may see serotonin syndrome -- tremor, agitation, hypomania (a mild degree of mania), tachycardia (rapid heart beat), vomiting, headache and even psychosis (thought disorder). TCA drugs at toxic levels can alter heart function. Sedation and confusion may also be seen. At therapeutic levels, dry mouth and drowsiness are significant side effects. When appropriate doses are used, drowsiness diminishes with regular use.
Other antidepressants include bupropion (Wellbutrin), which is contraindicated in patients with a history of seizures and in those taking ritonavir; nefazodone (Serzone), with drug levels increased by more than 3 times in the presence of ritonavir; and trazodone (Desyrel) and venlafaxine (Effexor), with levels of each drug increased by 1.5-3 times when taken with ritonavir.
Anxiety is common, especially at the time of HIV diagnosis or disease progression. Anxiety has been associated with the use of several medications, including corticosteroids, nonsteroidal anti-inflammatory drugs and sulfonamide antibiotics. Treatment is complicated by concerns about drug interactions with protease inhibitors and other drugs that use the CP450 system. Since blood levels of all benzodiazepine tranquilizers except lorazepam (Ativan), oxazepam (Serax) and temazepam (Restoril) are greatly increased in the presence of ritonavir, their use is contraindicated. Lorazepam, oxazepam and temazepam are metabolized more quickly in the presence of ritonavir, and may require increased dosage to achieve the intended effect. Because midazolam (Versed) and triazolam (Halcion) are metabolized more slowly when given with indinavir (Crixivan), dosages may need to be reduced.
Mania may be difficult to treat. The condition has been associated with the use of AZT, dapsone, androgenic steroids and corticosteroids, and may be exacerbated by the use of antidepressants. Disinhibition (leading to inappropriate behavior) and increased stressors may unmask an existing tendency toward mania. Where possible, the best approach is to treat the underlying cause.
The use of lithium requires very careful monitoring. Many drugs used to treat HIV and related conditions may impair kidney functioning and may cause lithium to concentrate in the kidneys. In addition, diarrhea and dehydration are common in HIV disease; lithium toxicity is increased in dehydrated patients. Perphenazine (Trilafon), valproic acid (Depakote) and carbamazepine (Tegretol) have been used successfully in people with HIV. Carbamazepine must be used judiciously because it may worsen bone marrow suppression caused by other HIV drugs. In addition, carbamazepine is itself a potent CP450 inducer. It can reduce blood levels of pro-tease inhibitors, thus predisposing the patient to the development of drug resistance.
Delirium (confusion) has an underlying cause. The condition may result from changes in drug levels due to drug interactions. It can also be seen with corticosteroid (e.g., prednisone), opiate (e.g., codeine) or TCA drug use. While delirium has been associated in clinical studies with acyclovir and the class of antibiotics called quinolones, this is rarely seen clinical practice.
Medical causes such as electrolyte imbalance, abnormal blood sugar levels, or reduced oxygen or increased carbon dioxide in the blood often underlie delirium. Where possible, one should treat the problem by treating its cause. If antipsychotic drugs are needed, high potency neuroleptics such as haloperidol (Haldol) should be used only briefly, as their side effects are reportedly more common in people with HIV.
Psychosis is characterized by the presence of auditory and visual hallucinations, delusions or other related disorders. When psychosis is present, it is important to look for all possible causes. Drug interactions (such as those noted elsewhere in this article) and the possibility of new central nervous system disease (e.g., a tumor) should be considered.
Because an increased tendency for neuroleptic malignant syndrome (a life-threatening condition characterized by confusion, high blood pressure, fever and involuntary muscle movements) and other motor abnormalities have been reported with high potency neuroleptics, these drugs must be used judiciously. Chlorpromazine (Thorazine), perphenazine (Trilafon), thioridazine (Mellaril), haloperidol and risperidone (Risperdal) are all increased 1.5-3 times in the presence of ritonavir. Clozapine (Clozaril) and pimozide (Orap) are contraindicated with ritonavir.
Manifestations of dementia, or HIV encephalopathy (also known as AIDS dementia complex or HIV-associated dementia) usually appear late in the course of HIV disease and have not always been found to be related to levels of viral load in the cerebrospinal fluid. Infection of the central nervous system is necessary, but not sufficient, to cause encephalopathy. Immune activation, the body's response to infection, is also required. (See AIDS Dementia Complex, BETA, December 1996.)
Macrophage activation plays an important causal role in dementia. When activated, macrophages pump out a variety of factors which damage neurons and impair their function. These factors include proinflammatory cytokines, platelet activating factor, nitric oxide and free radicals. Immune system activity directed against the invading virus damages cells in the brain. In addition, macrophage activation results in the release of more viral particles, initiating new cycles of infection.
Dementia is treatable. Optimal treatment requires early recognition while the symptoms are still reversible, vigorous treatment with high-dose antiretrovirals that cross the blood-brain barrier and consideration of neuroprotective agents and agents that block immune activation.
AZT is the nucleoside analog drug with the best central nervous system penetration. The dual combinations of AZT plus 3TC and d4T plus 3TC have been shown to decrease HIV RNA levels in cerebrospinal fluid to undetectable levels. Nonnucleoside reverse transcriptase inhibitors (NNRTI) are also powerful drugs. Nevirapine (Viramune) crosses the blood-brain barrier rapidly, in high concentration. Delavirdine (Rescriptor) concentrates in brain tissue at a level 4-5 times higher than that found in plasma. When using these NNRTI, it is important to consider their effects on protease inhibitor concentrations. Nevirapine appears to lower blood levels of protease inhibitors, while delavirdine appears to increase them. However, no change in dosage is necessary when either nevirapine or delavirdine is combined with either ritonavir or saquinavir. Selegiline (Deprenyl or Eldepryl), a monoamine oxidase inhibitor used to treat Parkinson's disease, has been reported to have efficacy for HIV-associated dementia.
Use of psychiatric medications in people with HIV disease is complex and demanding. Issues of potential drug interactions and the need for careful planning and coordination of therapeutic efforts make providing psychiatric care and stabilization difficult.
Mary Romeyn, MD, is Medical Director of the Andrew Ziegler Foundation. She is author of Nutrition and HIV: A New Model for Treatment and is a member of the San Francisco AIDS Foundation's Scientific Advisory Committee.
The author gratefully acknowledges the assistance and review of Evelyn Rose, PhD, clinical pharmacologist at Saint Francis Memorial Hospital in San Francisco.
Power C and others. HIVdementia scale: a rapid screening test. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 8:273-278. 1995.
Sacktor N and others. Depression subtypes in HIV infection. Fourth Conference on Retroviruses and Opportunistic Infections. January 1997. Abstract 348.
Capaldini L. Psychiatric complications and psychosocial issues in HIV disease. AIDSfile 8:2. June 1994.
Bowers M. AIDS dementia complex. BETA:11-15. December 1996.
This information is designed to support, not replace, the relationship that exists between you and your doctor.