psychopharmacological interventions in hiv infections

CZinicians working with HN-injected patients must be uwure of special psychopharmacological intetventions.

Psychopharmacological Interventions in HIV Infections Francisco Femandez

As the epidemic of human immunodeficiency virus (HIV) infection contin- ues to proliferate, we are coming to realize the magnitude of its complications and ramifications. One area in which serious investigation has begun is the neuropsychiatric effects of HIV-related disease. The virus has been discovered to act directly on the central nervous system (CNS) or peripheral nervous system (PNS) of the infected individual (Levy and Femandez, forthcoming; for further discussion, see Chapter Three). The disability caused by the resultant neuropsychiatric and neurological disturbance compounds the many varied psychosocial problems faced by the patient at the time of physical, emotional, and social crisis.

A positive test result for antibodies to HIV is generally a catastrophic event for any person. Common fears include the fear of losing one's social support, one's financial resources, one's physical or mental functioning, and, ultimately, one's life. The stress associated with these fears usually provokes very painful reactions within the infected individual. While a certain level of reactive distress would be considered normal, distress that becomes so pronounced or severe as to impair one's coping capacity and prevent adequate daily functioning requires prompt psychiatric assessment and intervention. It is important to understand the factors particular to HIV-infected patients, so that we can improve their prognosis for the highest possible quality of life. For example, patients with cancer and serious bums are subject to the same types of fears and stress reactions that HIV patients are, but the intensity of the psychological distress for H N patients is often significantly more severe (Forstein, 1984). By isolating the medical, psychological, and social factors that may be responsible for

NEW DlRECnONS FOR MENTAL HEALTH SEUWCES. no. 48. Winter 1990 @Josscy-azrS Inc.. Publishers 43

44 PSYCHIATRJC ASPECTS OF AIDS AND HIV INFECTION

this pertinent disparity, we may be better able to foresee and forestall the often overwhelming dysfunctional disability for most HIV patients, which results from the particular neuropsychiatric and psychosocial dimensions of this most complex viral syndrome. This chapter describes some of the most common psychiatric complications associated with HIV-spectrum disease (exclusive of dementia) and discusses the associated treatment of these complications, specifically with psychopharmacological agents.

Depression As might be expected, depression is extremely common among HIV-infected individuals. In fact, the incidence of depression in this group appears to be higher (Atkinson and others, 1988) than in any group of comparably ill patients with different medical diagnoses. Unfortunately, depression is a confusing concept because the term has been loosely used to describe a wide spectrum of symptoms and behaviors, ranging from mild, transient symptoms to mood disturbances and organic mood disorders. Nevertheless, the fact that depression is diagnosed, according to a wide range of criteria, in HIV patients proportionately more often than in comparable groups indi- cates that there are essential important factors specific to HIV-related depression, factors that must be assessed and addressed.

Several studies have indicated that depression in all medically ill patients is both underdiagnosed and undertreated (Rfkin and others, 1985; Cohen-Cole and Stoudemire, 1987). This diagnosis is particularly difficult with HIV patients, who physically manifest many of the usual diagnostic indicators of depression, such as anorexia, fatigue, and weight loss. These somatic symptoms may be common to both HIV systemic disease and depression, and the possibility exists that one may mask the other. There- fore, an all-inclusive approach is advisable in diagnosing depression in an HIV-infected individual, so that all symptoms are included in the initial assessment, regardless of any possible, probable, or unknown etiology. This inclusive approach parallels DSM-III-R criteria by first considering all sus- pected organic components of etiology. According to this recommendation, the individual clinician would be able to factor out organic components that would be reversible with proper treatment, such as CNS toxoplasmosis or cryptococcoses, or to rule out irreversible neurodegenerative processes, such as AIDS dementia complex (ADC) or progressive multifocal leukoence- phalopathy. In addition, the clinician should consider as pertinent the development of any psychological symptoms in the presence of endocri- nopathies, diarrhea, gastroparesis, gastritis, metabolic abnormalities, ane- mia, myopathy, neuropathy, or pain, since all these conditions have an influential bearing on mood and personality. Any or all of these physical symptoms should be treated, and the effects of treatment should be evalu- ated as reassessment of the diagnosis of depression is made. In the absence

PSYCHOPHARMACOLOGICAL INTERVENTIONS 45

of final conclusive evidence for the diagnosis of depression, the clinician should consider any previous personal or family history of mood disturbance on the part of the HIV patient as a positive indicator of depression for that patient.

Another important component to be considered in evaluating the diagnosis of depression in an HIV patient is the presence or absence of active or passive suicidal ideation (Marzuk and others, 1988). It may be tempting to assume that thoughts of suicide would seem almost understandable in a person facing a fatal prognosis, with its existential devastation; nevertheless, it is important to recall that terminally ill patients who have completed suicide have shown evidence either of being clinically depressed or of having stress-related impaired judgment (see, for example, Brown and others, 1986). Because of the neurovirulence and complicated psychosocial implications of HIV infection, the clinician should respond aggressively to the presence of suicidal ideation by providing a comprehensive and realis- tic assessment of the psychosocial situation and of the motivation for completing the suicide, along with a comprehensive diagnostic assessment to rule out a treatable mental disorder (depression, psychosis, and so on). Finally, the clinician should undertake a comprehensive neurobehavioral evaluation to assess organicity (delirium, dementia, and so on) or CNS toxicity from either chemotherapy or substance abuse (Frierson and Lipp- thann, 1988; Hall and Stevens, 1988).

The effective treatment of depression among HIV patients remains dependent, to a certain extent, on the clinician’s preference, clinical judgment, and experience. In this situation, because of the varied circumstances and variable etiologies for the depression, there is no specific drug of choice. As a general rule, however, it is best to be guided by an analysis of possible side effects in choosing from among equally effective antidepressant agents (Richelson, 1988). For example, the more anticholinergic antidepressants (such as amitriptyline, doxepin, protriptyline) should be avoided in cognitively impaired patients or patients with AIDS dementia, given these agents’ potential to unmask or aggravate cognitive difficulties and, in extreme cases, to precipitate a delirium. These anticholinergic agents can also cause excessive drying of mucous membranes, which, theoretically, can contribute to the development of candidiasis.

For depressed patients who are HIV-seropositive but are asymptomatic of AIDS, pharmacotherapy is often begun with tricyclic antidepressants (Fer- nandez, 1988b; Fernandez, Levy, and Mansell, 1989b). Like cancer patients (Massie and Lesko, 1989), depressed HIV patients tend to show therapeutic responses to tricyclic antidepressants at much lower doses (often only 25 to 100 mg. a day) than are usually required in nonmedically ill depressed patients. Thus, tricyclic antidepressants should be started at the lowest possible dose, especially in patients who are debilitated, beginning with 10 to 25 mg. at bedtime, with the dose increasing by 10 to 25 mg. every one to

46 PSYCHWNC ASPECTS OF AIDS AND HIV INFECTION

two days until amelioration or full remission of the syndrome is achieved. Once an adequate therapeutic effect has been achieved, patients are usually maintained on full therapeutic doses of the antidepressant for three to four months, after which time the dose is gradually lowered to a maintenance dose (usually half of the full dose to achieve remission) for an additional three months. Six to eight months from the time of remission, the agent may be slowly discontinued over two to three weeks.

The choice of an antidepressant depends largely on clinical experience and the clinician’s preference, but certain clinical guidelines may be helpful in selecting an appropriate agent. For example, in patients whose target symptoms include restlessness, agitation, and insomnia, sedating side effects may be beneficial, in which case trazodone, amitriptyline, trimipramine, imipramine, or doxepin may be chosen. In other situations, where fatigue and decreased interest are prominent symptoms, noradrenergic agents, such as protriptyline or desipramine, may be selected for their relative stimulating properties.

If a trial of antidepressants results in an ineffective therapeutic response or has precipitated intolerable side effects, one of the heterocyclic antidepressants, specifically fluoxetine or bupropion, should be considered. Moreover, if the patient progresses to a more advanced stage of HIV disease-specifically, AIDS-one must be ready to substitute for these antidepressants in order to limit side effects. The starting dose and daily therapeutic dosage of these agents also vary according to the compound used. Early clinical reports suggest that both fluoxetine (Barlow, 1989) and bupropion (Golden and others, 1988) may be useful for the HIV patient because of their activating effects and limited side effects. We have been successful with low doses of fluoxetine ( 5 mg. daily) for patients receiving concomitant treatment with AZT. In our experience, bupropion seems supe- rior to fluoxetine in activating withdrawn, anhedonic patients, whether an organic cognitive impairment is present or not (Femandez, 1990). Never- theless, the potential risk for seizures in neurologically compromised HIV patients is worrisome, and doses should be limited to 300 mg. per day or less, to avoid further complications (Femandez, 1990).

The use of a monoamine oxidase inhibitor is generally recommended only when a patient has responded well to that agent for treatment of a depression, before becoming HIV-infected (Femandez, 1988a). Even in that situation, however, careful consideration should be given to the associated dietary restriction on tyramine-containing foods. Care must also be taken in combining monamine oxidase inhibitors with AZT because AZT has been reported to have catecholamine-o-methyl-transferase-inhibiting effects (J. Reinhard, personal communication, 1986). In our clinical experience, therefore, the monoamine oxidase inhibitors have limited usefulness in the treatment of depressed, symptomatic HIV patients.

The psychostimulants (methylphenidate, dextroamphetamine, and


pemoline) may be prescribed for depressed HIV patients when the tricyclic antidepressants are relatively contraindicated or have proved ineffective, or when a patient has cognitive impairment (Femandez and others, 1988; Femandez, Levy, and Galiui, 1988; Femandez, Levy, Holmes, and Ware, 1988; Holmes, Femandez, and Levy, 1989). Methylphenidate, in particular, is effective in depressed H N patients who are symptomatic from their infection because it is useful in remitting the major signs and symptoms of depression, without serious adverse effects. Psychomotor activation, appe- tite stimulation, and qualitative as well as quantitative improvement on tests of relevant neuropsychological functions and affect can occur within hours. Psychostimulant treatment with methylphenidate can be initiated with 5 to 10 mg. (or the equivalent dose with the other stimulants) by mouth, feeding tube, or suppository. The dose is gradually adjusted upward until maximum clinical response is achieved. Methylphenidate has also achieved marked improvement in affective and cognitive disturbances among patients with ADC, organic personality disorders, and organic affective disorders. Psychostimulants are effective in treating various depressive signs and symptoms of different etiologies and can be continued safely for several weeks or months after the patient becomes asymptomatic.

Lithium carbonate is considered appropriate therapy for H N patients who were being treated with it for affective disorders before the diagnosis of H N disease. While a patient may be maintained on it throughout the course of the disease, dose reduction may become necessary as the disease progresses. Lithium carbonate should be prescribed cautiously for any patient with cryptosporidial infection or any other form of severe diarrhea or fluid loss. The greatest benefit of lithium carbonate may be seen in patients who are receiving AZT or immune-restorative agents and who may be experiencing confusional episodes (AIDS Task Force, 1988) or mania, since lithium carbonate may be useful in managing the development of secondary mania due to AZT (Maxwell, Scheftner, Kessler, and Busch, 1988; ODowd and McKegney, 1988), or, in my own experience, to DHPG.

Alprazolam, a triazelobenzodiazepine, has been shown to be an effective antidepressant and anxiolytic (Warner, Peabody, Whiteford, and Hol- lister, 1988). Therefore, it should be considered for HIV patients who may have mixed symptoms of anxiety and depression and may not be able to tolerate traditional antidepressant agents or psychostimulants. The starting dose should be 0.25 mg. orally three or four times a day, increased to a dose that usually ranges between 4 and 10 mg. daily.

Anxiety

Anxiety is certainly omnipresent among HIV-infected individuals. At some point in the course of the disease, virtually every patient will experience some degree of anxiety. The associated stress of antibody testing, diagnosis,

48 PSYCHIATRIC ASPEC~S OF AIDS AND HIV INFECTION

medical procedures, prognosis, and progression of the disease may all evoke episodes of acute anxiety (Forstein, 1984; Nichols, 1983; Holland and Tross, 1985; Nichols, 1985; Sonnex, Petherick, Adler, and Miller, 1987; Fishman and others, 1989; Perry and others, 1989). Of course, patients who were subject to chronic anxiety before the diagnosis of HIV disease will probably experience increased severe anxiety during their medical treatment, as will individuals who feel that they have a low level of inter- personal support (Fishman and others, 1989). Anxiety symptoms may also be features of withdrawal from narcotics, alcohol, benzodiazepines, and barbiturates. Because patients who abuse these substances generally under- report their substance intake to their clinicians, the physician must con- iider the possibility of a withdrawal reaction in any HIV patient who develops otherwise unexplained anxiety symptoms during the early days of a hospitalization. Alternatively, anxiety may be a feature of intoxication from stimulant agents or cocaine. Atkinson and others (1988) report that a group of homosexual men suffered more frequently from anxiety disorders than did a sociodemographically matched group of heterosexual men. This finding has relevance for clinicians dealing with HIV-associated anxiety, because of the relatively large number of homosexual men affected by HIV infection who may require treatment.

Anxiety that is limited to defined periods of transition or crisis may be alleviated by comforting reassurance and support from the patient's loved ones. When the anxiety is intense and extended, however, anxiolytic agents are often necessary and helpful in reducing these intolerable levels of stress-distress symptomatology. A patient who has symptoms of auto- nomic hyperactivity, or whose fears and anxiety are unmanageable with traditional support measures, may benefit from anxiolytic agents. Anxioly- tics may also be effective for patients whose anxiety may be secondary to acute pain or to acute or chronic respiratory distress. Anxiolytics may be particularly effective in the intensive care unit, where anxiety may inhibit the patient's being weaned from a respirator. Anxiety that accompanies acute pain is best treated with effective analgesia; anxiety that accompanies respiratory distress is usually relieved by improved oxygenation and low doses of benzodiazepines. Alternative agents for those whose anxiety inhib- its weaning from a respirator include beta blockers, antihistamines, and low-potency neuroleptics.

The benzodiazepines are typically the anxiolytics of choice for acute or chronic anxiety states that are not extraordinarily severe. All the benzodiazepines are equally effective agents, distinguished only by their elimination half- lives and their costs. Benzodiazepines can be divided into two groups, the long-acting and the short-acting agents. Long-acting benzodiazepines have longer half-lives because they are oxidized in the liver through multiple intermediate steps and have multiple active metabolites. The active metabolites often have even longer half-lives than their parent compounds and are responsible for most of the treatment-related side effects attributed to these agents.


The short-acting benzodiazepines are metabolized more simply and have a briefer duration of action. They generally do not have active metabolites, and this feature makes them safer for use in HIV-infected patients. They are particularly useful in treating HIV-infected patients who are cognitively impaired (Femandez, 1988a). Their short half-lives make them ideal for individuals whose anxiety is acute and limited to particular situations, such as imme- diately before or during diagnostic or therapeutic procedures. Treatment with the benzodiazepines should be brief, usually for two to three weeks, because guidelines for long-term treatment are not firmly established. Nevertheless, virtually no risk for abuse has been noted in this population.

Buspirone is a nonbenzodiazepine anxiolytic that exerts its own anxiolytic effect, with a relative lack of sedation and limited potential for dependence or abuse (Kastenholz and Crismon, 1984). It must be admin- istered on a fixed, time-contingent schedule to achieve an optimal therapeutic response, usually within the first two weeks of treatment. Buspirone is not useful in the management of acute or situational anxiety, such as preprocedurai jitters, simple phobias, or stress-related symptomatology, because the clinical response time of most patients ranges from a few days up to about two weeks. Reliable guidelines for its use have not been established, but limited clinical experience has noted some treatment-related dyskinesias (Straws, 1988) and myoclonus (Ritchie, Bridenbaugh, and Jab- ban, 1983) associated with the use of buspirone, findings that slightly dampen enthusiasm for its promise as a wide-ranging drug of choice for the treatment of anxiety, particularly in HIV-infected patients who are either cognitively or neurologically impaired.

Symptoms of anxiety and insomnia that may result from treatment with AZT or steroids are often relieved with short- to intermediate-acting benzodiazepines, such as lorazepam, alprazolam, and oxazepam (Fernan- dez, 1988a; Femandez, Levy, and Mansell, 1989a.

Anxiety severe enough to bring the patient to the point of irrational panic is better treated with neuroleptics. If used with caution, to avoid extrapyramidal side effects, the neuroleptics may help attenuate the anxiety, without further compromise of the patient’s coping capacity. Anxiety or restlessness may also appear in patients who are developing encephalopathy or who are in the early stages of ADC. In these circumstances, low doses of neuroleptics are favored over benzodiazepines, which may have a disinhibiting effect. Once again, however, care should be taken in treating individuals who show advanced HIV disease; they may be at increased risk for extrapyramidal symptoms (Breitbart, Marotta, and Call, 1988; Fernan- dez, Levy, and Mansell, 1989a).

Delirium Of all the organic mental disorders (OMDs), delirium is the most prevalent and is frequently left undiagnosed (Femandez, Levy, and Mansell, 1989a).

50 PSYCHIATRIC ASPECTS OF AIDS AND HN INFECTION

Detection of an OMD is clinically important because of its possible reversi- bility and the consequently diminished morbidity and mortality.

Delirium reflects diffuse cerebral cellular metabolic dysfunction (Lipowski, 1987). There is often a prodromal phase, during which the patient complains of restlessness, irritability, depression, difficulty in think- ing, anxiety, or insomnia interspersed with short periods of sleep and vivid nightmares. Further psychiatric complications may be avoided if this prodromal phase serves as the catalyst to a search for the cause of the delirious process. A brief mental-status examination during the prodromal phase should focus on arousal, attention, short-term memory, and orientation. A grossly normal mental-status examination is not unusual, however, because delirium is characterized by the clinical variability of its signs and symptoms, especially diurnal variations, with symptoms growing worse at night than during the day. Abnormal involuntary movements, such as tremor, floccillation, multifocal myoclonus, and asterixis, are also charac- teristic of delirium.

There are many possible causes of delirium in HIV patients (Femandez, 1988a; Femandez, Holmes, Levy, and Ruiz, 1989; Femandez, Levy, and Mansell, 1989a, 1989b), but certain frequent causes are life-threatening or may bring permanent brain damage. Therefore, delirium requires prompt diagnosis and treatment. Common causes include such urgent situations as Wemicke’s encephalopathy, hypoxemia, hyperglycemia, hypoglycemia, hemodynamic instability with cerebral hypoprofusion, hypoperfusion, central nervous system infections, metabolic dysfunctions, and electrolyte disturbances. The differential diagnosis of delirium in HIV patients should include specific offending etiologies, such as herpes and toxoplasma gondii encephalitis, cryptococcal meningitis, space-occupying lesions from cerebral tumors (either lymphoma or Kaposi’s sarcoma), progressive multileukoence- phalopathy, and neurotoxicities from various antiviral and immunorestora- tive agents. The treatment of delirium in HIV-infected patients is essentially conservative. Now, however, the use of high-potency neuroleptics has found increasing acceptance that is based on their safety and efficacy in trials during the past fifteen years (Ayd, 1978; Tesar, Murray, and Cassem, 1985; Adams, Femandez, and Andersson, 1986; Adams, 1988). Haloperidol was first used orally and intramuscularly, without any serious adverse effects, and investigators have since documented the safety and efficacy of intravenous haloperidol, either alone or in combination with lorazepam and/or hydromorphone, for agitated delirious patients (Tesar, Murray, and Cassem, 1985; Adams, Femandez, and Andersson, 1986; Adams, 1988). Delirious patients often respond well to combination chemotherapy with intravenous haloperidol and intravenous lorazepam (Femandez, Levy, and Mansell, 1989a). On occasion, a continuous infusion of haloperidol may be required to achieve full control (Fernandez, Holmes, Adams, and Kavanaugh, 1988b). The ideal dose of any therapeutic regimen with intravenous haloperidol,

PSYCHOPHARMACOLOGICAL INTERVENTIONS 5 1

either alone or in combination with other agents, is the smallest dose that accomplishes maximum clinical effects. Nevertheless, high initial doses of these medications may be indicated in situations where effective and imme- diate control of severe agitation is essential to the well-being of the individual, other patients, and staff. Rapid tranquilization with these agents may be vital to the swift attenuation of behavioral disturbances and cognitive or affective dysfunctions, and such treatment will aid in decreasing morbidity and mortality. Reports must be heeded that cognitively impaired patients actually do have higher fatality rates than cognitively intact patients do (Knights and Folstein, 1977; Guze and Daengsurisi, 1967).

Behavioral and environmental interventions with delirious patients may often increase the effectiveness of pharmacotherapeutics by reducing dis- orientation and overstimulation and minimizing the external agitation of patients (Fernandez, 1988a). Physical restraint of the patient may be necessary in cases of impulsivity or when mental-status changes jeopardize medical treatment and safety.

Conclusion

The psychiatric complications of HIV infection have established themselves as a two-edged sword against patients’ psychological integrity. One aspect concerns the varying stress-distress-anxiety-depression-spectrum disorders. The other concerns the potential of HIV infection, or its treatment, to induce severe organic mental disorders that masquerade as functional psychiatric disorders. Prompt adjuvant treatment of these conditions, per- haps with innovative measures, is warranted to optimize the patient’s com- fort and quality of life.

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Francisco Fernandez is associate professor of psychiaQ in the Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, and chief of the Psychiatric Consultation Service at St. Luke’s Episcopal Hospital.

psychopharmacological interventions in hiv infections

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