Human immunodeficiency virus (HIV)-related psychiatric complications pose a unique challenge to the practicing clinician.1 Analogous to the myriad of presentations reported with neurosyphilis, HIV infection can produce a variety of medical and psychological complaints. In addition, patients who are affected often have severe associated psychosocial stressors as well as numerous neuropsychological manifestations, which in combination can complicate any potential intervention. In this context, one study found that AIDS patients with concurrent psychiatric disorders who were hospitalized for medical reasons had significantly longer average lengths of stay than their counterparts without a diagnosable psychiatric disorder.2
From another perspective, mentally ill patients who have tested positive can pose some difficult management issues, particularly when they require hospitalization.3 For example, simply testing for the AIDS antibody is fraught with controversy, including such ethical and legal questions as:
* Who should be tested?
* When and to whom should the results be disclosed?
* What is the best way to balance a patient's right to privacy versus a "duty to warn"?4
Given this background, the article will address the issue of drug treatment for HIVinfected patients who are suffering from comorbid psychiatric conditions. I would note, however, the virtual absence of any controlled trials to help guide the therapeutic decision-making process.
HIV INFECTION AND COMORBID PSYCHIATRIC DISORDERS
While HIV-infected patients can be asymptomatic for indefinite lengths of time, acquired immunodeficiency syndrome (AIDS) and AIDSrelated complex (ARC) are characterized by weight loss, chronic fatigue, fevers, night sweats, oral leukoplakia, oral candidiasis, and generalized lymphadenopathy.5 Affected patients also show evidence of central nervous system (CNS) compromise (primarily subcortical neuropathology), as well as the betterknown lymphotropic features (Table). Postmortem studies on patients who suffered from AIDS have found that neuropathology abnormalities occur in about 80%. 6 These abnormalities have included toxoplasmosis, fungal infections, viral infections, vascular lesions, and neoplasms. In the central nervous system, tumors include primary and secondary lymphomas as well as the rare Kaposi's sarcoma. It is also thought that the HIV retrovirus itself may be encephalopathic.6
Up to 70% of these patients will have clinically apparent, but often subtle, mental changes during the course of their disease. Often, neuropsychological impairment is the first symptom of HIV-related disorders. Early studies have found that among HIV outpatients, 67% manifest adjustment disorder with mixed emotional features, and 80% of inpatients suffer from an organic mental disorder. Indeed, a recent study by the World Health Organization suggests that the significance of the psychopathological complications of symptomatic HIV-I infection may have been underestimated by earlier studies in more stable patient samples.7
An increasing number of patients with a concurrent psychiatric disorder and HIV infection are in need of intervention. Unfortunately, relative to the general population, chronic psychiatric patients typically have inadequate information about HIV and AIDS. Further, they are more likely to engage in lifestyles that substantially increase their risk of contracting this disease. Such factors include sexual impulsivity, transient and often dysfunctional social relationships, more frequent risk-taking behavior, and poor judgment.8 For example, DiClemente and Ponton recently reported that adolescents in psychiatric facilities engaged in a very high rate of sexual and drug-related behaviors that increased the risk for contracting HIV-related disorders.9
Etiology of Neuropsychological Disorders in Patients With HIV Infection
As noted earlier, while the most common diagnosis given to these patients is adjustment disorder with mixed emotional features, one must always be cognizant of the potential for an underlying but as yet unrecognized organic process. The common neuropsychiatrie complications can be divided into four major categories:
* AIDS-related dementia complex (ADC)
* Delirium and organic psychosis
* Mood disorders
* Anxiety states10,11
Often, these conditions may coexist, making diagnosis and treatment planning exceedingly complicated.
General nonpharmacological therapeutic approaches consist of supportive psychotherapy, psychoeducation, family therapy, mobilization of social support systems, and follow-up neuropsychological testing.4 Also, a growing number of AIDS-phobic individuals often benefit from empathie, informed reassurance, perhaps avoiding the need for HIV antibody testing or more intensive treatment. When informed that they have tested HIV positive, many patients will initially react to this knowledge with anger, depression, and suicidal thoughts.5 This may be further complicated by the potential for impaired judgment secondary to cognitive disruption and drug-induced adverse drug reactions (ADRs) (e.g., delirium) when medicating these sensitized individuals.
An important related problem is the trend toward demedicalization of state mental health facilities. Given a host of clinical and economic realities, many HIV-infected patients can only be served by such institutions.12 Their complicated psychiatric and medical presentations, however, require a high level of clinical sophistication, particularly in recognizing and managing their physical comorbidities.13'14 Indeed, an increasing number of patients suffer from a "triple" diagnosis (i.e., a psychiatric disorder with comorbid substance abuse and HIV-positive status).15
PSYCHOPHARMACOTHERAPY IN HIV-INFECTED PATIENTS
Because these patients may be exquisitely sensitive to the effects of medication, the general principle is to always start with the lowest feasible dose and to increase the medication only when necessary, and then very slowly16 The route of administration may also be problematic, because some patients have very poor oral absorption and medications may not be adequately assimilated. In more advanced stages of illness, parenteral administration may often be a problem due to decreased muscle mass, thrombocytopenia, and difficulty in finding veins.
Zidovudine (AZT) is the first agent approved by the Food and Drug Administration for the treatment of HIV infection, and there is also some evidence that it may partially reverse the cognitive disruption associated with AIDS dementia complex.17»18 This agent, however, may also cause CNS complications, such as headache, insomnia, and restlessness. It can also induce severe anemia, leading to the need for transfusions or discontinuance.
Some authors have also reported dramatic responses with psychostimulants, whether depression was present or not.19 In seven patients with AIDS-related cognitive and emotional deficits, Angrist and colleagues found three who had marked functional improvement and five who became more spontaneous, reactive, and animated after treatment with methylphenidate or dextroamphetamine.20 While these authors consider AZT the primary drug intervention, they believe CNS stimulants may help some who do not tolerate this agent or have reached a therapeutic plateau.
In cases of overt psychosis or delirium, pharmacotherapy using a moderately potent conventional neuroleptic with limited anticholinergic side effects is preferable. Thus, in those manifesting psychotic symptoms who have difficulty with the extrapyramidal side effects associated with the higher potency agents, and/or the anticholinergic complication with lower potency agents, loxapine or molindone may be better choices. These drugs may also be preferable in patients prone to seizures. In situations characterized by agitation, Gilmer and Bush have recommended lorazepam in small doses (0.5 mg) given intravenously by slow push or intramuscularly.1
Higher potency conventional neuroleptics should be avoided because of their tendency to produce unusually severe extrapyramidal side effects or neuroleptic malignant syndrome.21'22 This may be due in part to underlying damage in the basal ganglia, secondary to HIV-induced changes. Alternatively, IM or IV microdoses of haloperidol (i.e., 0.5 mg bid) may be helpful while minimizing the chances for a more severe extrapyramidal reaction.23
The recent introduction of the novel antipsychotic risperidone may be an important treatment option for this population. This agent may be particularly helpful in managing psychotic symptoms while avoiding some of the more troublesome ADRs experienced with conventional neuroleptics on the one hand and clozapine on the other.24 Because hypotension can be a problem, however, lower doses (i.e., 1 to 2 mg/day) should be given an adequate trial before attempting an escalation.
There are also some commonly used drugs that may induce organic syndromes with psychosis in these patients. For example, medications with anticholinergic properties such as antiparkinsonian agents (e.g., benztropine), tricyclic antidepressants (e.g., Imipramine), certain antipsychotics (e.g., chlorpromazine, clozapine), certain antiemetics (e.g., prochlorperazine), and antihistamines (e.g., diphenhydramine) may all induce a delirium characterized by visual and/or tactile hallucinations, confusion, and agitation. Treatment initially involves discontinuation of the offending agent and waiting for the symptoms to subside.
If an antiparkinsonian agent is needed to counteract neuroleptic-induced side effects, amantadine may be preferable to benztropine. The dose is usually 50 mg, twice a day, with a gradual increase to 100 mg twice daily, if necessary.
Mood disturbances can range from mild adjustment phenomena to a major episode with psychotic features.
Depression. Depression in this group can be categorized as
* reactive depressive syndromes, including adjustment disorders;
* concomitant major depressive disorders, either preexisting or recently identified; and
* organic depressive syndromes.25,26
One problem in making the diagnosis of depression in HIV- or AIDS-related disorders is the lack of specificity of the typical neurovegetative signs and symptoms, because fatigue, insomnia, anorexia, and weight loss are very common in both conditions.
Reactive depression secondary to knowledge of seropositivity or the onset of serious physical symptoms is best managed by supportive therapy and, only if necessary, antidepressants (ADs). While there is scanty information on the use of the more recent generation of heterocyclic antidepressants, monoamine oxidase inhibitors, or bupropion in these patients, the treatment strategy of choice is an agent with low anticholinergic potency started more slowly and maintained at a lower level than in nonAIDS patients. In this context, the selective serotonin reuptake inhibitors (SSRIs), venlafaxine, or nefazodone may be reasonable alternatives to earlier generation ADs due to their less problematic side effect profiles.27 The propensity to increase activity, the lack of sedation, gastrointestinal symptoms, and alterations in blood pressure are potential complications, however. Given AIDS-induced altered metabolism, therapeutic drug monitoring may be helpful in establishing an effective, nontoxic dose.
It is important to note the growing recognition that psychostimulants may be helpful in HIV- or AIDS-related mood syndromes. Both methylphenidate, 10 to 20 mg/day (up to 40 mg/day) and dextroamphetamine, 5 to 15 mg/day (up to 60 mg/day), have been helpful in patients with mild depression who also show symptoms of social withdrawal, fatigue, and apathy as well as mild cognitive impairment.20 At times, the combination of an antidepressant in low doses plus a psychostimulant may be more effective and less likely to induce adverse CNS effects.
Suicide is almost always an issue when a patient is severely depressed, and many with an HIV-related disorder will consider this option at one time or another during the course of their illness.28 Indeed, the relative risk for suicide in men with AIDS ages 20 to 59 years has been estimated to be 36 times that of their counterparts without AIDS and 66 times that of the general population.29 A more recent study, however, found that patients with AIDS had a lower frequency of suicidality than HIV-positive nonAIDS patients.30 One possible explanation offered by the authors of this study is an increased denial secondary to organic factors, which are more prevalent in AIDS.
The potential for suicide may increase, however, as the physical symptoms accelerate, in part due to the patients' fears that they will not be able to act on these thoughts when their debilitation becomes severe.30 ECT may be a treatment option in more emergent situations.31 Developing a good rapport early in the course of care is very important if the suicidal desire is to be diminished through counseling or psychotherapy.
Mania. While mania in AIDS patients may be relatively uncommon, such episodes can pose a serious hazard that requires rapid control.32 Gilmer and Bush reported on one patient who developed manic symptoms associated with AZT therapy whose affective symptoms remitted when the drug was discontinued, only to return when it was reintroduced.1 In two other patients, they were able to continue AZT when lithium was added to control manic symptoms. Haloperidol (0.5 to 5 mg IV) may be an effective strategy, in part because this route of administration may be less likely than oral doses to induce acute EPS.
Halman et al conducted a retrospective chart review on 11 patients who were HIV positive and presented with an acute manic episode.33 While the six patients with abnormal magnetic resonance imaging (MRI) findings demonstrated intolerance to standard drug treatment (i.e., lithium, conventional neuroleptics), all benefited from a trial with an anticonvulsant (e.g., divalproex sodium, carbamazepine, clonazepam).
The recent introduction of risperidone has spawned a series of case reports regarding its use for patients with severe mania, usually complicated by psychotic symptoms. For example, Singh and Catalan found this agent helpful in four male AIDS patients who were also experiencing a manic phase of their schizoaffective disorder.34 Notably, low doses (i.e., 1 or 2 mg bid) seemed sufficient.
During the initial, asymptomatic period of HIV disease, nearly all patients experience varying degrees of anxiety and bouts of dysphoria.35 Stress-reducing techniques and supportive psychotherapy may be effective in ameliorating such symptoms.
Benzodiazepines are indicated for those with severe episodic anxiety, often bordering on panic, that is not sufficiently responsive to these other, nondrug interventions. Patients should be counseled about and discouraged from using over-the-counter hypnotics that contain anticholinergic agents, because they are frequently exquisitely sensitive to their adverse effects.
In the management of anxiety, the cumulative effects of longer half-life benzodiazepines often result in excessive sleepiness, apathetic states, and confusion (with or without paradoxical agitation). Thus, shorter and intermediateacting agents such as oxazepam, lorazepam, and alprazolam are preferable. For example, lower doses (i.e., 0.5 to 1.0 mg) of lorazepam or 0.25 to 0.5 mg of alprazolam may be quite sufficient while avoiding unwanted complications such as excessive sedation and cognitive dysfunction. Agents with very short half-lives, such as midazolam and triazolam, are usually not well tolerated, especially in those with more severe neurocognitive disruption.
Because BZDs can cause excessive sedation and misuse, especially in drug-abusing HIV-infected patients, buspirone may be a useful alternative. Batki reported on the use of this agent in 17 opiate abusers with AIDS or ARC who were also taking methadone.36 In the 14 patients who remained on the drug for at least 2 weeks, there was a reduction in several aberrant behaviors without any incidence of abuse.
Small doses of trazodone (25 mg to 50 mg) at bedtime may be useful as a sedative hypnotic. More data are required on pain control and analgesia using low-dose opiates on a short-term basis, which may also benefit anxiety. For example, the use of morphine in patients with advanced disease has been found to be particularly helpful in decreasing their associated anxiety.37
The utmost sensitivity and constant support are often all we can offer in the face of this devastating illness. Intelligent application of both non-drug and drug therapies must always be complemented by the offer of hope and comfort. The aim should not be to simply prolong life, but, whenever possible, to improve its quality. When psychotropics are employed, druginduced delirium is a real and ever-present complication. This is due to CNS sensitivity as well as AIDS-induced gastrointestinal and hepatic compromise, which can alter a drug's metabolism and disposition. Thus, low drug doses that are increased only if necessary and then very gradually should be the guiding principle.38'39
1. Gilmer W, Busch K. Neuropsychiatrie aspects of AIDS and psychopharmacologic management. Psychiatr Med. 1991; 9:313-329.
2. Uldall KK, Koutsky LA, Bradshaw DH, et al. Psychiatric comorbidity and length of stay in hospitalized AIDS patients. Am J Psychiatry. 1994; 151:1475-1478.
3. American Psychiatric Association. AIDS policy: guidelines for inpatient psychiatric units. Am J Psychiatry. 1992; 149:722.
4. Binder RL. AIDS antibody tests on inpatient psychiatric units. Am J Psychiatry. 1987; 144:176-181.
5. Jobe TH. Neuropsychiatry of HIV disease. In: Flaherty J, Davis JM, Janicak PG, eds. Psychiatry: Diagnosis and Therapy. New York, NY: Appleton & Lange; 1993.
6. Faulstich ME. Psychiatric aspects of AIDS. Am J Psychiatry. 1987; 144:551-556.
7. Maj M, Janssen R, Starace F, et al. WHO neuropsychiatrie AIDS study, cross-sectional phase 1. Arch Gen Psychiatry. 1994; 51:39-49.
8. Kalichman SC, Kelly JA, Johnson J, et al. Factors associated with risk for human immunodeficiency versus (HIV) infection among chronically mentally ill adults. Am J Psychiatry. 1993; 151:121-127.
9. DiClemente RJ, Ponton LE. HIV-related risk behaviors among psychiatrically hospitalized adolescents and school-based adolescents. Southern Journal of Psychiatry. 1993; 150:324-325
10. Ostrow DG. Psychiatric aspects of human immunodeficiency virus infection. In: Current Concepts. Kalamazoo, MI: The Upjohn Co; 1990.
11. Atkinson JH, Grant I. Natural history of neuropsychiatrie manifestations of HIV disease. Psychiatr Clin North Am. 1994; 17:17-33.
12. CournosF,EmpfieldM,HorwathE,KramerM.Themanagement of HIV infection in state psychiatric hospitals. Hosp Community Psychiatry. 1989; 40:153-158.
13. Horwath E, Kramer M, Cournos F, et al. Clinical presentations of AIDS and HIV infection in state psychiatric facilities. Hosp Community Psychiatry. 1989; 40:502-514.
14. Jacobsberg LB, Perry S. Medical management of AIDS patients: psychiatric disturbances. Med Clin North Am. 1992; 76:99-106.
15. Batki SL. Drug abuse, psychoactive disorders and AIDS: dual and triple diagnosis. West J Med. 1990; 152:547-552.
16. Janicak PG, Davis JM, Preskorn SH, Ayd F Jr. Principles and Practice of Psychopharmacotherapy. Baltimore, MD: Williams & Wilkins; 1993.
17. Yarchoan R, Brouwers P, Spitzer AR, et al. Response of human-immunodeficiency associated neurological disease to 3'-azido-3'-deoxythymidine.Lancet. 1987; 1:132-135.
18. Brunetti A, Berg G, Bi Chiro G, et al. Reversal of brain metabolic abnormalities following treatment of AIDS dementia complex with 3'-azido-2', 3'-dideoxythymidine (AZT, zidovudine): a PET-FDG study. J Nucl Med. 1989; 30:581-590.
19. Fernandez F, Adams F, Levy JK, et al. Cognitive impairment due to AIDS-related complex and its response to psychostimulatants. Psychosomatics. 1988; 29:38-46.
20 Angrist B, D'Hollosy M, Sanfilipo M, et al. Central nervous system stimulants as symptomatic treatments for AIDS-related neuropsychiatrie impairment. J Clin Psychopharmacol. 1992; 12:268-272.
21. Burch EA, Montoya J. NMS in an AIDS patient. J Clin Psychiatry. 1989; 9:228-229.
22. Ostrow D, Grant I, Atkinson H. Assessment and management of AIDS patients with neuropsychiatrie disturbances. J Clin Psychiatry. 1988; 49(suppl): 14-22.
23. Menza MA, Murray GB, Holmes VF, et al. Decreased extrapyramidal symptoms with intravenous haloperidol. J Clin Psychiatry. 1987; 48:278-280.
24. Davis JM, Janicak PG, Preskorn SH, Ayd F Jr. Advances in the psychopharmacotherapy of psychotic disorders. In: Janicak PG, ed. Principles and Practice of Psychopharmacotherapy Update. Vol 1. Baltimore, MD: Williams & Wilkins; 1994.
25. Hintz S, Kuck J, Peterkin JJ, et al. Depression in the context of human immunodeficiency virus infection: implications for treatment. J Clin Psychiatry. 1990; 51:497-500.
26. Hollander H. Neurologic and psychiatric manifestations of HIV disease. J Gen Intern Med. 1991; 6(1 suppl):S24-S31.
27. Preskorn S, Janicak PG, Davis JM, Ayd F Jr. Advances in the psychopharmacotherapy of depressive disorders. In: Janicak PG, ed. Principles and Practice of Psychopharmacotherapy Update. Vol 1. Baltimore, MD: Williams & Wilkins; 1995.
28. Marzuk PM, Tierney H, Tardiff K, et al. Increased risk of suicide in persons with AIDS. JAMA. 1988; 259:1333-1337.
29 King MB. Psychological aspects of HIV infection and AIDS. What have we learned? Br J Psychiatry. 1990; 156:15M56.
30. McKegney FP, O'Dowd MA. Suicidality and HIV status. Am J Psychiatry. 1992; 149:396-398.
31. Schaerf FW, Miller RR, Lipsey JR, et al. ECT for major depression in four patients infected with human immunodeficiency virus. Am J Psychiatry. 1989; 146: 782-784.
32. Lyketsos CG, Hanson AL, Fishman M, et al. Manic syndrome early and late in the course of HIV. Am J Psychiatry. 1993; 150:326-327.
33. Halman MH, Worth JL, Sanders KM, et al. Anticonvulsant use in the treatment of manic syndrome in patients with HIV-I infection. J Neuropsychiatry Clin Neurosci. 1993; 5:430-434.
34. Singh A, Catalan J. Risperidone in HIV-related manic psychosis Lancet. 1994; 344:1029-1030. Letter.
35. Ochitill H, Dilley J, Kohlwes J. Psychotropic drug prescribing for hospitalized patients with acquired immunodeficiency syndrome. Am J Med. 1991; 90:601-605.
36. Batki SL. Buspirone in drug users with AIDS or AIDS related complex. J Clin Psychopharmacol. 1990; 10(3 suppl):1115-1155.
37. Lebovits AH, Smith G, Maignan M, Lefkowitz M. Pain in hospitalized patients with AIDS: analgesic and psychotropic medications. Clin J Pain. 1994; 10:156-161.
38. Fernandez F, Levy JK. Psychopharmacotherapy of psychiatric syndromes in asymptomatic and symptomatic HIV infection. Psychiatr Med. 1991; 9:377-394.
39. Grant I. The neuropsychiatry of human immunodeficiency virus. Semin Neurol. 1990; 10:267-275.
Etiology of Neuropsychological Disorders in Patients With HIV Infection