HIV Psychiatry: Epidemiology, Depression Diagnostic Issues and Treatment Choice, Drug Interactions

CE Schwartz¹, PA Selwyn<sup>1

1</sup>HIV Palliative Care Program, Department of Family Medicine, Montefiore Medical Center, Bronx, NY 10467

E-mail: chschwar@montefiore.org, pselwyn@montefiore.org

Keywords:

Q: What psychiatric syndromes are associated with HIV infection?

HIV infected individuals are subject to the full range of psychiatric syndromes. Major depressive disorder is twice as frequent in HIV positive patients (1) and as many as twenty percent of HIV infected patients may suffer from Major Depression when they first present for medical treatment. Symptoms of anxiety are very common in this patient population under substantial stress, while major anxiety disorders appear to occur with the same frequency as in the general population (3). Alcohol and substance abuse disorders are common in individuals across HIV risk factors, with HIV +gay/bisexual men having a lifetime risk of 42%, (4).

Psychiatric disorders often predate and are independent problems that interact with HIV infection and treatment, made worse under the biopsychosocial stress of HIV, and making HIV medical treatment more challenging (5)(6).

Psychiatric disorders may be directly caused by HIV, opportunistic infection, metabolic derangements and treatments. AIDS dementia complex and a broad range of manifestations of HIV brain disease may be present in as many as 10% at initial presentation, and 70% over the course of the illness, with 90% having CNS abnormalities at autopsy (7). Mania may occur in up to 9% of patients over the course of their HIV illness (2) and together with new onset, psychosis often emerges during later stages of AIDS.

An important proviso in understanding psychiatric epidemiology in HIV/AIDS is that much of the currently available data dates from the pre HAART era. Physicians delivering HIV medical care generally feel that the incidence of severe neuropsychiatric illness in HIV-infected patients has fallen substantially, and seems to occur later in the course of illness, when antiretroviral treatment fails or becomes intolerable and patients become progressively less responsive to treatment.

Q: How is clinical depression identified and diagnosed in HIV-infected patients with severe biomedical illness and substantial substantial psychosocial stress?

Accurately diagnosing depression in the medically ill is an ongoing challenge to clinicians and researchers (8)(9). Somatic symptoms including fatigue and insomnia are core components of depressive syndromes, but may be due to depression or HIV illness and/or its treatment (10)(11). While apathy may be more likely to be caused by depressive illness (12), diminished psychomotor speed and fatigue may be independent of depression and caused by HIV disease (13)(14). Transient and normal adjustment and bereavement reactions are also difficult to differentiate from depressive illness.

The high prevalence, substantial morbidity and efficacy of treatment for depression have led many experts to argue for a-etiologic "inclusive" diagnostic criteria that count all depressive symptoms that are present and that may be due to depressive or medical illness (15). Other experts have argued that the focus should be on symptoms that are more likely to be due to depressive illness, i.e., emotional and cognitive, and have added "substitutive" symptoms, beyond those in the DSM criteria, that may more accurately indicate depression in medically ill patients (16)(17)(18).

Given the complexity of the biomedical and psychosocial context in which depression occurs in HIV infected patients, experts agree that the best clinical approach is longitudinal. Distress is identified; a provisional working diagnosis is made; and a therapeutic intervention is instituted (e.g., counseling for adjustment and bereavement issues, correction of vitamin B12 deficiency )(19), institution of HAART to ameliorate neuropsychiatric symptoms secondary to HIV infection with low CD4 and high viral load (20)(21)(22); outcome is then assessed over the course of 6-12 weeks with reevaluation of diagnosis and addition/adjustment in therapy for continued neuropsychiatric symptoms, distress, and dysfunction (23)(24)(25).

Q: What treatments are effective for depression in HIV-infected patients?

In 1993, the Agency for Health Care Policy and Research issued a set of guidelines for depression treatment in primary care, which, on the basis of evidence from clinical trials and expert consensus, identified a broad range of treatments (antidepressant medications and psychotherapies) as effective when applied in an intensive (follow-up every 1-2 weeks) and structured manner (outcome evaluation and treatment changes at 6 and 12 weeks)(25). An updated review of RCT's during the 1990's added evidence-based support for the recommendations (26), and a Cochrane Collaboration review concluded that antidepressants are effective for depression in the medically ill (27).

The first and most critical intervention for depression and other neuropsychiatric syndromes emerging in HIV+ patients is aggressive treatment of HIV opportunistic infections and metabolic derangements, as mentioned above (19)(20)(21)(22)(23).

Evidence for the effectiveness of a broad range of biopsychosocial interventions recommended by the AHCPR in HIV-infected patients has been well summarized in practice guidelines issued by the American Psychiatric Association in November, 2000 (24).

Numerous trials have demonstrated the efficacy of multiple classes of antidepressant medications in HIV-infected patients (28)(29)(30)(31)(32)(33)(34). A large literature has emerged supporting the effectiveness of psychostimulants (dextroamphetamine and methylphenidate) in treating fatigue and cognitive impairment, depression in HIV-infected patients (35)(36)(37).

Psychotherapies and psychosocial interventions including support groups have been clearly demonstrated to be effective in reducing depression, anxiety, and general distress (38)(39)(40)(41)(42). Many experts recommend that these interventions be instituted first in conjunction with HIV medical care; employing medications when the diagnosis is more certain and patients have failed to adequately respond.

Q: What drug interaction issues have been identified in HIV-infected patients treated with psychotropic medication?

Medication regimens for HIV and opportunistic infections are complex and interact with psychotropic medication in absorption, protein binding and transport, hepatic metabolism by the P450 system and glucuronidation, and renal excretion. These interactions can result in clinically significantly elevating or depressing blood levels of HIV and/or psychiatric medications, leading to potentially morbid or mortal side effects and toxicities and loss of efficacy. Much of this information is summarized in a recent review in the New England Journal of Medicine (43). Drug interactions involving nonnucleoside reverse transcriptase inhibitors (NNRT's)(44), and regimens for mycobacterium avius complex (MAC) disease (45), are as critical as those of HIV protease inhibitors and nucleoside reverse transcriptase inhibitors.

Of the SSRI antidepressants, fluoxetine's long T 1/2 and significant P450, 2D6 and 3A4 inhibition may present significant drug interaction problems; sertraline and citalopram appear to have the lowest risk, with paroxetine and fluoxamine being midrange. Tricyclic antidepressants are metabolized by P450, 2D6, and may have blood level elevations in combination with 2D6- inhibiting protease inhibitors. The ability to obtain clinically useful blood levels for nortriptyline and desipramine, the secondary amines with the lowest incidence of side effects in the TCA group, marks these as potentially useful medications. Nefazadone is a potent 3A4 inhibitor, and may present a significant problem when used with complex HIV regimens. Bupropion, used for depression and smoking cessation, is 2B6 metabolized, and may need to be used with some caution (46).

Benzodiazepines, alprazolam in particular, may be problematic when used with 3A4 inhibitors, which may cause markedly elevated blood levels and sedation (47). Triazolam, a benzodiazepine, and zolipidem, a nonbenzodiazepine, which are both used as short-acting hypnotics and are 3A4 metabolized, may cause confusion, agitation, and psychosis, in addition to increased depth and duration of sedation, when co-administered with 3A4 inhibiting HIV regimens (48).

Opiate medications can also be significantly effected by co-administration of HIV regimens. Ritonavir may substantially elevate the toxicity of meperidine (49). Methadone may delay GI drug absorption (50) and may have its efficacy dramatically lowered when co-administered with 3A4 inducers, e.g., rifampin, rifabutin and ritonavir (51).

Complementary and alternative medicine, so widely used by HIV-infected patients (52), can lead to significant drug interaction issues. St. John's Wort has been reported to be an inducer of P450, 3A4, and to diminish blood levels of protease inhibitors and substantially compromise their antiretroviral efficacy, along with the efficacy of a broad range of 3A4 metabolized medications, including digoxin and warfarin (53)(54).

Sildenafil, metabolized by 3A4, may need to be used with some caution with 3A4 inhibiting HIV regimens (55).

Conclusion

HIV and opportunistic infections, HIV medications, and the psychosocial stress of HIV illness cause substantial psychiatric morbidity over the course of illness. Psychiatric syndromes seen in HIV-infected patients are of multiple and mixed etiologies (primary psychiatric disease predating HIV infection, substance-induced, medical illness and treatment-induced/exacerbated), and require aggressive screening, diagnosis and treatment. A broad range of medication and psychosocial interventions have been demonstrated to be effective when administered with frequent follow-up and outcomes assessment and treatment modification for inadequate response within the first 3 months. These should be administered in conjunction with high quality HIV medical care that addresses neuromedically- caused or exacerbated psychiatric syndromes. Psychiatric medication should be employed with careful attention to drug interactions with HIV medicines.

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