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Some of the medications used to treat HIV/AIDS and its complications have common neuropsychiatric side effects. Side effects may be related to cumulative dose or to peak levels or may be unpredictable and idiosyncratic. Furthermore, in patients with advanced HIV disease, the homeostatic mechanisms responsible for maintaining therapeutic drug levels may be disrupted by end-organ involvement, such as decreased renal excretion, hepatic metabolism, or cardiac output; diminished body fat; immunologic dysregulation; and a predisposition toward dehydration. These patients with HIV are, therefore, also more susceptible to side effects from more commonly used medications. The rule of thumb for prescribing to persons with advanced HIV is “say no, start low, and go slow,” that is, avoid unnecessary medications, use reduced dosages of those that are necessary, and increase doses slowly and cautiously. Most patients, however, will require conventional doses of medications used to treat psychiatric disorders, so the edict “go slow” includes reaching therapeutic doses eventually.
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Drug effects and toxicities must always be considered in the initial differential diagnosis of any neuropsychiatric abnormality. A few general principles should be kept in mind. First, use agents with favorable side effect profiles. Second, use caution in the coadministration of medications with similar side effect profiles or those that significantly affect one another’s pharmacodynamics. An example of the first situation is the simultaneous use of any combination of antidepressants, antihistamines, neuroleptics, or antimotility agents, all of which have substantial anticholinergic effects. The second concern arises in the use of agents, such as rifampin or rifabutin, which induces the hepatic cytochrome P450 enzyme system and thereby accelerates metabolism of many other drugs or conversely, agents such as ritonavir or delavirdine which inhibit the P450 enzyme.
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A third concern is that adherence to complex medication regimens is often unreliable. Incorrect dosing may result in undertreatment for some conditions, but confusion may also result in inadvertent overdosing. Always simplify the regimen and use the lowest dose of the fewest drugs likely to be effective. The assistance of a pharmacist is invaluable in addressing these concerns. If possible, the regimens of patients with advanced HIV/AIDS or on multiple medications should be periodically reviewed by a pharmacist.
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Persons with HIV/AIDS on average have higher levels of substance use, in part because of the association between preexisting drug use and the risk of acquiring HIV/AIDS, and perhaps because of self-medication for depression or anxiety. Stimulant drugs such as cocaine or amphetamines can cause agitation, psychosis, or delirium, as can withdrawal from sedating drugs such as benzodiazepines and alcohol. Sedatives and narcotics can not only cause somnolence, confusion, and psychomotor slowing but can also cause paradoxical reactions, including agitation, paranoia, and rage. This may be especially true of the short-acting benzodiazepines.
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With regards to specific antiviral agents, two specific points need emphasizing. First, cobicistat or ritonavir-containing regimens, through inhibition of cytochrome P450 enzymes, may dramatically raise the level of many prescribed and recreational drugs. These substrates include many anticonvulsants (carbamazepine, valproic acid, phenytoin), narcotics (meperidine, methadone), recreational drugs (3,4-methylenedioxymethamphetamine [MDMA] or Ecstasy), and other agents (warfarin, digoxin, estrogen). Patients receiving these antivirals should be monitored for potential interactions (see Table 36-1).
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Second, 2 weeks after starting efavirenz, patients may experience disrupted sleep, depression, agitation, and exacerbation of previously stable psychiatric disease. Whereas case and cohort studies report delayed or persisting neuropsychiatric symptoms due to efavirenz, a prospective double-blinded study failed to show any lingering or delayed CNS side effects attributable to the medication. Conversely, a recent cohort study showed an increased risk of suicidal ideation in patients taking efavirenz long term. Patients with stable psychiatric disorders may be prescribed efavirenz, but should be monitored for drug-associated agitation or depression. All patients who are starting efavirenz should be provided with sleeping medication for the first 2 weeks, either a standard benzodiazepine, or if substance misuse is a concern, a low-dose atypical antipsychotic.
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CASE ILLUSTRATION 2
Marjorie, a 36-year-old ex-intravenous drug user with a 5-year history of stable HIV disease (undetectable viral load, T cells 500 on HAART), is noted to have a viral load of 14,000. On interview, she reports missing “a few” doses due to “spacing out,” “just forgot.” She has maintained her sobriety but is not attending Narcotics Anonymous (NA) meetings—”too tired.” On further questioning, she reports morning fatigue, insomnia, anhedonia, and hopelessness. A diagnosis of depression is made and she is offered initial treatment with therapy or medication. After attending a support group she recognizes that she has been “depressed a long time” and agrees to both counseling and psychopharmacologic treatment. Because she also has chronic pain from peripheral neuropathy, a dual-active/serotonin norepinephrine reuptake inhibitor (SNRI) medication is initiated with the hope of decreasing pain, improving sleep, and treating her depression.
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Major depression is the most common psychiatric disorder in persons with HIV/AIDS. The lifetime incidence is unknown but rises dramatically as the disease progresses. As with non-HIV-infected depressed patients, the cardinal symptoms include depressed mood, anhedonia, feelings of worthlessness and hopelessness, disturbances in sleep and appetite, weight loss or gain, fatigue, psychomotor slowing, agitation, and preoccupation with morbid thoughts (see Chapter 25). A family history of an affective disorder or alcoholism may be present. Depression may be more difficult to diagnose in the presence of HIV/AIDS, however, for several reasons. First, its manifestations, and particularly the vegetative symptoms (fatigue, weakness, weight loss, and loss of libido) commonly overlap with the constitutional symptoms attributable to HIV infection or its complications. Second, organic impairment due to the HIV-associated dementia complex may have affective manifestations. Third, HIV-associated hypogonadism (low testosterone) may cause fatigue, impaired libido, and other depressive symptoms. For some patients, testosterone supplementation has been shown to reverse depressive symptoms. Finally, some medications and the use of or withdrawal from other psychoactive substances, can have mood-altering effects as described previously. Nevertheless, depressive disorders including major depression and dysthymia are diagnosed by the same criteria for HIV-infected as for non-HIV-infected persons and should never be treated as a normal finding. Indeed, recent surveys have documented that untreated depression is a major correlate of poor quality of life in people with HIV disease, and is an important risk factor for noncompliance with treatment.
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Certain clues may help to distinguish depressive from constitutional symptomatology. For example, progressive fatigue that worsens with exertion and over the course of the day is characteristic of somatic disease (e.g., anemia), whereas an inability to get going in the morning, which improves with activity, may suggest depression. Similarly, nondepressed patients may report that nausea or dysgeusia (an abnormal sense of taste) interferes with their appetite, whereas depressed patients often report simply no interest in eating. Nondepressed patients often report their symptoms and limitations with frustration and concern, whereas apathy and resignation are more characteristic of major depression. Anhedonia and a sense of worthlessness are rarely symptoms of a somatic condition, and should therefore be directly investigated as specific indicators of depression. Depressed patients may appear more anxious or preoccupied than sad. Patients with depression and anxiety may self-medicate with recreational drugs or alcohol; patients with substance use should be screened carefully for depression and anxiety disorders.
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The treatment of depression in HIV/AIDS does not differ from the non-HIV-infected population. Regular, empathic listening and short-term psychotherapeutic techniques may be effective. Explicit recognition and validation of the patient’s losses and fears help to establish a trusting therapeutic relationship and may permit developing joint strategies to cope with them. Emphasizing that depression is a common ailment in the setting of HIV/AIDS and is amenable to treatment is important. As with other patients, choosing among the many available agents should be largely a matter of selecting the most desirable or tolerable side effect profile.
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The clinician must be alert to how the activity and toxicity profile of particular agents may help in simultaneously addressing other concerns of the patient. For example, appetite and sleep-stimulating medications such as mirtazapine may be effective in patients who suffer from insomnia. A TCA such as nortriptyline or an SNRI may be an ideal choice in a patient with neuropathic pain, who may also benefit from the drug’s pain-modulating effects. The risk of cardiac arrhythmias associated with tricyclic drugs may be increased in persons taking ritonavir. Bupropion is especially useful in patients with fatigue, and along with mirtazapine is unlikely to cause sexual dysfunction. Selective serotonin reuptake inhibitors (SSRIs) are especially useful in patients with anxious depression or comorbid anxiety disorders.
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Stimulants may be used with other antidepressants in patients with severe refractory fatigue, and can also be used to palliate narcotic-associated fatigue and sedation. Because of their abuse potential, these agents must be used selectively, and their efficacy varies considerably from patient-to-patient.
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Isolation from family, religious or spiritual community, or friends can result in demoralization. Because of the stigma of HIV within certain communities, HIV-infected patients may feel cut off from the usual sources of fellowship and support. Support groups, pets, engaged case management, and counseling can help prevent isolation.
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As with some depressive symptoms, anxiety may be a normal response to many of the stressors associated with living with HIV. Symptoms of anxiety may include poor concentration, restlessness, preoccupation or intrusive thoughts, insomnia (particularly trouble falling asleep), and fatigue. Persons with poor coping skills may be particularly prone to periods of uncontrollable anxiety. Withdrawal from nicotine, alcohol, or illicit drugs, or overuse of caffeine may cause symptoms of anxiety.
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Treatment is indicated if anxiety impairs social or occupational functioning, or is persistently uncomfortable. Pharmacotherapy generally involves the use of SSRIs and other serotonergic antidepressants, or benzodiazepines. For episodic and unpredictable bouts of anxiety, short-to medium-acting benzodiazepines, such as lorazepam (Ativan) or alprazolam (Xanax) are generally more effective, due to their more rapid onset of action. The physician should carefully monitor the frequency of refilling of anxiolytic prescriptions; a pattern of escalating use may suggest that a longer-acting agent or antidepressant therapy is preferable. For chronic disabling anxiety, longer-acting benzodiazepines such as clonazepam (Klonopin), which maintain more stable blood levels, may be more effective and better tolerated. Selective serotonin reuptake inhibitors are useful maintenance agents in the treatment of anxiety syndromes like panic disorder, obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD).
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Patients with anxiety symptoms should be screened for PTSD. A recent study found that PTSD was the most robust predictor of medication and appointment non-adherence. Posttraumatic stress disorder symptoms include easy startling, flashbacks or nightmares, and dissociative symptoms. For some patients, the trauma of living with HIV rekindles memories of prior traumas (abuse, rape, accidents). Studies of incarcerated women with HIV have demonstrated a high rate of PTSD. Posttraumatic stress disorder is best treated with focused counseling, although SSRIs have been shown to help alleviate some of its symptoms.