November 30, 1999
There are significant direct consequences to the invasion of HIV into the nervous system that may present as neurological, neuropsychiatric, and/or psychiatric syndromes and disorders. In addition, as the immune system deteriorates, myriad secondary physiologic and psychological problems can cause additional disturbances of brain function. These problems may arise acutely and require rapid evaluation and intervention or they may be chronic, sometimes subtle, and often present along with physical complaints. Particularly during palliative or end of life care, attention to disturbances of brain function improves quality of life and the ability of providers to honor patient wishes about limits of care.
Early involvement of mental health clinicians, particularly psychiatrists who can help with the differential diagnosis of presenting neuropsychiatric and psychiatric symptoms, should be sought whenever possible. The assessment and treatment of neuropsychiatric complaints are essential to both the overall well-being of the patient and to the efficacy of other treatments, particularly palliative care. In addition to the enormous psychological burden of progressive illness and loss of physical function, even subtle and subclinical changes in brain function may significantly affect both quality of life and the ability for a person to participate in his or her own medical care. This, in turn, has impacts on family members, loved ones, providers -- that is, on the palliative care team itself. (See Chapter 20: Care for the Caregiver.)
Changes in a patient's mental state, either acute or chronic, throughout the course of HIV infection must be evaluated using a comprehensive conceptual framework that includes pre-existing medical and psychiatric disorders, as well as those arising from HIV (see Table 10-1, PDF).
Changes in mental status are always to be considered abnormal, not simply an understandable problem associated with having HIV, and should be considered a medical emergency. The initial assessment should begin by ruling out and treating any acute process (see Table 10-2, PDF). Some questions that may be useful to the clinician in the differential diagnosis are listed in Table 10-3 (PDF).
Since a patient may be unable to give a complete or accurate history, family and friends must be asked about any unusual behavior or sudden changes in the person's mental state. Any change in the patient's typical behavior or engagement must be evaluated urgently. Irritable and anxious patients often come to attention because they are obviously disturbed. Attention must also be paid, however, to the withdrawn and quiet patient.
Changes in personality, level of activity or interest in others may signal an acute CNS disturbance. Some changes are the direct effect of brain dysfunction, while others may be due to the acute psychological distress of a systemic problem. For example, the acute onset of pain in the feet due to neuropathy might affect cognition and behavior because of an acute anxiety or panic that the person is dying. On the other hand, the presence of transverse myelitis is often associated with HIV-related cognitive impairment.
The first step is to make an accurate diagnosis of one or more disorders that might account for the clinical presentation. The most common psychiatric diagnoses are depression, adjustment disorders, anxiety disorders, and the neuropsychiatric disorders resulting from HIV in the central nervous system. Table 10-4 (PDF) presents a format to use to conduct a complete mental status exam.
It is important to remember the following points:
HIV enters the brain at the time of initial infection. This may cause a cascade of immune responses that can cause acute or chronic cognitive impairment. With progressive disease, delirium often occurs as a consequence of illness and/or treatment, presenting with cognitive changes that are important to distinguish from depression or dementia.
HIV-infected patients with cognitive-motor impairment have increased mortality rates.1 While specific cognitive deficits may be assessed most accurately by neuropsychological testing, the real impact on patients is related to their functional status. Changes in cognition, motor capacity, mood or behavior may be subtle or overt and can be dramatic. Even subtle neurocognitive impairments may affect the ability to work and psychological coping.2, 3
In the untreated adult, HIV-related neuropsychiatric disorders are most likely to be evident in late-stage illness. The neuropsychiatric syndromes (due to HIV itself in the brain) are dementia (HAD), minor cognitive-motor disorder (MCM.D.), and subclinical cognitive-motor impairment. In all cases, the diagnosis of primary HIV cognitive-motor disorder must be made as a diagnosis of exclusion. It has been argued that focusing on minor cognitive-motor disorder may be more important a focus of treatment than overt dementia because it is more likely to be reversible.4
Clinical Neuropsychiatric Syndromes
While most primary brain impairment in adults occurs late in the course of infection, it is not possible to rule this out when patients present early with changes in mental status. (See Figure 10-1, PDF.)
Children and adults manifest the impact of CNS HIV infection somewhat differently. In adults the impact is on the developed brain and peripheral nervous system, with deterioration evident as the loss of neurological integrity or mental capacity. In children and adolescents HIV can prevent the normal growth and development of neural pathways, achievement of developmental milestones, or integration of cognitive, motor and affective components of the self at age-appropriate stages. For adults the impact is a loss of function whereas in children it is the failure to thrive or achieve some function altogether.
There is now evidence that the presence and severity of HIV dementia correlates with the levels of HIV production in the CNS, as well as with macrophage activation.5, 6 HIV vRNA in the peripheral blood may not reflect the level of brain vRNA nor the degree of neurological dysfunction.7-13
HIV dementia is classified as a subcortical dementia and manifests as one or more of a clinical triad of progressive cognitive decline, motor dysfunction, and behavioral abnormalities.14 Early symptoms include slowed information processing, cognitive and psychomotor slowing, and problems with verbal memory and new learning. Later on, evidence of difficulty with executive functioning appears, along with visual and spatial difficulties, and apraxias, and in the end stages may look similar to the global cortical dementias. (See Table 10-5, PDF.)
Neuropsychiatric Disorders in Adults
Adults typically present with complaints of difficulty with short term memory, difficulty paying attention and finding words, and feeling slowed down in thought process. Since memory difficulty is a common symptom, other psychiatric disorders and prior brain trauma must be ruled out. (See Table 10-6, PDF.)
HIV-infected patients may have mild neuropsychological impairment that does not meet criteria for any specific disorder. It is important to recognize that this may be the initial stage of developing disease and should be followed closely. In doing so, clinicians must consider other conditions such as head trauma, epilepsy, learning disorders, aging, low intellectual ability, and alcohol or substance use. Deficits due to HIV would be evident as decline from previous function prior to HIV infection, thus requiring monitoring of impairment over time. Cognitive deficits due to other conditions would not necessarily be expected to progress if the underlying condition was stable or in remission, whereas impairment due to HIV would be expected to progress over time.
While prior estimates of dementia had been reported at 20% to 25% of individuals with AIDS,15 it is now thought that the cumulative prevalence of dementia has been reduced to 7% to 10%, as a result of multidrug antiretroviral therapy.3 This figure may rise as drug resistance increases and adherence falls over time. This may be due to the relatively poor penetration of antiretrovirals into the CNS, leading to incomplete viral suppression, resistance and reseeding of the peripheral blood with drug resistant strains of virus. The blood brain barrier (BBB) thus creates a sanctuary for HIV in the CNS, making it impossible to achieve complete viral suppression.
The diagnosis of HIV-associated dementia (HAD) is made by excluding all potential causes for a change in mental state according to criteria set out by the American Academy of Neurology,16 shown in Table 10-7 (PDF). Risk factors for dementia are listed in Table 10-8 (PDF).
Minor Cognitive-Motor Disorder (MCM.D.)
Minor cognitive-motor disorder (MCM.D.) is also a diagnosis of exclusion, according to the criteria set out in Table 10-9 (PDF).16 Patients failing to meet these criteria yet who manifest functional impairments or related anxiety and fear warrant attention as well. MCM.D. may result from many of the same risk factors as dementia. It is important to distinguish between progressive dementia and MCM.D. because the latter is a less severe disorder and does not progress necessarily to full dementia. This information may ameliorate a patient's fear of a continuing decline.
Subclinical Neurocognitive Impairment
The impact of HIV in the CNS may show up in neurocognitive testing in the absence of significant or consistent clinical complaints, signs or symptoms. A patient may have a very mild problem with memory, for instance, which might show up on testing but does not affect the person's ability to function in his or her work or home life. Since such neurocognitive testing would show evidence of cognitive deficits in patients without HIV as well, the long-term implications of such findings are not yet clear. Whether such patients are more likely to progress to MCM.D. or HAD as their viral loads increase and immune systems decline needs to be determined.
Evaluation of Altered Mental Status
Additional elements may also be necessary for a comprehensive evaluation. For example, an acute change of mental state in a person known to be abusing drugs would require toxicological screening. Likewise, lumbar puncture and imaging studies may help confirm a diagnosis of HAD, as shown in Table 10-11 (PDF). It must be remembered that co-morbidity is common and changes can occur rapidly, often requiring repeated examinations over time.
Dementia and minor cognitive motor disorder are always diagnoses of exclusion. In late-stage disease, particularly when CD4 counts are below 200, there are many disorders that may present with similar clinical signs, as shown in Table 10-12 (PDF).18Table 10-13 (PDF) illustrates the distinguishing characteristics of progressive multifocal leukoencephalopathy and HIV-associated dementia.19 Laboratory and imaging findings are necessary for accurate diagnosis and appropriate intervention.
Neuropsychiatric Disorders in Children
CNS deficits in children may be due to the direct impact of HIV; intrauterine or perinatal insults; or, other environmental problems.20, 21 The terms HIV-associated progressive encephalopathy or HIV encephalopathy, rather than dementia, are used to designate the primary impact of HIV on developing neural tissue. Because there are other syndromes, such as mental retardation, prematurity and maternal drug use, that can present with similar symptoms, longitudinal assessment is necessary to make diagnoses of HIV encephalopathy in children.
Three profiles have been described in HIV-positive children: those without impairment in function, those with compromise of the CNS, and those with encephalopathy.22, 23 While progressive encephalopathy is generally observed in the context of immunosuppression, CD4 count and other markers of immunologic functioning do not correlate with the degree of cognitive impairment.24
Cognitive deficits in children with compromise of the CNS tend to be milder and less global than in children with encephalopathy. Children infected perinatally who experience early and severe immunodeficiency may show pronounced developmental problems. Progressive encephalopathic changes cause impaired brain growth, including motor dysfunction, impaired social skills development, dysprosody, flattened affect, and apathy, as well as abnormal developmental milestones. HIV-infected children may have impairments in intelligence and language functioning, with expressive language more impaired than receptive. Many HIV-positive children have poor academic performance, exacerbated by frequent absences due to medical illnesses. Visual motor deficits are common and may correlate with progression of disease.25
Treatment of Neuropsychiatric Disorders in Adults and Children
Treatment includes strategies for decreasing viral load in the brain and periphery, rapid and adequate treatment of co-occurring systemic illness, and restitution of metabolic and endocrine function. The major impediment to achieving viral suppression in the CNS has been the lack of penetration of antiretrovirals across the BBB. While AZT has the best evidence of being able to improve cognitive motor impairment associated with HIV, only high doses (1000-2000mg/d) have proven to be clinically significant.26Table 10-14 (PDF) shows the relative penetration of antiretrovirals into the cerebrospinal fluid.27-30
The nucleoside reverse transcriptase inhibitors, zidovudine (AZT), stavudine (d4T), lamivudine (3TC) and abacavir most readily penetrate the blood brain barrier (BBB). Non-nucleoside reverse transcriptase inhibitors nevirapine and efavirenz may reach inhibitory concentrations in the CSF.31 Protease inhibitors are of particular concern as indinavir is the only one able to reach viral inhibitory concentrations of >95%.32 Currently there are no published studies of the CNS penetration of newer antiretrovirals such as lopinavir or tenofovir. More recent studies have shown that there may not be a correspondence between antiretroviral levels in the CSF and the level of HIV activity in the brain. So far, the best predictor of maintaining cognitive function seems to be decreasing peripheral viral load as much as possible.
The incidence of cognitive impairment has decreased since the advent of highly active antiretroviral therapies (HAART), but may be on the rise because of incomplete viral suppression and increasing viral resistance. Since other AIDS-defining diagnoses have decreased in the era of multidrug therapy, dementia constitutes a higher percentage of AIDS-defining illnesses.
Immune modulation using calcium channel blockers (e.g., nimodipine, memantine), inhibitors of Tumor Necrosis Factor Alpha (TNFa) (e.g., pentoxifylline), and alpha interferon and naltrexone, have been studied. There are, however, no clear guidelines to their use in clinical practice at this time.
Psychostimulants, such as methylphenidate, dextroamphetamine, and pemoline, have generally been found to be clinically effective in enhancing attention and executive function.33, 34 Dosage information for these drugs appears in Table 10-15 (PDF). Modafinil, which has FDA approval for narcolepsy, has been clinically useful in some HIV patients with fatigue and excessive daytime sleepiness, although there is limited information as to its effect on cognitive function.
Dopaminergic agonists have improved neuropsychological performance in some instances. Case studies of carbidopa, L-dopa, and selegiline, a monoamine oxidase type B inhibitor, have suggested some preliminary benefit. The use of donzepil and tacrine to increase cholinergic transmission may also prove to be of value, but to date there are no studies to support this.35, 36
Correction of nutritional deficits in cobalamin (vitamin B12) and pyridoxine (vitamin B6) may boost a patient's cognitive function and general well-being. Other nutritional interventions that may prove to be useful include omega-3-fatty acids, folate, s-adenosylmethionine and zinc.37-39 The routine workup for a change in mental state should include vitamin B12 and folate levels.
Supportive and cognitive-behavioral psychotherapies are effective in addressing a patient's anxieties and fears about progressive cognitive decline. Associated with entering a more terminal phase of illness, end of life issues always arise, and providers can offer palliative treatment with antiretrovirals and psychostimulants to maximize cognitive capacity and quality of life.
Treatment of Late-Stage Dementia
HIV subcortical dementia may progress to a global dementia in the later stages. At this point, a patient's intellectual function, decisionmaking capacity and behavioral control may be impaired. Psychostimulants should be evaluated often and decreased if there are signs of agitation or excessive motor activity. Late-stage dementia is often complicated by concurrent delirium due to medications, metabolic disturbances, or acute infections. Agitation and psychotic features such as hallucinations or paranoia can best be treated with risperidone and/or lorazepam. If an oral route of administration is not possible, IV haloperidol (.25 to 1mg) and IV lorazepam may be helpful in controlling agitation and psychotic features.
Treatment of Cognitive Disorders in Children
There are limited studies of AZT and ddI showing improvement in children with AIDS and that for the most part, these medications are well tolerated.40-42 While psychostimulants have not been systematically studied in children and adolescents with HIV, there is a long medical experience with them in treating attention deficit disorders in children and adolescents.
Delirium and the Impact of Medications on Central Nervous System Function
Delirium in the HIV-infected patient can result from acute primary HIV infection of the brain, consequences of infections, metabolic derangement, medications, and acute substance intoxication or withdrawal, and is more likely in the setting of advanced illness or hospitalization.43, 44
Hypoxemia due to pneumocystis carinii pneumonia may cause an acute change in mental state, as can uremia secondary to HIV nephropathy or elevated ammonia levels due to hepatic disease. Table 10-16 (PDF) lists common side effects of medications used in the care of the HIV-infected patient that also must be considered.45
Intoxication or withdrawal from either prescribed or non-prescribed medications must be ruled out. There can be multiple causes of acute changes in mental status. If the delirious condition does not improve with treatment for an obvious potential cause, the clinician must look for other co-morbid conditions.
Psychiatric disorders are common in patients infected with HIV, and may either predate HIV or occur during the course of living with the disease. Many psychiatric disorders become apparent at an age when risk for HIV may be high, such as in late adolescence or early adulthood. The appearance of psychiatric symptoms is not necessarily directly attributable to the neuropathic effects of HIV.46-49
The diagnosis and treatment of psychiatric disorders is essential to the well-being of a person infected by HIV. Depression, for example, has been associated with shorter survival times in HIV-infected men50 and women. Appropriate mental health care is also essential if patients are to engage in treatment and sustain sobriety and protective sexual practices.
It is never appropriate to assume that a psychiatric symptom is merely an "understandable" emotional reaction to a particular situation. Table 10-17 (PDF) lists some common misperceptions in this regard.
Mood disorders are associated with substance use, impaired quality of life, mental suffering, suicide, poor adherence to antiretroviral regimens and increased risk for behaviors such as multiple sexual partners and drug use that transmit HIV.51
Studies show that depressive disorders are very common but underdiagnosed and undertreated in HIV infection.52, 53 Depressive symptoms increase over the course of HIV illness, especially after the onset of AIDS. These increases are not necessarily associated with HAD or MCM.D..
Depression must be differentiated from many other conditions common in HIV which are presented in Table 10-18 (PDF). Major depression is never a "normal" response to a particular situation. It must be approached with the same rigor as any other medical illness.
Patients often feel that they are depressed for good reason, or that they feel fatigued and sad because they are sick. Providers must understand and make clear that depression is a treatable medical illness that responds well to both psychotherapy and medications. Somatic symptoms, such as fatigue, trouble sleeping, decreased appetite or sexual drive, and mental slowing are also symptoms of HIV-related cognitive disorders. Symptoms of anhedonia, guilty feelings, sadness and loss of hope may be helpful in distinguishing depression from cognitive impairment.
Depression at the End of Life
Even at the end of life, depression is a disorder that requires treatment, and should never be considered a normal response to illness or dying. Patients who are not clinically depressed may talk about the sadness of leaving others behind, of dying, or of fear of the unknown. Depressed patients near the end of life will likely have flattened affect or an inability to respond appropriately to loved ones, or might be withdrawn and mute. When in doubt, using low dose psychostimulants may be very helpful in reducing the depression, and increasing cognitive function even in the last weeks of life. In the agitated or anxious patient very low doses of risperidone (.25 to 1mg) or olanzapine (1.25 to 5mg) may be a helpful treatment.
Providers must distinguish between depression and grief. While sadness may be present in both conditions, grief is a normal reaction to loss or impending loss. Further, grief may manifest differently across cultures. Anticipating the loss of function and quality of life, and acknowledging an impending death, can appear to observers like depression. Grief, however, is often accompanied by powerful and profound affective states and crying, while severe depression appears more like an emotional paralysis, with patients often unable to mobilize any affect other than hopelessness.
Affective Disorders in Children and Adolescents
Rates of psychiatric disorders among HIV-positive children and adolescents are generally similar to those among adults. One study showed 85% had at least one Axis I diagnosis54 and 53% had history of psychiatric contact prior to their HIV diagnosis. Among adolescents, 34% had major depression according to one study,54 and 25% had major depressive disorder and high rates of distress in another.55 Children and adolescents come to the attention of providers less with internalizing disorders (depression and anxiety) than externalizing disorders (conduct-behavioral disorders).56
Depression in children and adolescents must be evaluated in the context of HIV disease, the cognitive and emotional stage of development, and manifestations of HIV in the CNS. Suicidality must be thoroughly assessed and treated. One study showed 28% of HIV-positive adolescents reported a suicide attempt.57 Another study showed one third of HIV-positive adolescents required hospitalization because of a suicide attempt.54 Children and adolescents may express hopelessness over the future, fear of themselves or their infected parents dying, or being unable to participate with their peers as "normal" children due to physical or cognitive limitations.
As with depression, rates of mania increase as HIV disease progresses. Only 1 to 2% of patients with early HIV experience a manic episode. Since this is only slightly higher than rates for mania in the general population, this may reflect the increased risk for infection with HIV due to hypersexuality, poor judgment and/or substance use that are associated with bipolar disorder. However, as HIV progresses to AIDS, 4 to 8% may have a manic episode.58, 59 In addition, mania in advanced disease can be associated with cognitive changes or HIV dementia.
AIDS-related mania can differ clinically from the true mania of bipolar disorder in that irritability, rather than true grandiose euphoria, is the core symptom.60 Common symptoms of mania include the following:
The clinical presentation of mania requires emergency psychiatric intervention, particularly if psychotic symptoms are present and judgment is impaired.
Prescribed and illicit use of androgenic and/or anabolic steroids can cause or exacerbate mania or hypomania and should be ruled out in the work-up of this symptom. Gancyclovir and dapsone have also been associated with increased rates of mania.
Treatment of Mood Disorders
Treatment of mood disorders must be tailored to the individual patient's illness and circumstances. Although antidepressant medications are commonly prescribed by primary and palliative care providers, referral to a psychiatrist should be made when the patient experiences significant side effects or does not respond to the psychopharmacological intervention. Clinically depressed patients with HIV have been shown to benefit from a therapeutic relationship and from medications to alleviate depressive symptoms.61 Additional studies have indicated that some types of psychotherapy and medications together may be more effective in treating depression than either one alone.62 Additionally, management of psychotropic medications in the debilitated, fragile AIDS patient may be difficult and warrant specialist consultation.
Table 10-19 (PDF) provides information about antidepressants commonly used in the treatment of depression. Older antidepressants such as tricyclics may be effective and tolerated in early HIV; however, they may exacerbate both cognitive impairment and gastrointestinal disturbances as a result of their anticholinergic activity. Selective Serotonin Reuptake Inhibitors (SSRIs) are effective antidepressants but are often problematic because of sexual side effects. Newer antidepressants such as buproprion and venlafaxine are very effective, with few drug-drug interactions. Bupropion (more activating) and nefazodone (more sedating) are tolerated well. Nefazodone must be used cautiously with patients on protease inhibitors (particularly ritonavir), which may raise blood levels 4 to 8 times. Mirtazapine is a sedating antidepressant compatible with antiretroviral medications, and may also stimulate appetite and weight gain. A more recently approved SSRI, Escitalopram, is reported to have fewer side of effects, minimal interaction with other drugs metabolized by the P450 cytochrome enzymes, and may have a faster onset of action. So far there are no studies of its use in people with HIV.
Antidepressants should be started at low doses and gradually increased. It is important to use sufficient doses of medication to achieve a therapeutic level. Raising doses too quickly, however, may cause side effects and will not hasten a clinical response. Many patients who are in recovery may be reluctant to take antidepressants because they believe that mind-altering substances must be habit-forming. The patient must be educated and supplied with information about depression, its treatment, and the differences between antidepressants and benzodiazepines or narcotics.
Because they can present with similar symptoms (poor concentration, memory impairment, fatigue and/or mental slowing), depression and other mood disorders must be differentiated from MCM.D. or HAD. Psychostimulants are well tolerated in the medically ill patient and may treat symptoms of both depression and cognitive impairment. As depression and cognitive impairment often co-exist in advanced HIV, psychostimulants may be used alone or in conjunction with an antidepressant.63 Mood may improve significantly in the hypogonadal patient (male or female) with correction of the underlying androgen deficiency.64
People with HIV may be particularly sensitive to side effects of antidepressants. Starting with low doses and anticipating side effects for the patient increases his or her ability to tolerate the medication. It is important to allow a reasonable period of time to assess effectiveness of a particular medication and dose.
Psychological support is very important in adherence to antidepressants and other medications. Some clinical suggestions in this regard are as follows:
Treatment for mood disorders in children and adolescents also includes psychotropic medications and a variety of psychological and psychosocial interventions. Medications for mood disorders in children and adolescents with HIV have not been well studied, although the SSRIs are used clinically. Individual, group and family therapy are effective in treating issues specific to HIV in adolescents, such as future goals, intimacy issues and self esteem. In the later stages of disease, preparation for disability and death may require intensive, multidisciplinary approaches.
Suicidal ideation must always be taken seriously. Table 10-20 (PDF) contains important elements in evaluating suicide risk. Attempts increase under the influence of psychoactive substances and alcohol and in the midst of a delirium or psychosis.65
It is important to ask specific and direct questions such as the following:
When a patient admits to suicidal ideation, inquire about whether he or she has thought about a specific plan to carry it out. Ask about the consequences of doing so, to the patient and those in the patient's life. Assess whether there is an intent to die, even if the methodology seems not very lethal to the provider, for example, the patient says he or she will take 20 pills which may not be biologically lethal, but psychologically is intended to end life.
Providers are often reluctant to ask about suicidal ideation. Asking does not engender such ideas in people who do not have those thoughts to begin with. When a provider asks about suicidal ideation, it acknowledges the amount of pain and suffering the patient has endured, and often feels supportive and caring to the patient. It is also important to understand that the idea of suicide may provide to some a sense of ultimate control when it appears that control over the mind, body, or environment is slipping away. It would be unusual for anyone who experiences the shock of a new diagnosis of HIV, cancer or loss of function to not consider how much life is worth living and under what circumstances. Simply being able to verbalize the feeling of having ultimate control, and deciding if that is even a possibility, may help patients feel understood and more in control of their lives. Suicidal ideation may also be a sign of undiagnosed depression, undertreated pain, or other co-morbid conditions.
Anxiety is a common concern. Brief periods of anxiety directly related to specific events usually respond to support and help in coping with the specific problem. Anxiety disorders, however, can impair overall functioning and the capacity for self-care.67
Anxiety often coexists with depression and substance abuse. Anxiety disorders in HIV/AIDS patients range up to 40%. However, there is no clear association between specific types of anxiety and HIV status or stage of disease. Diagnosis of anxiety is important as anxiety can affect the capacity of the patient to take in information, plan ahead, or adhere to a treatment plan.
Health care providers must rule out biological causes -- presented in Table 10-21 (PDF) -- for anxiety symptoms. Once biological causes have been ruled out, it is important to diagnose the anxiety disorder correctly in order to determine the treatment.
Generalized Anxiety Disorder (GAD)
Generalized anxiety disorder (GAD) is diagnosed when another specific cause of anxiety cannot be found and the person suffers from persistent and significant anxiety that impairs function. GAD may or may not be associated with specific life events. Many patients may have been suffering with GAD prior to the diagnosis of their HIV disease, but develop a more profound and disabling anxiety disorder as they enter treatment. Likewise, chronic substance users may unmask GAD when they initiate sobriety as a result of being diagnosed with HIV. Major depression with anxiety must always be considered in the differential diagnosis of GAD.
Panic symptoms can be terrifying to the person and can, in severe or chronically untreated situations, lead to suicidal ideation and attempts. Many patients are worked up for cardiovascular, neurological, or respiratory disorders before a diagnosis of panic disorder is made. A medical evaluation should rule out alcohol withdrawal, cocaine or other stimulant abuse, overuse of caffeine, arrhythmia, hyperthyroidism, asthma, pneumonia, or the use of herbal compounds that include ephedra, gingko, ginseng, ma huang, or guarana. Signs and symptoms of panic disorder are described in Table 10-22 (PDF).
Obsessive-Compulsive Disorder (OCD)
About 2% of the general population have a lifetime prevalence of OCD symptoms including recurrent and intrusive thoughts (obsessions) and/or behaviors (compulsions) intended to reduce the obsessional thinking. People with HIV may obsess about CD4 counts, viral load, side effects of medications, physical symptoms, weight loss or change in body habits. These obsessions may lead to requests for repeated tests, or intense concerns about insignificant changes in physical signs.
Post Traumatic Stress Disorder (PTSD)
Post Traumatic Stress Disorder (PTSD) has not been well studied in HIV disease. Manifested by hypervigilance, exaggerated startle response, anxiety, social withdrawal and fears associated with the original trauma, PTSD is particularly associated with a history of physical and sexual abuse in people with HIV. Intrusive medical procedures, hospitalization, new providers and untoward reactions to medications can precipitate an increase in PTSD symptoms. PTSD may manifest itself with increased risk-taking behavior, depression, self-imposed isolation, and mistrust and anger towards others, including medical personnel, leading to disrupted care and/or negative interactions with providers and poor adherence to medication regimens and clinical care.
As with most psychiatric disorders, the treatment of anxiety disorders almost always involves both pharmacotherapy (see Table 10-19, PDF) and psychotherapy. For short-term treatment of symptoms of anxiety, benzodiazepines (BZs) may be used until psychotherapeutic treatment helps to re-establish coping mechanisms or the patient can learn behavioral techniques to manage symptoms. Benzodiazepines that are particularly useful in HIV are lorazepam, oxazepam, and temezepam, as they have short half-lives, hence less accumulation and side effects. There can be important drug interactions between these agents and some antiretroviral agents. Alprazolam is best avoided because of its very short half-life, and may interact with protease inhibitors.
Benzodiazopines are often the only immediately effective medications that can be tolerated and may help engage a person in treatment. Benzodiazepines should, however, be avoided in active substance abusers, because of the risk of dose escalation, dependence and intoxication. In people with a history of substance abuse, BZs must be used cautiously, with careful monitoring of use, frequent and limited prescriptions, and attention to the risk of relapse. See Table 10-23 (PDF) for clinical suggestions for prescribing medications that have potential to be abused.
Psychological counseling or group therapy to address use of controlled substances should be mandated as part of the management of patients with substance abuse history, and offered to anyone concerned about using controlled substances as part of his or her treatment.
For longer-term or chronic anxiety disorders, maintenance with antidepressants may help avoid the use of potentially addictive agents, and are generally effective for generalized anxiety disorder, panic disorder, obsessive compulsive disorder, and social phobia. Venlafaxine is effective for general anxiety disorder, usually well tolerated in people with HIV, and has few interactions with other HIV medications, although sexual side effects may interfere with the person's willingness to continue the medication. All of the SSRIs as well can cause significant sexual and gastrointestinal side effects sufficient to cause patients to be non-adherent. Anticipating such side effects and starting with lower than typical doses may help alleviate these problems and allow patients to accommodate more easily to the medications.
Adding buproprion to a regimen of other antidepressants to help counter the sexual side effects may enhance adherence. However, buproprion alone is not usually sufficient to treat anxiety, and is stimulating, so caution must be used in adding it into the regimen in anxious patients. Using long-acting (SR) formulations, and simply anticipating the potential problems will often comfort patients enough for them to try tolerating the medications. Buspirone may be effective for GAD but requires several weeks of bid-tid dosing to be effective.
Medications which are most effective in treatment of OCD include the SSRIs, particularly fluvoxamine, sertraline, and fluoxetine. These are typically required in higher dosages than for depression. Anafronil, strongly anticholinergic, is effective for OCD but not well tolerated in the person with HIV.
The SSRIs and some mood stabilizers may be useful for diminishing the physiological responses associated with PTSD.
Cognitive behavioral therapy may be particularly useful in addressing the underlying distorted thinking, irrational thinking, and maladaptive behavior. Specific techniques that address particular anxiety syndromes, short-term psychoeducational groups, individual therapy and ongoing therapy groups all may be useful in reducing anxiety symptoms.
Anxiety Disorders in Children and Adolescents
Anxiety symptoms and disorders occur more frequently in HIV-positive than HIV-negative children.68, 69 Anxiety in children may focus on life span, how they contracted HIV and health concerns. Ruminations about death may be excessive and disabling. Physiological changes, such as shortness of breath, gastrointestinal symptoms, or neurological problems may compound these concerns. The extent to which psychological functioning is affected varies with the cognitive and developmental stage of the child.
As in adults, treatment includes anti-anxiety medication and psychotherapy. Clinically, SSRIs are used for long-term anxiety and BZs for short-term, situation anxiety. Teaching children to use deep breathing exercises, progressive muscle relaxation and guided imagery may relieve symptoms and provide some sense of mastery to children feeling out of control of their feelings and bodily functions.
Conduct-Behavioral (Externalizing) Disorders in Children and Adolescents
Attention problems in children with HIV may be a direct consequence of HIV infection and CNS complications.70 Treatment of attention deficits in HIV-positive children is similar to treatment in non-infected children. Psychostimulants and alpha agonists can be effective.71 Social skills training can help children with HIV with attention deficits cope with stigma.
Conduct disorders and substance abuse are common among HIV-positive adolescents.57 Treatment must be specialized to reduce psychiatric morbidity and decrease associated risk-taking behaviors. (See Chapter 11: Substance Use Problems.)
Sleep disorders are common and distressing, and exacerbate other symptoms associated with HIV such as fatigue, cognitive impairment, memory loss, decreased work performance, diminished coping capacity, and reduced social interaction.72, 73 Sleep disturbance can contribute to poor adherence, failure to engage in treatment, relapse of substance use in the attempt to selfmedicate, poor impulse control and impaired judgment. Treating sleep disorders in people with HIV is not only helpful to the patient in terms of reducing fatigue, but also enhances the treatment alliance.
In HIV, sleep disturbance is marked by shorter total sleep time, longer sleep onset latency, reduced sleep efficiency, more frequent awakenings and more time spent awake. The impact of sleep deprivation becomes more significant as illness progresses and stamina and energy decline.
Sleep pathology has been associated with growth hormone dysregulation.74, 75 Hypersomnia, associated with advanced disease, may be related to elevated levels of TNFa. The differential diagnosis of sleep disturbance appears in Table 10-24 (PDF).
There are both non-pharmacologic and pharmacologic treatments for sleep disorders. Nonphamacologic treatments include the following:
Providers often fear overmedicating sleep disorders. Although habituation to sleeping medications occurs often, the potential for addiction is rare. Pharmacologic treatments for sleep disturbance are discussed in detail in Table 10-25 (PDF).
Substance Use Disorders
Substance use disorders complicate the psychiatric diagnosis and treatment of many patients with HIV. (See Chapter 11: Substance Use Problems.) Patients with a triple diagnosis of HIV, psychiatric disorder, and substance use are at increased risk for poor access to care, poor adherence to medical treatments and increased psychological distress leading to increased morbidity and mortality.
Substance-using patients, including those receiving methadone maintenance treatment (MMT), have high rates of prior psychiatric morbidity and suicidal ideation.76 Screening for substance abuse and psychiatric disorders should be routine.
Psychiatric Treatment of HIV-Positive Substance Users
The diagnosis and treatment of drug users with HIV is complicated by multiple risks for neuropsychiatric disturbance. Acute and chronic effects of alcohol and substances of abuse, methadone, head trauma, and HIV itself can each and in combination cause significant mental status impairments. Problems secondary to past trauma or substance use can be differentiated from current use and HIV neurocognitive effects by serial assessments. Past brain injury or substance abuse would not continue to cause increasing CNS impairment. Current substance use, CNS infection, or HIV related cognitive impairment would continue to show decrements of function over time.
There are few studies to show the safety or efficacy of pharmacological treatment of psychiatric disorders in substance-using patients with HIV. Safety, abuse potential and adherence capacity must all be considered when prescribing medications for cognitive or psychiatric disorders. Likewise, the capacity for adherence to antiretrovirals often impacts the decision to start or continue anti-HIV medications.
One national study of alcohol or other substance-using individuals with HIV reported less adherence to combination therapy (45% vs 59% adherence in the past seven days) than non-using counterparts.77 Some clinicians believe that waiting until the substance abuse and psychiatric disorder are stabilized will decrease the probability of poor adherence leading to viral resistance. Many experienced HIV clinicians encourage dual diagnosis treatment. Treating either the substance abuse or psychiatric disorder independently or in sequence has not been shown to be effective in stabilizing patients with co-morbidity. Harm reduction programs, when abstinence programs are not working, may offer an opportunity to keep patients engaged in treatment.
The use of antidepressants and anti-anxiety agents in substance-using patients may be fraught with difficulty. Substance users are usually impatient for a response to psychiatric medications, preferring the rapid onset of action of BZs rather than buspirone or antidepressants. Efficacy may be delayed or diminished by current substance use. Efforts should be made to engage the HIV-positive substance user in both drug treatment and psychiatric care at the same time. Patients with untreated psychiatric disorders may be less able to enroll and adhere to a drug treatment program.
The treatment of substance abuse in patients with HIV is often more complicated than in noninfected substance users. Concerns about illness, depressed mood, hopelessness, and suicidal ideation often impede progress in drug abuse treatment, requiring a harm-reduction approach. Inpatient detoxification may be necessary for medically ill HIV-positive substance users, as withdrawal from substances may precipitate relapse with serious potential for overdosing. After medical stabilization and detoxification, treatment is geared to maintain sobriety and reduce the incidence of relapses. Cognitive impairments and psychiatric distress will be more evident within a few weeks of detoxification.
Retention in substance abuse programs may be enhanced by early treatment of emerging psychiatric disorders, which may be precipitants for relapse. Methadone maintenance may be necessary for some opioid abusers to stay clean long enough to engage in psychiatric care. Methadone must be monitored carefully, with increases and decreases in dosing when interactions with medications occur. Nevirapine and rifampin may increase the elimination of methadone, requiring increased dosing to avoid opioid withdrawal. Methadone itself may reduce serum concentrations of ddI, d4T, and AZT. Table 10-26 (PDF) presents relevant medication interactions.78 Methadone must be maintained even when additional narcotics must be used to treat pain. Methadone maintenance provides for many patients a stablization of the narcotic addiction, allowing for more consistent HIV and psychiatric care.
In addition to intensive outpatient treatment, adjunctive pharmacologic treatments such as disulfuram for alcohol dependence and naltrexone for opioid and alcohol dependence may help patients manage cravings and enhance participation in 12-Step and dual diagnosis programs. Disulfuram is given in doses of 250 to 500mg per day, and naltrexone 50mg per day. While disulfuram is an aversive drug, creating intense nausea and vomiting if taken with alcohol, naltrexone requires abstinence from opioids for seven to 10 days prior to initiating treatment to avoid precipitating an acute opioid abstinence syndrome.79 It is particularly important to note that naltrexone must not be used in patients who are treated with narcotic analgesics for pain control. Clonidine has also been used to treat the effects of opioid withdrawal.
The Treatment of HIV in Psychiatric Patients
As many as one in every 12 adults who are in treatment for serious mental illness may have HIV infection and several studies have documented an overall HIV seroprevalence rate of 7.8% among severely impaired psychiatric patients.80 AIDS is the leading cause of death among young people experiencing their first psychiatric hospitalization.81
Cognitive changes associated with chronic psychotic illness may confound the diagnosis of HIV-related cognitive impairment, especially during the acute phase of psychiatric illness. Providers must understand their own preconceived notions about psychiatric patients. While during the acute phase of a psychotic or manic illness it may be difficult for patients to fully understand or engage in their treatment, the same patients may become quite able and willing to adhere to antiretroviral regimens. Patients who have been adherent to their psychiatric regimens may be likely to adhere to antiretroviral treatments as well.
Antiretroviral medications, however, should never be started in the acute phase of a psychotic or mood disorder. Every patient should be offered the same opportunity to be educated about how the medications work, why adherence is so crucial, and why taking psychiatric medications is important to help minimize an adherence failure. A low threshold for psychiatric hospitalization will minimize the impact of medication lapses and reduce the chances of resistance. Close monitoring of medication side effects, strategies to enhance adherence to all medications, and drug treatment programs may be required to provide the best medical care for patients with serious co-morbid disorders. A case management approach with an integrated care model addressing medical, psychiatric and substance use can be helpful.
Patients who have suffered from a serious mental illness may express ambivalence and despair about HIV. Periods of hopelessness and feelings of contamination and defectiveness may become prominent and require intensive psychiatric intervention. Suicidal ideation is common. Delusions about the nature of HIV infection, sexual anxieties, and paranoid ideation can complicate the treatment relationship. Reducing psychosis and enhancing cognitive capacity are important goals of treatment.
Psychopharmacologic treatment is effective in treating psychosis in the HIV-infected patient.82 Patients with manic psychosis showed more improvement than those patients with schizophreniform psychosis, and positive symptoms responded more readily than negative symptoms. Anti-anxiety agents, antidepressants and mood stabilizers can be helpful as adjunctive agents. Two case reports suggested that catatonia responded to lorazepam.83
It is important for providers to recognize serious character pathology as soon as possible in the treatment of HIV. Compared to uninfected patients, those with HIV have higher rates of personality disorders in the range of 19% to 37%.84 Borderline and histrionic disorders tended to be the most common.85, 86 Those personality disorders found among people with HIV are associated with increased rates of psychiatric symptoms, injection drug use, depression and maladaptive coping mechanisms.87, 88
Essentially, character pathology is syntonic to the individual but problematic to those around him or her. The most serious character disorders in terms of complicating the treatment of HIV are antisocial personality, narcissistic personality, borderline personality and histrionic personality. These disorders tend to create difficulty for patients in relationships with providers, whereas other personality disorders, such as avoidant or passive patients, may elicit provider feelings of not being able to do enough to engage patients in ongoing treatment.
Problematic character traits are distinguished from serious character disorders by the consistency and intractability of the behavior regardless of the external environment. Many patients may exhibit some traits that seem to be components of their basic personality, but are evident only under extreme duress. Patients with cognitive impairment who are frightened and having trouble completing automatic tasks, patients in pain, and patients intoxicated or withdrawing from either substances of abuse or prescribed medications are particularly at risk for exhibiting problematic behavior which usually resolves when the underlying problem is adequately addressed. Social stressors that often complicate treatment relationships include homelessness or unstable living situations, unstable support systems, rejection from families of origin, and relapsing criminal or drug related behaviors.
A provider's reactions to a patient's character pathology may include anger, fantasies of abandoning or withdrawing care, impulses to limit access to the provider, or frank fear of encounters with the patient. These emotional reactions to a patient should alert the provider to the likelihood that the patient may have a difficult character disorder.
While each type of character disorder has particular defense mechanisms, most employ denial (the inability to acknowledge or believe something; e.g., "I can't infect others because I really don't have HIV"), projection (putting onto others what one is feeling or believing; e.g., "you must hate me"), and splitting (telling different things to different providers with the hope of confusing each provider or getting one provider to believe that another is being unjust, uncaring or incompetent). Lying, or confabulating, to acquire, for example, increased pain medication, is common. The fear of abandonment often provokes in the patient an increased neediness and unwillingness to admit any improvement for fear the provider may withdraw or decrease the level of involvement. Projective identification (feeling what a patient is feeling) often leads providers to think something is wrong with themselves, instead of identifying the problem as a projection onto them by a patient.
People with character disorders are also vulnerable to psychotic, mood, and anxiety disorders, and have rates of substance abuse at least comparable to the general population. Providers often may find that granting requests made by such patients provokes a sense of being abused. Errors in treatment can follow from either withholding appropriate treatment or overgratifying a request in order to end more quickly an encounter with the patient.
Communication With Other Providers in Personality Disorder
Unless there is constant communication among members of the palliative care team, a patient's splitting will wreak havoc on the team's effectiveness. When a patient states something about a member of the team to another member (reporting what was said or done), confirmation is imperative. The provider should never rely on the patient to convey information.
While no specific psychotherapeutic technique has been shown to be effective in treating personality disorders in HIV, some clinical guidelines may be helpful; see Table 10-27 (PDF). Other psychiatric syndromes may be present along with personality disorders and should be treated appropriately.
HIV-Associated Syndromes With Psychiatric Implications
Several HIV-associated syndromes such as wasting, fatigue, sexual dysfunction and pain have psychiatric implications. As with sleep disturbance, treating complaints that are important to patients and that affect cognitive functioning will increase patient adherence to care and help build a therapeutic alliance between patient and provider. Pain and fatigue are discussed elsewhere in this guide. (See Chapter 4: Pain and Chapter 5: Constitutional Symptoms.)
Wasting syndrome and sexual dysfunction are often associated with impaired self image, a sense of being defective, and body dysmorphia. These feelings can lead to obsessional concerns and behaviors. Testosterone replacement may be beneficial in these settings.87, 88 While testosterone may improve libido, it may not address all sexual dysfunctions. Underlying problems such as neuropathy, vascular disease, autonomic insufficiency, premorbid psychological disease, and drug side effects should be addressed so that as normal a sexual life as possible is possible. Erectile dysfunction may be facilitated with sildenafil but caution must be urged with regard to dosing in the presence of protease inhibitors.
Psychotherapy, particular behavior and cognitive therapies to treat sexual inhibitions and anxieties, and couples therapy may enhance both sexual function and adaptation to declining sexual function.89
Psychological and Psychosocial Issues
Even with the advent of multidrug therapy, the future of most people with HIV is uncertain. Living with such a tremendous burden of unpredictability often affects people's ability to maintain emotional stability and retain control over their lives. Many issues arise throughout the course of HIV infection. Each change in medical status, every blood test result, and every recognition of a new change in mental or physical function can create enormous stress on an infected individual and the people in his or her life.90
Primary care providers are increasingly faced with complex medical and social issues. The importance of mental health and practical support to help patients meet these challenges cannot be overstated. All too often, medical providers do not see the need for mental health care or understand the contributions that mental health clinicians can make to a treatment team, and may convey that bias unwittingly to patients. Early involvement of mental health care in the treatment of the HIV- infected patient allows the development of a relationship that can prevent crises from becoming disruptive to the care of the patient or the medical provider's practice.
Table 10-28 (PDF) lists some of the most important issues facing people over the course of their HIV infection. Two of the most emotionally difficult issues for many patients are permanency placement for minor children, and creating advance directives.
Permanency placement evokes powerful feelings in parents who fear abandoning their children, and who grieve the probability that they will not see their children grow up. Accepting that permanency placement is necessary means accepting one's inevitable death, a problem for both the patient and his or her health care providers. Guilt and shame inevitably emerge as parents get sick and face the possibility that they will die, leaving others to care for their offspring. Particularly in cases where there are difficult family relationships, many parents feel ambivalent about having to place their children with family members they don't like or don't trust with their children.
Providers can support parents with HIV by acknowledging that permanency placement planning is a very painful process that takes time and continued reflection and consideration, and often involves wavering back and forth from one decision to another. Helping parents to establish a working relationship with a mental health provider before permanency planning issues must be addressed can make it easier for them to deal with such powerful concerns when they do arise. For patients, trying to establish a strong, trusting relationship with a provider brought in during a crisis is very difficult. With a relationship built early in the care of the infected parent, a skilled mental health clinician can raise issues of permanency placement before the acute fears and denial set in when a medical crisis occurs.
Another difficult issue for HIV-infected people is the establishment of advance directives. (See Chapter 18: Legal and Financial Issues.) Psychologically this requires the patient to acknowledge that life is finite and death may be imminent. Again, a relationship with a mental health provider can provide a safe place for the patient to explore fears of dying, and of death. Helping a patient to think about the quality of life near the end of life is best done in the context of ongoing relationships with both a primary provider and a mental health clinician, working together to explain the medical details and the emotional components of the decisionmaking process.