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Introduction

HIV clinical care providers are increasingly confronted by comorbid psychiatric illness among their patients. Prevalence rates of psychiatric disorders among HIV-infected patients approach 50%.[1] These conditions commonly manifest around the time of diagnosis,[2] but many patients develop symptoms later in their course of illness.[1] Axis I disorders, including anxiety and depression, are particularly likely to occur at times of stress-including an illness episode, a psychosocial stressor such as divorce or loss of a loved one, and when facing a new disability. Anxiety and depression are among the most commonly diagnosed psychiatric conditions affecting HIV-infected patients.[3,4] These can complicate the treatment of HIV, presenting numerous diagnostic and interventional challenges for the clinician.

Adherence to highly active antiretroviral therapy (HAART) can be markedly reduced by comorbid psychiatric disorders, but proper treatment of the psychiatric disorder can reverse this effect.[5-8] The appropriate evaluation and treatment of psychiatric symptoms can significantly affect a patient's quality-of-life, as well as the risk of relapse into injection drug use and willingness to return for medical care.[9] Undiagnosed and untreated mental illness may lead to HIV risk behaviors and therefore contribute to the acquisition and spread of HIV.[10,11]

In this article, we review diagnostic and treatment approaches designed to assist the treating HIV clinician in the management of depression and anxiety among HIV-infected adults. While the impact of drug and alcohol dependence on care for affected patients is briefly touched upon, the true complexities of managing patients with active substance abuse problems are beyond the scope of this article and have been discussed elsewhere.[12,13]

Depression

Epidemiology

Major depressive disorder (MDD) has been the most extensively studied psychiatric comorbidity affecting HIV-infected patients, with estimates of lifetime prevalence ranging from 4% to 45%. The wide variation in these prevalence rates is due to several factors, including the patient population studied, the practice setting, and the method used to diagnose MDD. For example, studies which rely on medical record diagnosis of the condition likely underestimate the true prevalence rate.[6] Perhaps the best estimate of the 12-month prevalence of MDD among HIV-infected patients was reported in a study utilizing the HIV Cost and Services Utilization Study data, a stratified national sample of 2864 adults. Using a structured psychiatric interview, the Composite International Diagnostic Interview, these authors found the 12-month prevalence of MDD to be 36%.[1] There is evidence of increased rates of MDD among certain subgroups of HIV-infected patients, in particular those with histories of substance use disorders,[14] older patients,[15] or female patients with histories of trauma.[16] The rates of MDD have been found to be higher among HIV-infected female patients than among control groups matched on relevant variables such as age, socioeconomic status, and social support-even when correcting for substance use patterns.[17] Suicidal ideation, attempts, and completion of suicide have been found to be higher among many HIV-infected populations than among the general population.[18,19]

Symptoms

Fewer than half of patients with MDD are correctly diagnosed by their primary care providers.[20] The reasons for this underdiagnosis are complex. Clinicians should refer to the criteria for diagnosing a major depressive episode, provided in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR).[21] It may be difficult for the HIV clinician to differentiate between somatic symptoms of HIV disease and symptoms arising from MDD,[22] as there is significant overlap between the neurovegetative symptoms of depression and symptoms associated with HIV, opportunistic infections, or common comorbidities such as hepatitis C. Somatic complaints such as abdominal distress, amplification of chronic pain complaints, agitation and restlessness[23] should prompt an evaluation for MDD if the patient reports a personal or family history of depression, suicidality, substance use, or anxiety disorders.[24] It is of note that men and women often exhibit similar symptoms of MDD, but women report more atypical symptoms such as anxiety, somatization, increased appetite and weight, hypersomnia, and hostility.[24]

Depressive symptoms may mask somatic symptoms arising from HIV disease.[23] Patients who are in the asymptomatic stage of HIV infection are less likely than more advanced-stage patients to experience opportunistic infections, neurological diseases or cognitive impairments such as dementia; all of which may present as depression.[9] Dementia may coexist with MDD and the patient's cognitive function may improve upon initiation of antidepressant therapy.

Diagnostic Evaluation

No specific laboratory tests screen for MDD, and many different disorders may result in a depressed mood. Infectious processes, metabolic disorders, and medication effects should be considered before establishing the diagnosis of MDD (see Table 1). Clinicians who suspect MDD should always screen for manic symptoms to determine whether a depressive episode may be a manifestation of bipolar syndrome.

Depression rating scales are useful in making the diagnosis of MDD and following the response to treatment. Numerous scales of symptom severity are available. Removing the somatic subsets of depression symptoms may improve the clinical utility of several depression screening instruments.[25] Although the Hospital Anxiety and Depression Scale (HADS) is one such validated scale that has been specifically designed to exclude somatic items,[26] the Patient Health Questionnaire (PHQ) version of the PRIME-MD diagnostic instrument may be the most clinically useful depression screen. The PHQ (Table 2)[27] includes the nine items used to evaluate a major depressive episode, and a diagnosis can therefore be made directly from the PHQ. In addition, recent evidence suggests this screening tool may outperform the HADS.[28] To further simplify screening, a two-question screen has a sensitivity of 83% and a specificity of 92% for the MDD diagnosis among patients seen in a primary care setting.[29] Such simple screening measures should be incorporated into the routine of patient encounters in the HIV primary care setting to better identify patients in need of treatment.[30]

Another routine screening exercise conducted in the HIV primary care setting should be a neuropsychological examination, which may reveal the distinction between depressive signs and cognitive impairment.[31] In addition to performing memory tests and investigating the duration of onset of symptoms in order to distinguish depression from cognitive impairments such as dementia, some physicians recommend using the Folstein Mini-Mental State Examination and the Functional Activities Questionnaire to distinguish depression from cognitive impairments.[32] The distinction between depression and neurological diagnoses is important for both the aging HIV population who may be affected by dementia from other causes[33] and the younger HIV-infected persons who may be affected by AIDS Dementia Complex (ADC). ADC presents with apathy and withdrawal, but also has an insidious onset and features motor problems like weakness and imbalance. Memory loss and language impairment can occur in later stages. While ADC should be distinguished from MDD, it should be noted that ADC patients can still exhibit signs of depression, which should be treated with care because ADC patients are more susceptible to the sedative properties of antidepressant medications.[34]

If indeed the screening and examination reveals that the HIV-infected patient likely has MDD, the clinician should also ask patients directly about suicidal ideation. Most HIV-infected patients have had thoughts of death and even suicide, and a discussion may relieve anxiety in a patient who has been otherwise unable to discuss the issue.[9] A proper suicide screening should include past psychiatric history (especially suicide attempts or friend/family history of suicide), mental status evaluation (psychotic symptoms, especially command hallucinations), a review of major life stressors (especially losses), current levels of financial and social support, patient beliefs about personal disease progression and future, and a discussion about any specific suicidal plans.[24] A contract should be established with the patient, specifying an emergency plan to be implemented in the event that the patient experiences increased suicidal ideation.[9] An emergency psychiatric assessment is necessary when a patient has clear intention to act on suicidal ideations.

Treatment

Both pharmacologic and non-pharmacologic interventions have been shown to be beneficial[9,35] and cost-effective[36] among HIV-infected patients with depression. Although the following discussion presents various treatment options, the specific treatment in an individual patient should be guided by the patient's symptom severity, pharmacological interactions (especially with HAART), and patient comorbidities. Clinicians should begin with a low dose of antidepressants and slowly titrate upwards to minimize side effects, which are described more fully below. The known pharmacological interactions are summarized in Table 3.

Serotonin-specific reuptake inhibitors (SSRI) are the most widely prescribed medications for depression.[37,38] They may also be more effective than tricyclic antidepressants (TCA) among patients with atypical symptoms such as hypersomnia, hyperphagia, and hypersensitivity to rejection.[24] SSRI are metabolized through the P450 system, which presents the possibility of significant interaction with HIV-related medications (see Table 3).[39] All of the SSRI appear to be equally effective in the treatment of MDD. Selective serotonin/norepinephrine reuptake inhibitors such as venlafaxine and duloxetine are often used among patients who do not tolerate or respond to SSRI therapy; venlafaxine has been associated with diastolic hypertension and should be used cautiously in patients with hepatic or renal disease.[24]

TCA have been favored by some clinicians due to their low cost and history of efficacy against major depression, but they have come into disfavor in recent years due to the dangers of overdose (particularly arrhythmias) and the difficulty of titrating to therapeutic levels.[39,40] At low doses (such as 10 mg nortriptyline or 25 mg amitriptyline), TCA can be very useful for treating the insomnia experienced by many HIV-infected patients. These medications may also be helpful for the treatment of chronic pain, especially neuropathic pain.[41] Of note, TCA do not appear useful for the treatment of depression in children, and only marginal evidence supports their mild efficacy among adolescents.[42]

During treatment, a patient should be assessed every 2 weeks. If patients undergo remission while on antidepressants, treatment should continue without dose modification for at least 16-20 weeks. If patients do not respond to an initial trial of antidepressant treatment or if their condition worsens after 4-8 weeks, several factors must be considered: the accuracy of the initial diagnosis (e.g., patient's depression is an episode of bipolar disorder), the possibility of inadequate medication dosage or treatment duration, poor patient adherence to therapy, or the possibility of the presence of other comorbid psychiatric illnesses (e.g., anxiety, personality or substance use disorders). After elimination of these possibilities, a trial of a second antidepressant is warranted. Patients should be reassured that 60-70% of patients will respond to a second SSRI after they failed to respond to a first one. If the depression is refractory to a second antidepressant trial, the patient should be referred to a psychiatrist.[24]

Antidepressants generally take 2-6 weeks to achieve therapeutic effect, and both inadequate dosing and short duration of medication use have been noted as key causes of treatment failure. Between 70 and 80% of patients eventually achieve significant reduction in symptoms with appropriate treatment; however, up to half of patients may not respond to initial treatment. Even with successful treatment of an acute episode, the risk of recurrence of MDD among the general population is 50-80%; the risk of recurrence among HIV-infected patients has not been specifically reported, but is presumably at least as great.[24]

Several non-pharmacologic interventions have been demonstrated to be effective treatments of depression among persons with HIV. These include some psychotherapy modalities, specifically cognitive behavioral therapy (CBT) and interpersonal psychotherapy, which have been shown to be effective in decreasing depressive symptoms in small trials. CBT is a structured intervention designed to teach patients specific skills to modify thoughts and behaviors that lead to depression. This technique involves learning coping strategies for dealing with distressing or depressing situations, and exercises to reframe their approach to living with their illness.[2] Several studies have demonstrated the effectiveness of CBT among groups of HIV-infected gay men,[43,44] and both individual and group formats have been shown to be effective in short-term studies (15-16 weeks). One study of 60 depressed HIV-infected men demonstrated reduced illicit drug use among patients treated with CBT.[45]

Interpersonal psychotherapy is generally conducted by an individual therapist and focuses on grief, interpersonal relationships and life transitions.[2] When 16 HIV-infected patients treated with interpersonal psychotherapy were evaluated against matched controls, the interpersonal psychotherapy group was found to experience significantly lower scores on two common depression inventories.[46] Most of the psychotherapy studies were conducted on small samples in the pre-HAART era, and there is a need for randomized controlled trials of psychotherapy interventions that are conducted on larger and more representative samples for longer treatment durations.

More recently, other treatment modalities for depression have been studied and appear to be useful either in addition to medication or psychotherapy, or perhaps as an alternative in cases of mild depression. Exercise has been found to be effective in reducing depressive symptoms among HIV-infected persons.[47,48] In a study of HIV-infected adolescents, weekly massage over 12 weeks reduced anxiety and depression symptoms (as well as significantly increased CD4 and NK cell counts and CD4/CD8 ratio) among the massage group than among matched peers in a muscle relaxation control group.[49] This study was in an adolescent population only and adult studies are needed to confirm the effect. However, because the effect of massage is presumed to be similar between adult and adolescent populations, HIV-infected adults may benefit from this intervention as well.

Referral

Psychiatric or psychological referral may be particularly helpful not only when primary care physicians feel uncomfortable managing psychiatric therapy or lack psychotherapeutic experience, but also when patients are in need of more intensive treatment. Patients should be referred to a psychiatrist when they are refractory to a second course of antidepressant therapy, as described above, or when a specialized form of treatment is considered. Referral to a psychotherapist can be considered at any time, and may be particularly important when patients are reluctant to receive pharmacological therapy. Inpatient care should be considered when outpatient management is unsuccessful or the patient is at risk of self-harm or harm to others.[24] The pharmacologic management of these complex patients can be very challenging. Several HIV clinics in urban areas have intergrated psychiatrists who specialize in the treatment of patients with HIV disease into their clinical infrastructure, but psychiatrists with this specialization may be more difficult to find in rural areas.[6]

Anxiety Disorders

Epidemiology. The prevalence rate of anxiety disorders among HIV-infected patients has been estimated to be as high as 38%.[4] Symptoms of anxiety, especially anxiety around death, has been noted to significantly impede antiretroviral adherence.[4,17,50] Death anxiety is common among HIV-infected patients, and has been associated with symptoms of post-traumatic stress disorder (PTSD). Along with PTSD, panic disorder has also been frequently observed among HIV-infected patients.[4]

PTSD may result from exposure to or witnessing of an unusually traumatic event, which involves the actual threat of death of serious physical injury.[21] Rates of violence and abuse faced by HIV-infected patients are extremely high; violence faced by HIV-infected women in particular has been extensively described.[51] Among a nationally representative sample of 1421 patients in HIV care, 26.8% of those in a close relationship (14% of the overall sample) reported being abused in that relationship.[52]

Symptoms. Anxiety has a large differential diagnosis, and may range in severity from a nearly undetectable, mild sense of unease to debilitating panic attacks.[9] Too often, symptoms of anxiety are attributed to patient personality; patients should be properly screened for anxiety disorders both for their well being (health and quality of life) and to prevent conflict and poor outcomes when managing the patient's HIV infection.[23]

Clinicians may notice that treated anxiety reduces or eliminates somatic symptoms that were initially attributed to HIV disease. Somatic and autonomic symptoms may include chest pain, sweating, tingling, palpitations, hyperventilation, shortness of breath, gastrointestinal irritation, nausea, muscle tension and headaches. Because anxiety is associated with endocrine changes and the neurotransmitters norepinephrine and serotonin, patients with untreated anxiety can experience arrhythmias and hypertension. Chronic anxiety has been associated with increased cardiovascular morbidity and mortality.[53] In addition, there is a growing body of evidence that emotional stress, like that produced during anxiety, may, through neuroendocrine mechanisms, impact immunological functions.[54-58] Because the amount of stress individuals with anxiety disorders experience is on a continuum, the clinical relevance of such effects, if they occur, is currently unknown. When symptoms of anxiety are severe, patients are at risk for suicide when provoked by a stressful trigger (especially those patients with panic disorder), even when the anxiety is not accompanied by depression.[9]

Specific criteria for diagnosing panic disorder and PTSD are provided in the DSM-IV-TR.[21] The symptoms of panic disorder include not only the sympathetic symptoms common to many anxiety disorders (palpitations, accelerated heart rate, sweating), but also symptoms such as a sense of choking, shortness of breath, nausea, dizziness, shaking, paresthesias, and hot or cold flashes. These symptoms will occur as intermittent panic attacks, during which fear and somatic symptoms will peak within 10 minutes and generally resolve within a half-hour if the patient is left untreated in a calm environment. To meet the DSM-IV-TR criteria of panic disorder, a patient's panic attacks must be associated with more than 1 month of persistent worry about having another attack, the consequences of an attack, or significant behavioral changes related to the attack.[21] Panic disorder may coexist with mood disorder; in the general population, the lifetime prevalence of MDD is 50-60% among patients diagnosed with panic disorder.[59] Women are more likely than men to be diagnosed with anxiety disorders, particularly panic disorder.[60]

The symptoms of PTSD include nightmares, marked physiologic hyper-responsiveness, avoidance of situations or activities that remind a patient of the traumatic event, detachment and isolation from other people, and a foreshortened sense of the future. PTSD can be an especially challenging clinical management problem, as 80% of patients with PTSD have a co-morbid psychiatric disorder, and patients with PTSD may exhibit their symptoms after a delay of several months following the trauma.[21] PTSD symptoms may manifest as avoidance of the healthcare system.

Diagnostic Evaluation. The diagnostic workup of an HIV-infected patient presenting with signs of anxiety disorder should begin with an evaluation of the patient's recent medication and substance use history (especially stimulants like cocaine and methamphetamine), previous psychiatric history, and sleep patterns. Because most anxiety disorders appear in adolescence or young adulthood, patients will often have a history of symptoms before being infected with HIV.[4] A notable exception is panic disorder, which has a bimodal distribution of onset (15-24 years of age and 45-54 years of age).[61] A detailed history and review of symptoms can expose the anxiety symptoms. Screening should include questions about the patient's consumption of caffeine-containing foods and beverages, over-the-counter medications (e.g., pseudoephedrine), herbal drugs and street drugs. Information regarding the patient's sleep patterns, including episodes of apnea or jerking movements, may be ascertained from the patient's partner. A suicide screening, as described above, should be performed. Finally, HIV-infected patients with symptoms of anxiety should be screened for exposure to domestic violence.

Patients with panic disorder will often present to the emergency department with dyspnea, chest pain, or worsening symptoms of underlying asthma or chronic obstructive pulmonary disease. The emergency room physician must first rule out medical causes.[61] A full evaluation of anxiety in the HIV-infected patient includes an evaluation to rule out infectious diseases and metabolic etiologies (see Table 4). If anxiety presents atypically, or if there are specific physical exam findings, a more detailed assessment may begin with ruling out central nervous system disorders through electroencephalography, lumbar puncture, or brain computed tomography, depending upon clinical suspicion.

Instruments designed to assist in the diagnosis of anxiety have not been as well studied as those used to diagnose depression. The PRIME-MD section on panic disorder is among the most commonly used instruments for this purpose.[62] The Hamilton Rating Scale for Anxiety[63] is a more general measure of anxiety, which is commonly used in psychiatric clinical trials. If a provider elicits a history of significant trauma, a diagnostic instrument for PTSD might be useful; the PTSD Checklist has been shown to be a reliable and valid measure of symptom severity.[64,65] If the patient's symptoms have resulted in an impaired functional status or the symptoms appear unmanageable for the primary care physician, the patient should be referred to specialty care.

Treatment. While anxiety symptoms are well managed with pharmacological therapies, many anxiety syndromes can be treated without the use of medications. Patients should begin treatment with the cessation of caffeine and over-the-counter products containing ephedrine. Additionally, a regular exercise program can also reduce symptoms. Basic counseling has been helpful when patients have concerns revolving around particular situations or conditions (e.g., death); support groups may be particularly useful in addressing these concerns.[61] One model program tested among asymptomatic HIV-infected men involved 20 biweekly sessions of stress management; this produced significant improvements in anxiety, mood and CD4 cell counts among participants, as compared to untreated matched subjects.[66]

CBT for stress management has been found to reduce anxiety in a population of HIV-infected gay men compared to matched controls,[67] as well as among a group of 39 HIV-infected patients referred to a psychiatry service.[68] CBT has also been found useful for patients with specific phobias, obsessive-compulsive disorder (OCD) and panic disorder.[69] Marital, family, and group therapy have been used to treat a variety of severe anxiety disorders.[70] Medications may nevertheless be necessary when the symptoms of anxiety are severe and are not responsive to psychotherapy. Early treatment has been found to improve prognosis and limit impairment, but the clinician may attempt to treat all other potential sources of anxiety first before prescribing medications for anxiety symptoms.[4]

SSRI are the first-line pharmacologic therapy for several anxiety disorders.[61] Specific agents have been approved by the Food and Drugs Administration for each of the major anxiety disorders: generalized anxiety disorder (paroxetine), social phobia (paroxetine), OCD (fluoxetine, sertraline, paroxetine, and fluvoxamine), and PTSD (sertraline). Nevertheless, all of the SSRI are likely to be of equal efficacy for any of the anxiety disorders. Clinicians should be aware that treatment of anxiety disorders may require higher SSRI dosages than treatment of depression. The partial serotonin (5-HT1A) agonist, buspirone, has been shown to be effective for treating several anxiety disorders. Buspirone has a low abuse potential. It is minimally sedating and has no known withdrawal effects. Buspirone may, however, take up to 4 weeks before producing noticeable therapeutic effects.

Propanolol and similar beta-adrenergic antagonists may be used as pharmacologic augmentation agents for anxiety disorders, but they are not appropriate monotherapies for panic disorder. These medications are contra-indicated in patients who are using cocaine and may also cause depression, fatigue, and sexual dysfunction.[71] TCA have been used as alternative second-line agents.[35]

Benzodiazepines are effective anxiolytics and therefore may have a place in the care of patients with severe anxiety disorders, or in those who cannot tolerate the initiation of an SSRI trial.[23] Benzodiazepines may be most useful in the short-term, during the initial 2-4 weeks, while SSRI treatment is begun.[23] There is understandable hesitancy among many clinicians to prescribe benzodiazepines to patients with substance use histories, given their ease of abuse, potential for dependence and potential for diversion.[35] Establishing a relationship based on trust is crucial to a clinician's knowledge of how to appropriately prescribe and dose potentially addictive medications.

Benzodiazepines are most useful when patients are experiencing acute situational anxiety disorder, for panic attacks that need immediate control, or if they will be receiving pharmacological therapy for less than 6 weeks.[9] However, benzodiazepine use is associated with poorer outcomes when used among patients with PTSD.[72,73] Tolerance to benzodiazepines develops rapidly, even at low doses. Additionally, many benzodiazepines have significant pharmacokinetic interactions with antiretroviral therapy.[23] Within the class of benzodiazepines, all drugs tend to have equal efficacy; however, based on drug interaction profiles, lorazepam and temazepam might have advantages.[35] Clinicians should be particularly careful when discontinuing benzodiazepines, as they require a taper to prevent acute withdrawal symptoms. Withdrawal from benzodiazepines may prompt relapse of anxiety symptoms, along with an influenza-like illness that may include life-threatening seizures and delirium.[9] Although anticonvulsant agents have also been used in patients with histories of substance use to treat anxiety disorders,[67,71] such modalities should be used only by experienced psychiatrists.

During treatment, a patient should be assessed every 2 weeks. If patients do not respond to initial therapy several factors must be considered: re-assessing the accuracy of the initial diagnosis, confirming patient adherence to therapy, adjusting the medication dosage or treatment duration, and screening for other comorbid psychiatric illnesses (e.g., substance use disorders or obsessive-compulsive disorder). After screening out these confounding elements, a referral to a psychiatrist is warranted.

Future Areas of Research

While effective strategies are available to identify and treat depression and anxiety in HIV-infected patients, several areas of uncertainty call for further research. Future prospective, controlled trials must be conducted to evaluate the impact of various psychological intervention strategies on larger, more generalizable cohorts; this is particularly important for clinicians seeking to decrease pill burdens for patients hesitant to take many pills. Research on the efficacy of depression and anxiety treatments for adolescents, women, and the aging HIV-infected population are also key topics for future research as current data on these populations is limited. We suggest that researchers also extend their studies to construct and evaluate new simplified screening instruments that may be specially designed for the HIV-infected population. Finally, because substance use is frequent in HIV-infected individuals with depression and/or anxiety, the development of reliable instruments able to distinguish true depression and/or anxiety in the setting of substance use from substance induced mood disorders would be of great value.

Conclusion

Management of the HIV-infected has become increasingly complex. It requires that the HIV treating clinician be aware of and have facility with diagnosing and treating co-morbid psychiatric conditions. There is ample evidence that depression and anxiety can be effectively treated by the primary care provider, including the treating HIV clinician.



Table 1. Diagnostic Workup for Depression in the HIV-infected Patient

Table 1

Table 2. Depression Screening Instrument

Table 2

Table 3. Use of Common Antidepressant Medications in HIV-infected Patients

Table 3

Table 4. Diagnostic Workup for Anxiety in the HIV-infected Patient

Table 4