Clinical Presentation

• Most of the information in this section, including the epidemiology, is taken from Medical Management of HIV Infection by John G. Bartlett, M.D., Joel A. Gallant, M.D., M.P.H., and Paul A. Pham, Pharm.D.[3]

MOOD DISTURBANCES

• Major depression: seen in about 20% of HIV patients presenting for medical treatment
  • Symptoms: depressed mood, loss of pleasure from activities, anorexia, morning insomnia or hypersomnia, difficulty concentrating, thoughts of suicide
  • Treatment: antidepressants, starting with low doses and titrating slowly:
    • The mainstay of treatment has been SSRI and SNRI antidepressants, although other antidepressants seem to be effective as well.
    • Tricyclic antidepressants (TCAs) may be beneficial in individuals with chronic pain, stomach distress, chronic diarrhea, and depression due to anticholinergic actions.
      • Levels need close monitoring when these drugs are used because of a narrow margin of safety.
• Demoralization (adjustment disorder): seen in about 20% of HIV patients presenting for medical treatment
  • Symptoms: grief, sadness, hopelessness, often precipitated by life circumstances
    • Unlike depression, patients often can enjoy some facets of life and feel best in the mornings.
  • Treatment: psychotherapy and support
• Bipolar disorder: seen in about 9% of hospitalized AIDS patients and in about 3% of HIV patients presenting for medical treatment
  • Symptoms: manic episodes, depressive episodes, and mixed episodes
  • Treatment: For AIDS-related mania, acute management includes antiretroviral therapy (ART)
    • In addition, mood stabilizers such as valproic acid and other anticonvulsants are used, as well as neuroleptics
    • AIDS mania: A syndrome occurring in late stage of HIV infection that has been associated with HIV dementia and rapid deterioration
      • Treatment is ART and low-dose neuroleptics to stabilize behavior.
• Anxiety: a common symptomatic complaint
  • Generalized anxiety disorder shows an 8-fold increase over background, but poor discrimination for specific diagnosis.
  • Panic attacks show a 4-fold increase over background
    • Panic attacks: characterized by recurring anxiety attacks with fear plus somatic symptoms of excitation lasting < 1 hour
    • Treatment is often an SSRI with management by a psychiatrist.

DELIRIUM

• Reported in 12-29% of HIV-infected patients throughout course of illness

• Symptoms: waxing and waning symptoms and level of consciousness, inability to attend, global derangement of brain function, disorganized thinking, may have hallucinations, delusions, paranoid or other psychotic symptoms
• Treatment: correct underlying condition, which is usually multifactorial
  • Minimize anticholinergic drugs, improve orientation and stimulation including improved day-night cues and cycles, and correct medical conditions.
  • Always consider occult sepsis or abscess.
  • For agitation, lowest useful dose of neuroleptics

COGNITIVE DISTURBANCES

• The neurocognitive disorders (NCDs) that result from HIV infection have historically shown a "subcortical pattern" with prominently impaired executive function, slowing of processing speed, problems with more demanding attentional tasks, difficulty in learning new information, and subtle motor difficulty.
  • Unlike those with some other dementias, these individuals show fewer problems with recall of learned information.
  • This pattern has changed with an aging HIV population and ART to include more cortical deficits, resulting in a more mixed picture of deficits.
• Although it varies by stage of disease, one-third to one-half of HIV-infected individuals have at least mild NCD[4].
  
  • 25% of individuals with HIV will have signs and symptoms that meet criteria for mild NCD.
  • 5% of individuals with HIV will have signs and symptoms that meet criteria for major NCD.
  • NCD due to HIV infection has not declined significantly with the advent of combined ART, although the most severe presentations have decreased sharply.
• More prevalent in individuals with prior episodes of severe immunosuppression, high viral loads in the cerebrospinal fluid (CSF), and indicators of advanced HIV disease.
• In most severe cases, may see neuromotor features such as severe incoordination, ataxias, and motor slowing.

SUBSTANCE USE DISORDER

• Concern arises when there is use of substances despite clear evidence of negative consequences.

• Dependence: persistent use or seeking use, withdrawal, tolerance, and physical dependence
• As in other individuals, those infected with HIV benefit from methadone or buprenorphine treatment for opiate dependence.

Tests and Procedures

• HIV antibody test confirmed by Western Blot is the current standard, but it is dependent on the development of HIV antibody, which might be delayed for some weeks after infection.
  • Because of the potential benefits of early treatment, and because acutely infected patients can present with mental state changes, in cases with a high index of suspicion (known risk factors for HIV infection), use PCR as a direct measure of viral particles.
• CSF analysis may be helpful if it shows a disproportionately high viral load in CSF vs. the plasma, as well as for ruling out CNS opportunistic infections (such as tuberculosis, cryptococcal meningitis, syphilis, and cytomegalovirus).
• Neuroimaging (in particular MRI) is useful in patients with advanced disease to rule out AIDS-related illnesses.
  • e.g. opportunistic infections such as toxoplasmosis or cryptococcus
  • e.g. CNS malignancy such as lymphoma
  • Neuroimaging may also show reduction in total brain volume, cortical thinning, reduction in white matter volume, and patchy areas of abnormal white matter (hyperintensities)[1].

Differential Diagnosis

• Infection: e.g., opportunistic infections of the brain (toxoplasmosis, cryptococcus)
• Deficiencies: e.g., vitamin B6, B12, A; zinc
• Endocrine Disorder: e.g., thyroid disease, adrenal insufficiency, hypogonadism
• Neoplasia: e.g., CNS lymphoma
• Medication Adverse Reactions: e.g., efavirenz, corticosteroids, interferon
• Substance misuse
• If cognitive impairment, other neurodegenerative disorder: e.g., Alzheimer disease

General

• Ideally, treatment of HIV-infected individuals takes place within a multidisciplinary team.
  • On that team, there should be an infectious disease physician, a psychiatrist, social workers, case managers, and nursing staff.
• Priority must be given to adherence to ART, while at the same time focusing on adherence to any prescribed psychiatric pharmacotherapy.

Pharmacotherapy

• Drug-drug interaction monitoring is vitally important, especially since individuals with HIV are often on multidrug regimens[5].
  
  • Despite this, there are many options for treatment of psychiatric conditions.
• It is not clear how often psychotropics adversely impact antiretroviral blood levels (causing either toxicity or failure).
• All protease inhibitors and nonnucleoside (or nucleotide) reverse-transcriptase inhibitors (NNRTIs) are metabolized by the cytochrome P450 system and possess enzyme-inhibiting or enzyme-inducing properties.
  • Ritonavir (metabolized by CYP3A4 and 2D6) may be associated with the most significant interactions because of its potent inhibition of CYP3A, 2D6, 2C9, and 2C19 isoenzymes.
  • Amprenavir, indinavir, and nelfinavir are all metabolized by CYP3A4 and are moderately potent CYP3A4 inhibitors.
  • Nevirapine and efavirenz are potent inducers of CYP3A4, whereas delavirdine and efavirenz may inhibit CYP3A4, 2C9, and 2C19.
• The nucleoside reverse-transcriptase inhibitors (NRTIs) have fewer theoretical P450 interactions, making them less vulnerable to interactions with psychotropic medications.
  • Zidovudine plasma levels, however, can be increased by concurrent use of methadone or valproic acid.
• Please review the drug modules of the guide for detailed information on how each drug class affects the cytochrome P450 system. In brief:
  • All SSRIs may potentially interact with ART leading to a potential for increased levels of SSRI when used in combination with P450 inhibitors.
  • Trazodone, often used as an adjunctive sleeping agent, may show increased levels when combined with P450 inhibitors.
  • Bupropion levels may be increased when used with P450 inhibitors; studies have not shown an increase in the number of seizures.
  • TCAs when combined with P450 inhibitors increase TCA levels; close monitoring for symptoms of TCA toxicity are important.
  • Of the benzodiazepines, alprazolam, midazolam, and triazolam are dependent on P450 metabolism, and potent inhibitors, such as ritonavir, can decrease clearance of these drugs and result in oversedation and possibly death.
    • Oxazepam, lorazepam, and temazepam are metabolized by glucuronidation, and ART that increases the activity of glucuronidation, such as ritonavir or nelfinavir, may lower the levels of these drugs.
  • Valproic acid does not appear to exhibit significant P450-based drug interactions with ARTs.
  • Concentration of neuroleptics may be increased by ARTs with P450 inhibition.

Psychotherapy

• Supportive psychotherapy, whether informal or formal, has a role for all HIV-infected patients.
• Cognitive behavioral therapy (CBT) may be a useful method for helping patients with medication adherence.