Clinical Manual for Management of the HIV-Infected Adult
2006 Edition

Section 8: Neuropsychiatric Disorders

Depression

Background

Major depression is a cause of significant morbidity among people with HIV disease. Management of this condition may be complicated by its multifactorial etiology. A diagnosis of HIV may not only cause psychological crisis, but may also complicate underlying psychological or psychiatric problems (eg, preexisting depression, anxiety, or substance abuse). In addition, direct viral infection of the central nervous system (CNS) can cause several neuropsychiatric syndromes. Finally, both constitutional disease and medications can impair neurologic function and mood.

The clinician's task is 4-fold:

• Maintain a high index of suspicion for depression and screen frequently for mood disorders.
• Elicit any history of psychiatric diagnoses or treatment.
• Rule out organic causes of mood or functional alterations.
• Refer for appropriate psychiatric evaluation and psychosocial support, including substance abuse counselors and domestic violence service providers.

Patients with untreated depression experience substantial morbidity and may become self-destructive or suicidal. They are also at continuing risk for unsafe behaviors that may lead to HIV transmission.

Major depression in persons with comorbid medical illness, including HIV infection, has been associated with numerous adverse events, such as the following:

• Decreased survival
• Impaired quality of life
• Decreased treatment adherence
• Longer hospital stays
• Increased risk behaviors
• Suicide

Although depression occurs independently of physical symptoms, recent research has concluded that it is associated with higher mortality rates in HIV-infected individuals. Stress and depressive symptoms, especially when they occur jointly, are associated with diminished immune defenses in HIV-infected individuals.

S: Subjective

The patient may complain of the following:

• Appetite changes with weight changes (increase or decrease)
• Decreased ability to concentrate
• Depressed mood, sadness, hopelessness
• Diminished interest or pleasure in activities
• Fatigue or loss of energy
• Feelings of worthlessness or guilt
• Insomnia or hypersomnia
• Psychomotor agitation or retardation
• Recurrent thoughts of death or suicide

History

Inquire about the symptoms listed above, and about associated symptoms. If 5 of these symptoms occur on most days for at least 2 weeks, a clinically significant major affective disorder is present and requires intervention. Depressed mood or diminished interest or pleasure must be 1 of the 5 symptoms present.

Take a careful history of the timing of symptoms, their relationship to life events (eg, HIV testing, loss of a friend) and any other physical changes noted along with the mood changes. Elicit personal and family histories of depression or suicidal behavior. Probe for suicidal thoughts, plans, and materials to execute the plans. Inquire about hallucinations, paranoia, and other symptoms. Take a thorough history of medication use and substance abuse.

O: Objective

Perform mental status examination, including affect, mood, orientation, appearance, agitation, or psychomotor slowing; perform neurologic examination if appropriate.

A: Assessment

Partial Differential Diagnosis

Rule out nonpsychiatric causes of symptoms, which may include the following:

• Vitamin B12, folate (B6), zinc, or vitamin A deficiency
• Hypothyroidism or hyperthyroidism
• Endocrine disorders such as Addison disease or hypotestosteronism (hypogonadism)
• HIV dementia or minor cognitive motor disorder
• HIV encephalopathy
• Neurosyphilis
• Opportunistic illnesses affecting CNS (eg, toxoplasmosis, cryptococcal disease, CNS cytomegalovirus, progressive multifocal leukoencephalopathy)
• Medication adverse effects (eg, from steroids, efavirenz, isoniazid, interferon-alfa)
• Substance-induced mood disorder (intoxication or withdrawal)

Partial Psychiatric Differential Diagnosis

• Adjustment disorder (eg, acute reaction to a life crisis, such as HIV diagnosis, bereavement, job loss)
• Anxiety disorders
• Bereavement
• Dysthymia (depressed mood of long duration with less intensive symptoms)
• Psychotic depression

P: Plan

Laboratory

Check thyroid function tests and vitamin B12, folate, and testosterone levels.

Treatment

Make sure that the patient has been referred to available community organizations for support.

Refer immediately for psychiatric evaluation or treatment if the patient is:

• Suicidal (see chapter Suicidal Ideation)
• Displaying psychotic symptoms
• Debilitated or functionally impaired by severe symptoms
• Not responding to treatment

Psychotherapy

Individual psychotherapy with a skilled, HIV-experienced mental health professional can be very effective in treating depression. The combination of psychotherapy and antidepressant medication is more effective than either treatment modality alone.

Pharmacotherapy

When selecting antidepressant medications, consider their side effect profiles as a means to treat other symptoms. For example, activating medications can be taken in the morning if the patient complains of low energy; medications that increase appetite may be useful for patients with wasting syndrome; sedating medications may be taken at bedtime if the patient complains of sleep problems.

Monitor patients closely after starting antidepressant medications. Some patients may be at risk of worsening depression, including suicidality, after initiation of therapy.

Because of the potent inhibition of the microsomal cytochrome P450 isoenzymes by protease inhibitors (especially ritonavir), antidepressants used concomitantly with protease inhibitors should be started at low dosages and titrated cautiously to prevent antidepressant adverse effects and toxicity. Interactions between selective serotonin reuptake inhibitors (SSRIs) and HIV medications are fairly common. For patients who are starting antiretroviral medications (particularly protease inhibitors) and are on a stable antidepressant regimen, an empiric dosage reduction of antidepressant therapy should be considered, especially if the antidepressant dosage is at the high end of the range or the patient is having adverse effects of the antidepressant before starting antiretroviral therapy. Consultation with an HIV expert, psychiatrist, and clinical pharmacist can assist in developing an effective antidepressant and HIV therapy combination.

A therapeutic trial consists of treatment for 4-6 weeks at a therapeutic dosage. Medications should be continued for 6-9 months beyond the resolution of symptoms to reduce the risk of recurrence. After this time, treatment may be gradually tapered if the patient wishes, with careful monitoring for recurrence of symptoms. The risk of recurrence is higher if the first depressive episode is inadequately treated or if the patient has had multiple depressive episodes.

Table 1 lists the available antidepressant medications (SSRIs and serotonin/norepinephrine reuptake inhibitors [SNRIs]), including therapeutic dosages and possible positive and negative effects.

Table 1. SSRI and SNRI Antidepressant Medications and Possible Positive and Negative Effects

Medication: Usual Dosage Possible Positive Effects Possible Negative Effects Fluoxetine (Prozac): 10-40 mg once daily Rarely sedating, often energizing, no cardiovascular adverse effects, no anticholinergic effects, nonfatal in overdose Insomnia, agitation, nausea, headache, sexual dysfunction in men and women, long half-life Paroxetine* (Paxil): 10-40 mg once daily May be sedating (for patients experiencing sedation with paroxetine, dose at bedtime; can be useful with depression-associated insomnia) Insomnia, agitation (for patients experiencing these effects, administer dose in mornings), nausea, headache, sexual dysfunction in men and women Sertraline (Zoloft): 50-100 mg once daily May have lower incidence of significant drug-drug interactions compared with fluoxetine and paroxetine; nevertheless, start with lower dosages when this medication is used with protease inhibitors Insomnia, agitation, nausea, headache, sexual dysfunction in men and women, long half-life Venlafaxine XR** (Effexor XR): 75-375 mg once daily May have lower risk of significant drug-drug interactions compared with SSRIs Nausea, headache, nervousness, sexual dysfunction Citalopram (Celexa): 10-60 mg once daily or escitalopram (Lexapro): 10-20 mg once daily May have lower risk of significant drug-drug interactions than other SSRIs Mild nausea, possible sedation

* When discontinuing paroxetine therapy, carefully titrate the dosage reduction to avoid serious adverse effects associated with abrupt discontinuation. Such effects include confusion, agitation, irritability, sensory disturbances, and insomnia. ** Note: Monitor blood pressure at higher dosages of venlafaxine.

Other Agents

Newer antidepressants such as mirtazapine may be particularly useful in patients who have significant insomnia and in those who have experienced sexual dysfunction with other antidepressant agents such as SSRIs.

• Mirtazapine (Remeron) should be administered at bedtime because of its sedating effects. Sedation is commonly noted with the starting dosage of 15 mg once daily, but may be lessened by increasing the dosage to 30 mg at bedtime. Individuals may also experience an increase in appetite, weight gain, and dry mouth. Mirtazapine has minimal drug-drug interactions. The therapeutic dosage range is 15-45 mg once daily. Consider starting with 15 mg at bedtime for 7 days, then increasing to 30 mg if sedation is problematic.
• Bupropion (Wellbutrin) sustained-release (SR) or extended-release (XL) formulation may be used in individuals with depression who experience sexual dysfunction with other antidepressant agents. Bupropion SR or XL dosing should not exceed 400 mg per day (the SR formulation should be administered twice daily in divided doses) because of an increased risk of seizures at higher bupropion dosages, particularly in individuals who have other risk factors for seizures. For patients taking protease inhibitors, caution should be used as the dosage approaches 300-400 mg per day because of possible increases in levels of bupropion. Bupropion may have an activating effect, which some patients may experience as agitation, insomnia, or both, and also may have an appetite suppressant effect.
• Nefazodone (Serzone) may cause liver toxicity and generally is not recommended as an antidepressant for patients with HIV/AIDS because of the high rates of preexisting liver abnormalities in HIV-infected patients. This medication has recently received a black box warning regarding severe liver toxicity from the U.S. Food and Drug Administration. If the patient has ever had liver toxicity from the drug, restarting is contraindicated.
• Tricyclic antidepressants may be effective, but in general have a higher risk of adverse effects than SSRIs and are dangerous if overdosed.
• Treatment may involve antidepressant combinations, including psychostimulants.
• Patients with prominent insomnia may benefit from the addition of trazodone 25-50 mg, given 1-2 hours before bedtime.
• St. John's wort is an herbal antidepressant that is contraindicated for use with protease inhibitors and nonnucleoside reverse transcriptase inhibitors. St. John's wort can significantly decrease serum concentrations of these HIV medications.

Patient Education

• Providers should explain to patients that illness (physical or emotional) is not a character flaw or a moral or spiritual weakness. It is an expected aspect of HIV infection. Sadness is a normal part of life, but major depression is always abnormal and often can be alleviated with medication, therapy, or both.
• Antidepressants typically are given for a long time, usually for a year or longer, to help patients with the chemical imbalances associated with depression.
• When starting an antidepressant medication, patients should expect that it will take 2-4 weeks for them to notice any improvement. Their symptoms should continue to decrease over the following weeks. If they do not have much improvement in symptoms, their providers may choose to adjust the dosage of the medication or to change medications. Patients must continue taking their medications so that the symptoms of depression do not return.
• Some patients develop problems with sexual function while they are taking antidepressants. They should report any problems to their prescribers.
• Patients should note the major symptoms of depression and be aware of what factors led them to seek treatment. They will need to monitor themselves for recurrences and get help if the symptoms come back. Providers should explain to patients that if they notice changes in their sleep, appetite, mood, activity level, or concentration, or if they notice fatigue, isolation, sadness or helplessness, it is time to get help.

References

• American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Washington: American Psychiatric Association; 1994.
• Ickovics JR, Hamburger ME, Vlahov D, et al. Mortality, CD4 cell count decline, and depressive symptoms among HIV-seropositive women: longitudinal analysis from the HIV Epidemiology Research Study. JAMA. 2001 Mar 21;285(11):1466-74.
• Leserman J, Petitto JM, Perkins DO, et al. Severe stress, depressive symptoms, and changes in lymphocyte subsets in human immunodeficiency virus-infected men. A 2-year follow-up study. Arch Gen Psychiatry. 1997 Mar;54(3):279-85.
• Mayne TJ, Vittinghoff E, Chesney MA, et al. Depressive affect and survival among gay and bisexual men infected with HIV. Arch Intern Med. 1996 Oct 28;156(19):2233-8.
• Motivala SJ, Hurwitz BE, Llabre MM, et al. Psychological distress is associated with decreased memory helper T-cell and B-cell counts in pre-AIDS HIV seropositive men and women but only in those with low viral load. Psychosom Med. 2003 Jul-Aug;65(4):627-35.
• Schatzberg AF, Nemeroff CB, eds. Textbook of Psychopharmacology. Washington: American Psychiatric Press Inc.; 1998:257-263, 1017.
• Stober DR, Schwartz JAJ, McDaniel JS, et al. Depression and HIV disease: prevalence, correlates and treatment. Psychiatric Annals 1997:27(5):372-377.