Major Depression and Other Depressive Disorders


Major depression is the most prevalent psychiatric comorbidity among people with HIV infection and commonly has a significant impact on health. The etiology may be multifactorial, as with depression in HIV-uninfected persons, but HIV infection may bring additional complexity. A diagnosis of HIV may cause a psychological crisis, but also may complicate underlying psychological or psychiatric problems (e.g., preexisting depression, anxiety, or substance abuse). Direct viral infection of the central nervous system (CNS) can cause several neuropsychiatric syndromes. In addition, both HIV-related medical conditions and HIV medications can cause or contribute to depression.

Patients with untreated depression experience substantial morbidity and may become self-destructive or suicidal. They are at continuing risk of engaging in unsafe behaviors that may lead to HIV transmission and poor adherence to care and treatment.

Major depression in persons with comorbid medical illness, including HIV infection, has been associated with the following:

  • Decreased survival
  • Impaired quality of life
  • Decreased adherence to antiretroviral therapy (ART)
  • Increased risk behaviors
  • Suicide
  • Longer hospital stays and more frequent medical visits (e.g., emergency room, medical clinics)
  • Higher treatment costs

Stress and depressive symptoms, especially when they occur jointly, are associated with diminished immune defenses in HIV-infected individuals, and severe depression is associated with higher mortality rates. Anxiety symptoms are common among people with major depression (see chapter Anxiety Disorders). Psychotic symptoms may occur as a component of major depression and are associated with an increased risk of suicide. Even one or two symptoms of depression increase the risk of an episode of major depression.

All clinicians should do the following:

  • Maintain a high index of suspicion for depression and screen frequently for mood disorders.
  • Elicit any history of psychiatric diagnoses or treatment.

Rule out medical conditions that may cause mood or functional alterations.

Refer for psychiatric evaluation and psychosocial support, including, as appropriate, to substance abuse counselors and domestic violence service providers.

A screening test for depression such as the Patient Health Questionnaire-2 (PHQ-2) should be administered yearly or whenever a patient's complaints or symptoms suggest depressive disorders.

Patient Health Questionnaire-2 (PHQ-2)

Over the past 2 weeks, how often have you been having little interest or pleasure in doing things?

0 = Not at all
1 = Several days
2 = More than half the days
3 = Nearly every day

Over the past 2 weeks, how often have you been feeling down, depressed, or hopeless?

0 = Not at all

1 = Several days

2 = More than half the days

3 = Nearly every day

Calculate the total point score:

Score interpretation: Patient Health Questionnaire-2 (PHQ-2)
ScoreProbability of major depressive disorder (%)Probability of any depressive disorder (%)

Depression is diagnosed, as in HIV-uninfected individuals, according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5.

Major Depression

The patient may complain of either or both of two cardinal symptoms:

  • Diminished interest or pleasure in activities
  • Depressed mood, sadness

If either or both of these are present, other complaints may be used to diagnose major depression, including the following:

  • Decreased ability to concentrate
  • Appetite changes with weight changes (increase or decrease)
  • Fatigue or loss of energy
  • Feelings of worthlessness or guilt
  • Insomnia or hypersomnia
  • Psychomotor agitation or retardation
  • Recurrent thoughts of death or suicide

The diagnosis of major depression is made if five of the above symptoms occur on most days for at least 2 weeks. Depressed mood or diminished interest or pleasure must be one of the five symptoms present.

Other subjective symptoms of depression may include the following:

  • Hopelessness
  • Helplessness
  • Irritability or anger
  • Somatic complaints in addition to those noted above

Other Depressive Disorders

  • Persistent depressive disorder: A new DSM category that subsumes dysthymia and chronic major depressive disorder. This is another very common depressive disorder found among HIV-infected patients. Treatments for major depression and persistent depressive disorder are similar.

Dysthymia has been characterized by more chronic but less severe symptoms than those found in major depression. The diagnosis is made when a person has had a depressed mood for most of the day, for more days than not, for at least 2 years. While depressed, the patient exhibits two or more of the following symptoms:

  • Poor appetite or overeating
  • Insomnia or hypersomnia
  • Low energy or fatigue
  • Low self-esteem
  • Poor concentration or difficulty making decisions
  • Feelings of hopelessness

In addition, the symptoms must cause clinically significant distress or impairment in functioning, and there can have been no major depressive episode during the first two years of the disturbance.

  • Bipolar disorder: Major depression may be a manifestation of bipolar disorder. Bipolar disorder should be ruled out before giving an antidepressant to a patient with major depression, as bipolar disorder usually requires the use of mood stabilizers before, or instead of, beginning antidepressant medications (antidepressant therapy may precipitate a manic episode). Bipolar disorder should be suspected if a patient has a history of episodes of high energy and activity with little need for sleep, has engaged in risky activities such as buying sprees and increased levels of risky sexual behavior, or has a history of taking mood stabilizers (lithium and others) in the past. If bipolar disorder is suspected, refer the patient to a psychiatrist for further evaluation and treatment.
  • Other forms of depression include adjustment disorder with depressed mood (acute reaction to a life crisis, such as the loss of a job), premenstrual dysphoric disorder, disruptive mood dysregulation disorder, and depressive disorder not otherwise specified.

S: Subjective

  • Inquire about the symptoms listed above, and about associated symptoms.
  • Take a careful history of the timing and duration of symptoms, their relationship to life events (e.g., HIV testing, loss of a friend, onset of physical symptoms), and any other physical changes noted along with the mood changes.
  • Elicit personal and family histories of depression, bipolar disorder, or suicidal behavior.
  • Probe for suicidal thoughts, plans, and materials to execute the plans (see chapter Suicide Risk).
  • Inquire about hallucinations, paranoia, and other symptoms.
  • Ask about current and past medication use and substance abuse.

O: Objective

Perform mental status examination, including evaluation of affect, mood, orientation, appearance, agitation, or psychomotor slowing; perform thyroid examination, inspection for signs of self-injury, and neurologic examination if appropriate.

A: Assessment

Partial Differential Diagnosis

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

  • Hypothyroidism or hyperthyroidism
  • Hypotestosteronism (hypogonadism) - very common with HIV disease in both men and women
  • Other endocrine disorders such as Addison disease
  • Substance-induced mood disorder (intoxication or withdrawal)
  • Medication adverse effects (e.g., from steroids, efavirenz, isoniazid, or interferon-alfa)
  • HIV dementia or minor cognitive motor disorder
  • HIV encephalopathy
  • Neurosyphilis
  • Opportunistic illnesses affecting the CNS (e.g., toxoplasmosis, cryptococcal disease, CNS cytomegalovirus, progressive multifocal leukoencephalopathy)
  • Vitamin B12, folate (B6), zinc, vitamin A, or vitamin D deficiency

P: Plan


The diagnosis is based on clinical criteria as indicated above. Rule out medical and other causes. An initial screening includes the following:

  • Complete blood count, electrolytes, creatinine, blood urea nitrogen (BUN), glucose
  • Thyroid function tests (thyroid stimulating hormone [TSH], T4)
  • Vitamin B12, vitamin D, and folate levels
  • Testosterone (both in men and women)
  • Other tests as suggested by history and physical examination


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

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

The combination of psychotherapy and antidepressant medication is more effective than either treatment modality alone. Social support interventions (e.g., community-based HIV support groups) also can help; refer to available resources. Patients should be encouraged to discontinue alcohol or substance use, and should be referred for treatment as indicated.


Individual psychotherapy with a skilled, HIV-experienced mental health professional can be very effective in treating depression. Several specific types of individual and group psychotherapies for depression (e.g., interpersonal therapy, cognitive-behavioral therapy, behavioral activation, supportive psychotherapy, coping effectiveness) have been shown to be effective for HIV-infected individuals.


For most patients, a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) is the most appropriate initial treatment for depression. For patients who experience treatment failure with these agents (or have an incomplete response) at a customary therapeutic dosage, consultation with a psychiatrist is recommended.

When selecting antidepressant medications, consider their side effect profiles as a means to manage other symptoms the patient may be experiencing. For example, activating antidepressants (taken in the morning) may help patients who complain of low energy; antidepressants that increase appetite may be useful for patients with wasting syndrome; sedating antidepressants (taken at bedtime) may help patients with insomnia. Medications that may be lethal if overdosed (e.g., tricyclic antidepressants) should not be prescribed to patients for whom suicidality may be a concern.

The information below describes specific antidepressant medications, with information on dosage and possible adverse effects. Most antidepressants should be started at low dosages and gradually titrated upward to avoid unpleasant side effects that might lead to nonadherence. Antidepressant effect usually is not noticed until 2-4 weeks after starting a medication. If there is no improvement in symptoms in 2-4 weeks, and there are no significant adverse effects, the dosage may be increased.

A therapeutic trial consists of treatment for 4-6 weeks at a therapeutic dosage. If the patient's symptoms have not improved, an increase in dosage or a switch to another medication should be considered. Patients who remain depressed should be referred to a psychiatrist.

Monitor all patients closely after starting them on antidepressant medications. Depressive symptoms may continue to worsen while on medication; improved energy is the initial effect of antidepressants, whereas hopelessness and sadness improve later. In addition, some young persons are at risk of worsening depression caused by antidepressants. Black-box warnings advise that antidepressants may cause increased risk of suicidality in children, adolescents, and young adults (<24 years of age) with major depressive or other psychiatric disorders, especially during the first month of treatment.

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 tapered down gradually if the patient wishes, with careful monitoring for depressive symptoms. The risk of recurrence is higher if the first depressive episode is inadequately treated or if the patient has had multiple depressive episodes. For patients with recurrent depression, consider long-term maintenance antidepressant treatment. See "Discontinuing antidepressant medication," below.

Potential ARV Interactions

Interactions may occur between certain ARVs and agents used to treat depression. Some combinations may be contraindicated and others may require dosage adjustment. Refer to medication interaction resources or consult with an HIV expert, psychiatrist, or clinical pharmacist before prescribing.

Some ARV medications (particularly protease inhibitors [PIs]) and the pharmacokinetic booster cobicistat may affect the metabolism of some antidepressants via cytochrome P450 interactions. For example, ritonavir can significantly increase serum levels of tricyclic antidepressants, increasing the risk of tricyclic toxicity. In the case of most other antidepressants, interactions with ARVs generally are not clinically significant, but most antidepressants used concomitantly with PIs or cobicistat should be started at low dosages and titrated cautiously to prevent antidepressant adverse effects and toxicity. On the other hand, some PIs may decrease levels of paroxetine, sertraline, and bupropion, and efavirenz also lowers sertraline and bupropion levels; these antidepressants may require upward titration if used concurrently with interacting ARVs. Further information is presented under individual agents and classes, below.

For patients who are starting ARV medications (particularly PIs) or cobicistat and are on a stable antidepressant regimen, monitor carefully for adverse effects and for efficacy of the antidepressant; dosage adjustments may be required.

The available antidepressant medications (SSRIs and SNRIs), including therapeutic dosages and possible positive and negative effects, are listed in Table 1.

Table 1. SSRI and SNRI Antidepressant Medications and Possible Positive and Negative Effects
Medication/Usual DosagePossible Positive EffectsPossible Negative Effects
SSRIsNo anticholinergic or cardiovascular effects, nonfatal in overdose; may help treat anxiety
  • Sexual dysfunction (men and women)
  • Serotonin withdrawal syndrome if discontinued abruptly
Citalopram (Celexa):
10-60 mg QD
May have lower risk of significant drug-drug interactions than other SSRIsMild nausea, possible sedation
Escitalopram (Lexapro): 10-20 mg QDMay have lower risk of significant drug-drug interactions than other SSRIsMild nausea, possible sedation
Fluoxetine (Prozac):
10-40 mg QD
Rarely sedating, often energizing, lower risk of SSRI withdrawal syndrome if discontinued abruptlyInsomnia, agitation, nausea, headache, sexual dysfunction in men and women, long half-life
Paroxetine (Paxil): 10-40 mg QDMay 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, higher risk of SSRI withdrawal syndrome, weight gain
Sertraline (Zoloft): 50-200 mg QDMay have lower incidence of significant drug-drug interactions compared with fluoxetine and paroxetineInsomnia, agitation, nausea, headache
  • Nausea, headache, nervousness, sexual dysfunction (men and women)
  • Serotonin withdrawal syndrome if discontinued abruptly
Duloxetine (Cymbalta): 30-60 mg QDMay be used also for pain management and neuropathy; may have lower risk of significant drug-drug interactions compared with SSRIsNausea, somnolence

Venlafaxine (Effexor): 37.5-75 mg BID or TID


Venlafaxine XR (Effexor XR): 75-375 mg QD

May have lower risk of significant drug-drug interactions compared with SSRIs

Hypertension (monitor blood pressure at higher dosages)


Higher risk of SSRI/SNRI withdrawal syndrome

Desvenlafaxine (Pristiq): 50 mg QDMay have lower risk of significant drug-drug interactions compared with SSRIsHigher risk of SSRI/SNRI withdrawal syndrome

Other agents

  • Bupropion (Wellbutrin and others): Bupropion is available in immediate-release form (requires TID dosing), sustained-release (SR) (requires BID dosing), or extended-release (XL) (QD dosing) formulations. At higher bupropion dosages, there is an increased risk of seizures, and this drug is contraindicated in patients who have risk factors for seizures. For patients taking PIs, caution should be used as the dosage approaches 300-400 mg per day because of possible increases in levels of bupropion (however, tipranavir and efavirenz may decrease bupropion levels). Bupropion may have an activating effect, which some patients may experience as agitation, insomnia, or both, and also may have an appetite suppressant effect. It usually does not cause sexual dysfunction, and therefore may be helpful for individuals with depression who experience adverse sexual effects with other antidepressant agents.
  • Mirtazapine (Remeron): (15-45 mg QPM) May have lower risk of significant drug-drug interactions compared with SSRIs; can be useful when weight gain and sleep induction are needed. Potential adverse effects include sedation, increased appetite, weight gain, constipation, and dry mouth. Note that the higher dosages may result in increased activation owing to increased norepinephrine (NE) receptor antagonism.
  • Tricyclics: Tricyclic antidepressants may be effective, but generally are not recommended for treatment of depression because they have a higher risk of adverse effects than do SSRIs and SNRIs. They also are more dangerous (potentially fatal) in overdose. Adverse effects include anticholinergic effects, sedation, and cardiac conduction abnormalities. Levels of tricyclics are increased by ritonavir, so lower dosages may be needed for patients taking ritonavir or ritonavir-boosted PIs.

    Routine monitoring of blood levels of tricyclics should be performed on patients receiving higher doses
    (e.g., 100 mg per day; 50 mg for nortriptyline), those on concurrently on ritonavir, and those with risk factors for cardiac conduction abnormalities.A routine electrocardiogram should be performed before prescribing tricyclics, and this class of drugs should not be prescribed to patients with cardiac conduction problems.

    The adverse effects of tricyclics can be used to treat insomnia or diarrhea, for example, and tricyclics can be effective for neuropathic pain.
    • Imipramine (Tofranil): FDA indications for depression and chronic pain. The full recommended dosage for either problem is 150-300 mg QHS. Starting dosage: 25-75 mg PO QHS.
    • Doxepin (Sinequan):FDA indications for depression and anxiety at adult dosages of 150-300 mg QHS. Starting dosage: 25-75 mg PO QHS.
    • Three other available tricyclics have an FDA indication for depression only: nortriptyline (Pamelor) at dosages of 50-150 mg QHS; desipramine (Norpramin) at dosages of 50-200 mg a day; and protriptyline (Vivactil) at dosages of 5-10 mg, either TID or QID.
    • Tricyclics need to be started at low dosages and titrated gradually. Lower dosages (or alternative agents) often are more appropriate for patients who are elderly, medically ill, or taking ritonavir or a ritonavir-boosted PI.
    • Trazodone: a highly sedating antidepressant that is rarely used at an antidepressant dosage. Rather, it is often given at lower dosage for insomnia associated with depression, at a dosage of 25-50 mg 1-2 hours before bedtime. Ritonavir and other PIs can increase trazodone levels significantly; start at low dosage and use the lowest effective dosage; monitor for adverse effects.
    • Nefazodone (Serzone): an antidepressant that usually should be avoided in people with HIV infection. Little information on interactions with ARVs is available, but it appears that nefazodone may increase levels of maraviroc and saquinavir, and that ritonavir may increase nefazodone levels. It has a black-box warning for severe liver toxicity. If the patient has ever had liver toxicity from the drug, restarting it is contraindicated.
    • St. John's wort: an herbal antidepressant that can significantly decrease serum concentrations of PIs, NNRTIs, and maraviroc; it is contraindicated for use by patients taking those ARVs.

Treatment may involve antidepressant combinations, including psychostimulants; consult with a psychiatrist.

Discontinuing antidepressant medication

Antidepressant medication generally should be continued for at least 6 months following resolution of a first episode of major depression. Longer term, and even indefinite, maintenance treatment may be necessary for people with recurrent major depression. When discontinuing antidepressants, it is important to taper them gradually to avoid withdrawal symptoms or rebound depression. Abrupt discontinuation of SSRI and SNRI antidepressants often precipitates unpleasant withdrawal symptoms such as confusion, agitation, irritability, sensory disturbances, and insomnia. This is particularly true for paroxetine and venlafaxine. Fluoxetine, because of its long half-life, is uncommonly associated with withdrawal symptoms.

Brain stimulation treatments

There are a variety of brain stimulation treatments that usually are reserved for patients who have inadequate responses to medication. Electroconvulsive therapy (ECT) is the best known of these treatments and, despite the stigma associated with it, is more effective than antidepressant medication. Newer brain stimulation treatments also are available. These treatments require referral to the specialty care locations that offer them. Antidepressant medication often is used for maintenance after stabilization with ECT, but for some people, maintenance ECT is needed to prevent the relapse of depression.

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 a common aspect of HIV infection. Sadness is a normal part of life, but major depression always is abnormal and often can be alleviated with medication, psychotherapy, or both.
  • Providers should help patients identify the symptoms of depression and the factors that led them to seek treatment. Patients will need to monitor themselves for recurrences or exacerbations and get help if the symptoms recur. Patients should be told to contact providers if they notice changes in their sleep, appetite, mood, activity level, or concentration, or if they notice fatigue, isolation, sadness, or feelings of helplessness.
  • 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, 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.
  • Providers should let patients know that St. John's wort can lower levels of ARVs and cannot be taken if they are on ART.
  • Antidepressants typically are given for a long time, usually for a year or longer, to help patients with the chemical imbalances associated with major depression. Patients should be told that they should not suddenly stop antidepressants they have been taking for a long time, and that these medications need to be discontinued gradually.
  • Some patients develop problems with sexual function while they are taking antidepressants. They should report any problems to their prescribers. (Note: Providers should let patients know that sexual well-being is fundamental to quality of life and can be talked about and addressed in the clinical setting.)


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