Clinical Guide > Neuropsychiatric Disorders > Depression

Major Depression and Other Depressive Disorders

January 2011

Chapter Contents


Major depression is the most prevalent psychiatric comorbidity and a common cause of significant morbidity among people with HIV infection. 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:

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:

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)-IV.

Major Depression

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

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

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:

Other Depressive Disorders

S: Subjective

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:

P: Plan


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


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

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 selective 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. Some patients may be at risk of worsening depression, including suicidality, after initiation of therapy; 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 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. 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 pharmacist before prescribing.

Some ARV medications (particularly protease inhibitors [PIs]) 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 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) 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 once dailyMay have lower risk of significant drug-drug interactions than other SSRIsMild nausea, possible sedation
Escitalopram (Lexapro): 10-20 mg once dailyMay have lower risk of significant drug-drug interactions than other SSRIsMild nausea, possible sedation
Fluoxetine (Prozac): 10-40 mg once dailyRarely 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 once dailyMay 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 once dailyMay 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 once dailyMay 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 once daily

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 once dailyMay have lower risk of significant drug-drug interactions compared with SSRIsHigher risk of SSRI/SNRI withdrawal syndrome
Other agents
Discontinuing antidepressant medication

Antidepressant medication generally should be continued for at least 6 months following improvement from 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, except for the few mentioned above (e.g., fluoxetine), they need to be tapered gradually to avoid withdrawal symptoms (as below) or rebound depression.

Abrupt discontinuation of SSRI and SNRI antidepressants often precipitates the emergence of unpleasant withdrawal symptoms. This is particularly true for paroxetine and venlafaxine. Withdrawal symptoms may include confusion, agitation, irritability, sensory disturbances, and insomnia. The abrupt discontinuation of SSRIs is associated with a return or worsening of depressive 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


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