Jeffrey Hsu, M.D.
- Studies have suggested significant rates of depression in HIV+ populations in sub-Saharan Africa.
- Experts strongly suggest screening for depression in all HIV+ patients.
- In Zambia, a majority of patients with mental health disorders will consult a traditional health practitioner before seeking conventional care.
Zambia Information Author: Paul Auwaerter, M.D.
- Prevalence of major depressive disorder (MDD) in HIV pts 2-3x higher than general population; most common psychiatric condition in HIV+ pts. Prevalence of depression 57% in HIV+ pts. and 70% in HIV/HCV coinfected pts.
- Lifetime risk of developing MDD 2x greater in women vs. men. Prevalence of MDD in HIV+ women up to 4x higher than HIV-negative women and 3x higher than HIV+ men.
- 1st degree relatives of pts with MDD at greater risk than general population.
- Alcohol, cocaine or amphetamine dependence may contribute to onset or exacerbation of MDD.
- MDD in HIV pts. often under-Dx'd as many Sx similar to Sx of HIV infection or AIDS-related medical complications: e.g., decreased energy, weight loss, insomnia, neurocognitive disturbance.
- Pts with untreated MDD less likely to adhere to medications and keep medical appts; more likely to engage in high risk sexual behavior and substance abuse. Untreated depression associated with increased morbidity and mortality in HIV pts.
- Suicide rate in AIDS pts 7x higher than in general population. Risk for suicide greatest in 1st few mos. following initial Dx of HIV and with onset of medical complications of AIDS.
- MDD: Sx lasting >2 wks with depressed mood and/or anhedonia and >4 of following:appetite changes, sleep changes, psychomotor agitation or retardation, fatigue or loss of energy, worthlessness or guilt, poor concentration, recurrent thoughts of death or suicide
- MDD with psychotic features: Major depressive episode with presence of mood-congruent hallucinations and/or delusions.
- Dysthymic disorder: Chronically depressed mood >2 yrs with >2 of following: appetite changes, sleep changes, fatigue, low self-esteem, poor concentration, hopelessness
- Adjustment disorder with depressed mood: Development of depressed mood, hopelessness or tearfulness occurring in context of identifiable stressor
- Medical conditions that can cause depressive Sx include hypothyroidism, hypogonadism, CNS infections or neoplasms, HIV dementia, psychoactive substance use/dependence, medication side effects (esp. EFV).
- Common medications causing depressive Sx: EFV, interferon, beta-blockers, steroids
- All antidepressants have approximately 60% response rate and seem to be equally efficacious.
- 90% of depressed pts. eventually respond to >1 antidepressant(s) after multiple trials.
- Pts must be on therapeutic dose of antidepressants for at least 4-6 wks for adequate trial.
- Successful choice of antidepressant depends on favorable side effect profile.
- 50% of pts achieve complete remission on continued antidepressant therapy after 6 mos.; up to 75% experience remission within 2 yrs.
- Usual dosages: amitriptyline 50-200 mg/d (blood level >120ng/ml); nortriptyline (NTP) 50-150 mg/d (50-125 ng/ml); imipramine 50-200 mg/d (>225 ng/ml); desipramine (DMI) 50-200 mg/d (>125 ng/ml)
- Only NTP has well-documented therapeutic blood level.
- Blood levels should be drawn after drug has achieved steady-state levels (usually 5 days) and approximately 12 hrs after last dose.
- After pt at therapeutic dosage, continue to monitor blood levels (2x/yr or more frequently with medication changes, worsening of Sxs). Baseline EKG should be obtained prior to treatment in the elderly and pts with prior Hx of cardiac illness.
- Common side effects: dry mouth, blurred vision, orthostatic hypotension, sedation, urinary retention, weight gain
- Serious side effects: heart block, tachyarrhythmias, delirium, seizures
- Secondary amines (NTP, DMI) less anticholinergic and more tolerable than parent compounds (amitriptyline, imipramine).
- Increase in TCA levels possible when coadministered with CYP2D6 inhibitors: SSRIs, PIs (esp. RTV). RTV documented to increase DMI levels. Monitor closely for increased TCAs ADR.
- Usual dosages: fluoxetine 10-80 mg/d; sertraline 25-200 mg/d; paroxetine 10-60 mg/d; citalopram 10-80 mg/d, escitalopram 10-40 mg/d
- Common side effects: initial anxiety or agitation, nausea, diarrhea, headaches, sexual dysfunction
- Most SSRIs inhibit and are metabolized by CYP2D6; use caution when using with other meds metabolized by CYP2D6. RTV documented to increase levels of SSRIs (risk of serotonin syndrome), with exception of escitalopram. Citalopram, escitalopram, and sertraline are weak inhibitors and should be considered with PI-based regimens.
- Discontinuation of SSRIs requires tapering to avoid discontinuation syndrome (dizziness, nausea, insomnia, headaches, diarrhea, myalgias, paresthesias) . This is more likely in agents with shorter half-lives, eg., sertraline, paroxetine, citalopram, escitalopram.
- bupropion 100-450 mg/d; side effects: agitation, insomnia, headache, tremor, constipation. Seizure risk 4/1000 pts
- venlafaxine 75-375 mg/d in divided doses; side effects: headache, nausea, dizziness
- mirtazapine 15-60 mg/d; side effects: sedation, wt. gain, dizziness
- nefazodone 150-600 mg/d in divided doses; side effects: headache, dry mouth, nausea, sedation, visual trails, hepatic failure 1/300,000 pt-yrs.
- duloxetine 20-60 mg/d in divided doses; side effects: nausea, dry mouth, constipation, dizziness
- selegiline transdermal patch 6 mg-12 mg/24 hrs.; tyramine-restricted diet if dose >6mg/24 hrs. to avoid hypertensive crisis.
- dehydroepiandrosterone (DHEA) may be useful treatment in pts. with dysthymia or subsyndromal MDD.
- Psychostimulants (dextroamphetamine, methylphenidate): useful in select pts with profound fatigue, but, tolerance develops quickly and may cause weight loss and addiction
- Atypical antipsychotics (olanzapine, risperidone, ziprasidone, quetiapine, aripiprazole): can be used to augment antidepressant Rx in pts with agitation and/or psychotic Sx; monitor glucose and triglycerides regularly because of increased risk of metabolic abnormalities
- Other agents commonly used for augmenting antidepressants: triiodothyronine (T3), buspirone, pindolol (with SSRIs), adding another antidepressant with different mechanism of action
- Combination psychotherapy and medication is most effective in treating patients with MDD.
- Psychotherapy is mainstay of treatment in patient with dysthymic disorder or adjustment disorder with depressed mood: little evidence that antidepressants are helpful
- Types of psychotherapy effective in treating MDD: (1) supportive psychotherapy: therapist helps pt identify innate strengths to improve coping; (2) cognitive-behavioral therapy: therapist focuses on changing self-defeating behaviors and patterns of thinking; (3) interpersonal therapy: therapist helps pt resolve interpersonal conflicts contributing to depression.
|SSRIs (general considerations)||Advantages: side effects more tolerable than TCAs, effective for comorbid anxiety disorders, safer in overdose, no need for blood level monitoring. Disadvantages: long-term administration may cause apathy syndrome, insomnia, sexual side effects (delayed orgasm, decreased libido)
|fluoxetine||Long half-life: better for pts with adherence difficulties, discontinuation syndrome less likely; many studies document effectiveness in treatment of HIV+ depressed patients.
|sertraline||More likely to cause GI side effects (nausea, diarrhea) so less useful in pts with weight loss and decreased appetite
|paroxetine||Has anticholinergic properties, so less activating; short half-life so discontinuation syndrome more likely. More sedating and less likely to cause diarrhea than other SSRIs.
|citalopram/escitalopram||Weak CYP450 inhibitor, so good agent to use when drug-drug interactions are a concern
|TCAs (general considerations)||Advantages: causes sedation and weight gain, so useful in patients with insomnia and anorexia; pt adherence can be measured by blood levels; may relieve neuropathic pain. Disadvantages: HIV+ pts more sensitive to anticholinergic side effects, more likely to cause delirium, can be fatal in overdose, so contraindicated in pts at high suicide risk. NTP and DMI less anticholinergic and may be better tolerated.
||Activating, so useful in treating depressive pts with profound anergy; not associated with sexual dysfunction or weight gain; decreases seizure threshold so use cautiously in with intracranial pathology, not effective for treating pts with comorbid anxiety disorders
|venlafaxine||Has dual mechanism of action (serotonin reuptake inhibitor at doses <75 mg/d; norepinephrine reuptake inhibitor >75 mg/d), more activating, may cause hypertension and GI disturbance, useful in patients with comorbid anxiety and chronic pain disorders, short half-life so discontinuation syndrome can occur, decrease in IDV AUC documented with co-administration but clinical significance unclear.
|mirtazapine||Causes wt gain and sedation, so helpful in pts with HIV wasting and insomnia. Has same benefits as TCAs without cardiotoxic effects, administered at bedtime, less likely to cause sexual side effects, available in orally disintegrating tablet
|SSRI + mirtazapine; venlafaxine + mirtazapine||Very potent antidepressant combination because multiple neurotransmitter systems targeted; useful in treating refractory depression
|nefazodone||Useful in treating pts with comorbid anxiety symptoms; does not cause sexual side effects or weight gain; may cause serious hepatotoxicity and liver failure (avoid use in pts with liver disease); inhibitor of CYP3A4 so may increase levels of certain benzodiazepines (alprazolam, midazolam), PIs and NNRTIs; withdrawn from market by manufacturer but generic still available
|duloxetine||Approved by FDA for treatment of MDD and diabetic neuropathy; has dual mechanism of action (serotonin and norepinephrine); side effects similar to SSRIs; use higher doses for Rx of neuropathy
||Usual antidepressant dosages (400-600 mg) too sedating for most pts. but useful in combination with activating antidepressants (SSRIs, venlafaxine, bupropion) to alleviate drug-induced insomnia.
|monamine oxidase inhibitors (MAOIs)||Not recommended for use in HIV+ pts because of dietary restrictions and potential interaction with antiretrovirals causing hypertensive crises. Selegiline transdermal patch may be an option because no dietary restrictions needed at dosage of 6mg/24hrs.
- 50-85% of pts with MDD will have recurrent episode
- Risk factors for recurrence include prior Hx of depressive episodes, presence of comorbid psychiatric Dx, presence of comorbid chronic medical Dx, persistent dysthmic symptoms
- 6-12 mos of maintenance treatment recommended post remission; longer if >1 risk factor for recurrence.
- When discontinuing therapy, taper medication to minimize recurrence and medication discontinuation syndrome (documented in short-acting SSRIs and venlafaxine).
- Pts should be regularly asked about depressive Sxs and suicidal ideation/intent at follow up visits and, if present, referred to more intensive psychiatric intervention and/or inpt admission.
- Although both MDD and adjustment disorders can occur in context of life stressors, Dx of MDD more likely in pt with personal or family Hx of mood disorders, comorbid substance abuse, psychotic symptoms, or Hx of suicidal ideation or attempts
- Rates of comorbid substance dependence high. Rx of substance use disorder should occur concurrently with treatment of depression.
- Patients on HAART should be cautioned to avoid ingestion of St. John's wort, an OTC herbal antidepressant that has been associated with decreased serum levels of IDV.