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Slide 1-

Mental Health & HIV/AIDS Murray Bennett, MD, FRCPC Clinical Assistant Professor Psychiatry University of Washington Director Psychiatry Madison Clinic Harborview Medical Center
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Mental Health & HIV/AIDS HIV/AIDS Impact (2003) Worldwide: 35 Million People with HIV/AIDS 18 million HIV Related deaths United States: >1 Million People with HIV/AIDS (~ 1 in 300) >500,000 HIV Related Deaths
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Mental Health & HIV/AIDS I Changes In HIV AIDS Epidemic II Psychiatric Epidemiology III Medication Interactions IV Challenging Patients V Substance Abuse
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Mental Health & HIV/AIDS Changes in the HIV/AIDS Epidemic In USA & Developed Nations Dramatic & significant reduction in the mortality rate by more than 50% since 1995 Now moved to 14th leading cause of death overall Moved from 1st to 5th leading cause of death amongst 25-44 year olds
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Mental Health & HIV/AIDS Changes in the HIV/AIDS Epidemic However, rate of new HIV infections in USA is stable at 40,000 new cases per year Demographics of new cases reflect significant shifts & changes in affected populations
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Changes in the HIV/AIDS EpidemicNew Infections USA Men 70% 60% MSM 25% IDU 15% Heterosexual Women 30% 75% Heterosexual 25% IDU
Slide 7-

Changes in the HIV/AIDS Epidemic Medical Treatment Evolution Monotherapy in early 1990s Dual agent approach by mid 1990’s Combination antiretroviral therapy (ART), also called highly active antiretroviral therapy (HAART), since late 1990s: 3 or more agents
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Changes in the HIV/AIDS Epidemic ART Has produced dramatic & significant improvement in prognosis for HIV infection But has also emphasized the importance of: Adherence Medication Interactions
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Changes in the HIV/AIDS EpidemicARV Medications NRTIs Abacavir (Ziagen) Didanosine (Videx) Emtricitabine (Emtriva) Lamivudine (Epivir) Stavudine (Zerit) Tenofovir (Viread) Zalcitabine (Hivid) Zidovudine (AZT) NNRTIs Efavirenz (Sustiva) Nevirapine (Viramune) Delavirdine (Rescriptor) Protease inhibitors Amprenavir (Agenerase) Atazanavir (Reyataz) Darunavir (Prezista) Fosamprenavir (Lexiva) Indinavir (Crixivan) Lopinavir/ritonavir (Kaletra) Nelfinavir (Viracept) Ritonavir (Norvir) Saquinavir (Fortovase) Tipranavir (Aptivus) Fusion Inhibitor T20 (Fuzeon)
Slide 10-

Changes in the HIV/AIDS Epidemic Challenging Illness to Treat >20 antiretroviral medications Challenging Patient Populations Comorbid Psychiatric Disorders Substance Abuse Poverty Homelessness Social isolation
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Mental Health & HIV/AIDS Psychiatric Epidemiology
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Mental Health & HIV/AIDSPsychiatric Epidemiology Depression >2 fold increase at risk populations high rate PTSD high-risk populations women/prisoners/minorities Dementia decreased with ART Prevalence? MCMD? Bipolar primary & secondary 10 x higher Schizophrenia at-risk population 2- 10 x higher
Slide 13-

Mental Health & HIV/AIDSDepression Prevalence estimated at twofold higher Meta-analysis 10 studies (Ciesla & Roberts 2001) Risk factor for HIV Infection (Regier 1990) 2.5 fold increase when CD4 cell <200 cells/mm³ (Lyketsos 1996)
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Mental Health & HIV/AIDSDepression Negative effects noted Adherence to ART (Dimatteo 2000) Quality of Life (Lenz & Demal 2000) Treatment outcomes (Holmes & House 2000) Mortality & disease progression (Ickovics 2001) Personal Health Questionnaire 9 (PHQ9) Patient completed survey Research validated Primary Care Clinics (Spitzer 1999) APA advocates implementation
Slide 15-

Mental Health & HIV/AIDSDepression #1 Complexity “Patient has a good reason to be..” or “Well, you would be to if you were....” or “It’s reasonable to be depressed…” Fact: The majority of patients with chronic medical illness are not depressed (prevalence is never >50%)
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Mental Health & HIV/AIDSDepression #2 Complexity Overlapping Symptoms - 4 out of 9 Sx could be caused by physical illness: Appetite changes Sleep disruption Energy changes Slowed motor movement
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Mental Health & HIV/AIDSDepression Inclusive Model for Diagnosis of Major Depression Count all physical symptoms unless they are clearly and fully caused by physical or medical illness (positive predictive value 54 – 80%)
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Mental Health & HIV/AIDSDepression Psychosocial Stress High suicide rates Initial HIV diagnosis & later stages of illness Multiple comorbid factors Substance abuse Poverty Homelessness Social isolation Physical stigma of ART Lipoatrophy, lipodystrophy: disclosure of infection
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Mental Health & HIV/AIDSDepression Multiple studies indicate almost all antidepressants are effective Concern for P450 interactions with some antiretroviral medications Favor citalopram & sertraline over paroxetine & fluoxetine (2D6) Caution with nefazodone & fluvoxamine (3A4) Side effect profile guides choice of agent Mirtazipine favored for sedation and appetite stimulation
Slide 20-

Mental Health & HIV/AIDSDepression Psychotherapy Many studies showing benefit with and without antidepressants Group therapy – prominent modality Cognitive Behavioral Therapy (CBT) Interpersonal Supportive Themes of guilt, shame, anger
Slide 21-

Mental Health & HIV/AIDSPTSD Greatly increased rates 42% HIV+ women, County Medical Clinics (Cottler 2001) 30% pts develop in reaction to HIV diagnosis (Kelley 1998) Predicts lower CD4 counts (Lutgendorf 1997) Higher levels of pain (Smith 2002)
Slide 22-

Mental Health & HIV/AIDSPTSD SSRIs show 50% improvement in sx prefer to use sertraline (Zoloft) or citalopram (Celexa) Prazosin often used for intrusive nightmares current studies (Raskind SVAMC) Psychotherapy effective, using variety of approaches (CBT, Abreaction, Supportive)
Slide 23-

Mental Health & HIV/AIDSPanic Disorder Panic Disorder & Generalized Anxiety Disorder > 4 times more prevalent (Bing 2001) Affects accessing primary care, adherence to treatment, and quality of life Especially agoraphobic/housebound Responds well to treatment
Slide 24-

Mental Health & HIV/AIDSPanic Disorder First line treatment: SSRIs Then consider dual action agents (venlafaxine (Effexor) or duloxetine (Cymbalta)), mirtazepine (Remeron), or tricyclics (TCAs) Wellbutrin of little benefit Responds well to psychotherapy: CBT Best outcomes = both meds & psychotherapy Use benzodiazepines as last resort eg, clonazepam preferred (longer half life)
Slide 25-

Mental Health & HIV/AIDSSocial Phobia Fear of social situations, scrutiny and criticism of others, unable to eat or speak in public Relates to internalized stigma of illness exacerbated by lipoatrophy and lipodystrophy caused by ART Responds well to psychotherapy & meds First line: SSRIs
Slide 26-

Mental Health & HIV/AIDSDementia CNS Infection 10% AIDS pts present with neurological dx 75% AIDS pts: brain pathology at autopsy gliosis, white matter pallor & multinucleated giant cells HIV-Associated Dementia (HAD) & Minor Cognitive Motor Disorder (MCMD) predict shorter survival
Slide 27-

Mental Health & HIV/AIDSDementia HIV-infected macrophages directly enter CNS early in HIV infection CNS may be sanctuary for HIV replication CSF HIV viral load not correlated with plasma viral load when CD4 count <200 cells/mm³ CSF viral load correlates dementia severity
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Mental Health & HIV/AIDSDementia With effective ART, incidence of CNS OIs dropped significantly, since early 1990’s 2/3 decreased incidence HAD (Saktor 1999) 75% decrease CMV & lymphoma on autopsy However 60% with some evidence of HIV encephalopathy on autopsy* (Neuenburg 2002)
Slide 29-

Mental Health & HIV/AIDSDementia Risk Factors Seroconversion illness Anemia Vitamin deficiencies (B6, B12) Low CD4 count High CSF HIV viral Load ETOH, cocaine & amphetamine Depression
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Mental Health & HIV/AIDSDementia HIV CNS infection has predilection for subcortical brain structures Basal ganglia: Caudate, putamen, nucleus accumbens, globus pallidus, substantia nigra, subthalamic nucleus Leads to unique clinical manifestations
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Mental Health & HIV/AIDSDementia Early signs & symptoms Decreased attention & concentration Psychomotor slowing Reduced speed of information processing Executive dysfunction Abstraction Divided attention Shifting cognitive sets
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Mental Health & HIV/AIDSDementia Later signs & symptoms Memory impairment Language problems Visual-spatial difficulties Apraxias
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Mental Health & HIV/AIDSDementia Associated behavioral changes Apathy Depression Sleep disturbance Agitation & mania Psychosis
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Mental Health & HIV/AIDSDementia Neurocognitive problems 30-50% Subclinical Neuropsychological testing impaired ---------(threshold clinical significance)------------ 20% MCMD Minor Cognitive Motor Disorder 2-4% HAD HIV Associated Dementia
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Mental Health & HIV/AIDSDementia Mild Manifestation MCMD Minor Cognitive Motor Disorder Severe Manifestation* HAD HIV Associated Dementia *functional impairment Diagnostic Criteria 1) At least 2 of: impaired attention, concentration, memory, mental & psychomotor slowing, personality change 2) Rule out other cause Diagnostic Criteria 1) Acquired cognitive abn* 2) Acquired motor abn* 3) No clouded LOC & rule out other cause
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Mental Health & HIV/AIDSDementia Treatment Most effective treatment is ART Raises question of lumbar puncture to confirm effectiveness on CSF HIV viral load….. Slows progression of dementia (Ferrando 1998) Reversed periventricular white matter changes seen on MRI scan in some cases
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Mental Health & HIV/AIDSDementia Potential neuroprotective agents Most promising are memantine (Namenda) & selegeline (L-Deprenyl) Many adjuvant agents commonly used, with some controversy about use of stimulants Improved cognitive performance (Brown 1995, Hinkin 2001) Accelerated HAD sx’s (Czub 2001, Nath 2001)
Slide 38-

Mental Health & HIV/AIDSDementia Adjuvant treatments Selegeline (L-Deprenyl) Buproprion (Wellbutrin) SSRIs (Prozac, Paxil, Celexa, Zoloft, Lexapro) Dual-action antidepressants (Effexor, Cymbalta) Atomexitine (Strattera) Modafinil (Provigil) Anabolic steroids Atypical or second generation antipsychotics
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Mental Health & HIV/AIDSBipolar - Mania Prevalence of bipolar disorder in HIV infection is 10 times higher than in general population (Lyketsos 1993) Stress of HIV infection exacerbates pre-existing bipolar disorder – complicating adherence New-onset or secondary mania result of HIV infection, opportunistic infections or due to antiretroviral medications
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Mental Health & HIV/AIDSBipolar - Mania Patients with bipolar disorder (primary) at increased risk of HIV infection Impulsivity, poor judgment, & libido changes all part of mood episodes Secondary mania seen in later stages of HIV infection Harder to treat More chronic, less episodic course
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Mental Health & HIV/AIDSBipolar - Mania Secondary mania Associated with impaired cognition Increased risk of dementia Different clinical features Irritable > elevated mood Psychomotor slowing More chronic than episodic More resistant to treatment
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Mental Health & HIV/AIDSBipolar - Mania Treatment Not well studied with mostly anecdotal case reports Depakote (VPA) well tolerated Avoid with impaired hepatic function Risk anemia with AZT Lithium Conflicting reports of good response (increases WBC) versus intolerable side effects Tegretol (carbamazepine) Avoid as risks medication interactions (inducer) & bone marrow suppression
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Mental Health & HIV/AIDSBipolar - Mania Treatment Second generation (atypical) antipsychotics all have indication as mood stabilizers, well tolerated and effective for psychotic sx’s Olanzapine (Zyprexa) > risperidone (Risperdal) & quetiapine (Seroquel) > ziprasidone (Geodon) & aripiprazole (Abilify) - Risk of metabolic effects: wt gain, DM, hyperlipidemia, etc *Note: clozapine (Clozaril) contraindicated for several reasons
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Mental Health & HIV/AIDSSchizophrenia Patients with chronic mental illness at increased risk for HIV infection Prevalence rates 2 to 10% Medical providers often do not test for HIV Incorrectly assume pts not sexually active Substance abuse significant co-morbidity Pts do not implement HIV risk behavior knowledge
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Mental Health & HIV/AIDSSchizophrenia Treatment Coordinate between medical & psychiatric providers as much as possible Typical or 1st generation antipsychotics Increase risk of EPS & tardive dyskinesia Atypical or 2nd generation antipsychotics are preferred but risk weight gain: Olanzapine (Zyprexa) > risperidone (Risperdal) & quetiapine (Seroquel) > ziprasidone (Geodon) & aripiprazole (Abilify) *Note: clozapine (Clozaril) contraindicated for several reasons
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Mental Health & HIV/AIDSSchizophrenia Substance-induced psychosis Least studied & most resistant to treatment Methamphetamine > cocaine > hallucinogen Possibly increased susceptibility in patients with later stage HIV infection (C3)
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Mental Health & HIV/AIDS Medication Interactions
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Mental Health & HIV/AIDSMedication Interactions Metabolism & excretion Hepatic metabolism Phase I – prepare for excretion Phase II – conjugation Renal metabolism Creatinine clearance Affects lithium or gabapentin P-Glycoproteins Present in gut, liver, gonads, kidneys, & brain Transport hydrophobic substances
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Mental Health & HIV/AIDSMedication Interactions Hepatic metabolism Phase I Oxidation – Cytochrome P450 Reduction Hydrolysis Phase II Glucuronidation - UGT Acetylation Sulfation
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Mental Health & HIV/AIDSMedication Interactions Drug-drug interactions - metabolism: Substrate (goes through the funnel) drug metabolized by an enzyme Inducer (opens the funnel) drug increases activity of metabolic enzyme Inhibitor (plugs the funnel) drug decreases activity of metabolic enzyme
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Mental Health & HIV/AIDSMedication Interactions Induction May cause decreased amounts circulating drug, thereby lowering therapeutic effect Funnel is opened wider… Inhibition May cause increased amounts circulating drug, thereby creating toxic effect Funnel is plugged….
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Mental Health & HIV/AIDSMedication Interactions Occur in 3 situations Add interacting drug (inhibitor or inducer) to existing regimen containing a substrate drug Withdraw interacting drug (inhibitor or inducer) from existing regimen containing a substrate drug Add substrate drug to a regimen containing an interacting drug (inhibitor or inducer)
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Mental Health & HIV/AIDSMedication Interactions Hepatic cytochrome P450 Enzyme system that catalyzes Phase I reactions Responsible for most metabolic drug interactions 11 families 3 of which are important to humans designated by a number e.g. CYP1, CYP2, CYP3
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Mental Health & HIV/AIDSMedication Interactions Hepatic cytochrome P450 Families are broken down into subfamilies designated by capital letter e.g. CYP3A Subfamilies are broken down into isoenzymes designated by a number e.g. CYP3A4
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Mental Health & HIV/AIDSMedication Interactions Hepatic cytochrome P450 Most important cytochrome P450 enzymes: 1A2 2C9 & 2C19 2D6 3A4*
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Mental Health & HIV/AIDSMedication Interactions Phase II Glucuronidation H2O-soluble molecules conjugated = more easily excreted Uridine Glucuronosyltransferase (UGT) 2 clinically significant subfamilies 1A & 2B
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Mental Health & HIV/AIDSMedication Interactions Phase II Glucuronidation eg, UGT 2B7 site of conjugation of benzodiazepines Lorazepam (Ativan), temazepam (Restoril) & oxazepam (Serax) are substrates at UGT 2B7 Inhibited by NSAIDS Induced by ritonavir, phenobarbital, rifampin & oral contraceptives
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Mental Health & HIV/AIDSMedication Interactions Antiretrovirals Major culprit: ritonavir Most potent known inhibitor of 3A4!
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Mental Health & HIV/AIDSMedication Interactions Antiretrovirals 1A2 Induction by ritonavir & nelfinavir 2C9 Induction by ritonavir & nelfinavir Inhibition by delavirdine 2C19 Induction by efavirenz & nelfinavir Inhibition by efavirenz & delavirdine
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Mental Health & HIV/AIDSMedication Interactions Antiretrovirals 2D6 Inhibition by ritonavir 3A4 Induction by ritonavir, nelfinavir, efavirenz, nevirapine Inhibition by ritonavir, fosamprenavir, indinavir, nelfinavir, saquinavir, tipranavir, delavirdine
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Mental Health & HIV/AIDSMedication Interactions Remember Most interactions are not clinically significant Impossible to memorize all interactions Must look up or reference to be sure www.madisonclinic.org http://hivinsite.ucsf.edu/arvdb?page=ar-00-02
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Mental Health & HIV/AIDSMedication Interactions Antidepressants Most metabolized at 2D6 Exceptions: Fluvoxamine (Luvox) AVOID Nefazodone (Serzone) AVOID or dose cautiously Bupropion (Wellbutrin, Zyban) @ 400 mg, dose cautiously with ritonavir
Slide 63-

Mental Health & HIV/AIDSMedication Interactions Antidepressants SSRIs Fluoxetine (Prozac) & paroxetine (Paxil): some interactions, but not clinically significant for most antiretrovirals Citalopram (Celexa), escitalopram (Lexapro), & sertraline (Zoloft): have fewest interactions
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Mental Health & HIV/AIDSMedication Interactions Antidepressants Tricyclic antidepressants Generally well tolerated with antiretrovirals Nortriptyline & desipramine (secondary amines) Narrow metabolism at 2D6 Levels can be elevated by other medications Get a blood level if in doubt
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Mental Health & HIV/AIDSMedication Interactions Antidepressants Dual-action agents: Venlafaxine (Effexor) & duloxetine (Cymbalta) Well tolerated without adjusting dose Mirtazipine (Remeron) Well tolerated
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Mental Health & HIV/AIDSMedication Interactions Anxiolytics Mostly metabolized at 3A4 Avoid Alprazolam (Xanax) Triazolam (Halcion) Midazolam (Versed)
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Mental Health & HIV/AIDSMedication Interactions Anxiolytics Safest to use glucuronidated benzodiazepines: Lorazepam (Ativan) Temazepam (Restoril) Oxazepam (Serax) Caution with buspirone (Buspar), and dosing of other benzodiazepines with ART (3A4)
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Mental Health & HIV/AIDSMedication Interactions Antipsychotics Typicals (first generation = D2 blockers) Atypicals (second generation = multiple neurotransmitters) Both are mostly metabolized at 2D6
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Mental Health & HIV/AIDSMedication Interactions Antipsychotics: for use with ritonavir, start with low dose 1A2 & 2D6 Haloperidol (Haldol) (risk EPS & TD) Avoid chlorpromazine (Thorazine), thioridazine (Mellaril) Olanzapine (Zyprexa) & clozapine (Clozaril) 3A4 Aripiprazole (Abilify) & clozapine (Clozaril) Avoid pimozide (Orap)
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Mental Health & HIV/AIDSMedication Interactions Stimulants Atomoxetine (Strattera*) * = nonstimulant Caution with impaired hepatic function Metabolized at 2D6 Inhibits at 2D6 Modafinil (Provigil) – be cautious Metabolized at 3A4 Induces at 1A2 & 3A4
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Mental Health & HIV/AIDSMedication Interactions Herbal remedies Kava Kava Anxiolytic Increases bleeding time Risk of hepatotoxicity St John’s Wort Mild antidepressant effect Induces 3A4 Caution with certain ARV medications- may lead to regimen failure
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Mental Health & HIV/AIDS Challenging Patient Population
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Mental Health & HIV/AIDSChallenging Patient Population Dual, Triple, & Quadruple Diagnosed: HIV-AIDS diagnosis Psychiatric diagnoses Axis I & Axis II Substance abuse & dependence Co-morbid medical illness Hepatitis C Diabetes mellitus….
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Mental Health & HIV/AIDSChallenging Patient Population Multiple comorbid psychiatric disorders: Substance abuse & dependence Personality disorders Chronic mental illness Further challenges Poverty, lower SES Minorities over represented Language and cultural barriers to care
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Mental Health & HIV/AIDSChallenging Patient Population Personality disorders Cluster B traits predominant: Borderline, Antisocial, Histrionic, & Narcissistic Common features of impulsivity, risk taking, novelty seeking, self destructive behavior place themselves and others at risk of HIV infection Added factors exploitative, manipulative, chaotic, entitled, dramatic, and demanding all make provision of care more challenging
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Mental Health & HIV/AIDSChallenging Patient Population Goal as provider to take empathic approach yet able to set non-punitive limits Narcissism – reaction or defense to low self esteem, need to devalue others, unable to make empathic connections with others Splitting & manipulation – manner in which patients understand their world (Borderline) or get their needs met (survival on streets) Multidisciplinary team approach: improve communication, minimize splitting
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Mental Health & HIV/AIDSChallenging Patient Population Chronically Mentally Ill: Bipolar, schizophrenic, schizoaffective At increased risk of HIV infection Less adherent to medical & psychiatric care Receive care across systems Community Mental Health system not integrated with Primary Care, Medical Clinics, or Hospitals
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Mental Health & HIV/AIDSChallenging Patient Population Strategy: Communicate between providers & systems Utilize mental health case managers to assist with adherence to ART, appointments Monitor blood work Do not assume other provider is following hepatic or renal function, electrolytes or blood levels Monitor for medication interactions Communicate between pharmacies
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Mental Health & HIV/AIDSChallenging Patient Population Lower Socio-Economic Status Most needs Fewest resources Increased risk of violence Increased chaos in daily lives Affecting adherence to ART Not showing for appointments Access to chemical dependency treatment
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Mental Health & HIV/AIDS Substance Abuse
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Mental Health & HIV/AIDSSubstance Abuse Triple Diagnosis HIV infection, psychiatric diagnosis, & substance abuse Epidemiology 30% AIDS patients are Injection Drug Users >50% HIV patients have some kind of substance abuse/dependence Madison Clinic ~ 65% psychiatric pts < 5% self report a problem with drugs or EtOH
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Mental Health & HIV/AIDSSubstance Abuse Substances Alcohol Amphetamines Cocaine Heroin Club drugs: GHB, MDMA (Ecstasy), Ketamine (Special K)
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Mental Health & HIV/AIDSSubstance Abuse Injection drug users (IDU) Present later in illness for medical care Once in care, do not have accelerated course Active use impairs access & complicates care through non-adherence Alcohol, amphetamines, cocaine, & heroin suppress immune function or increase HIV replication (Kibayashi 1996)
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Mental Health & HIV/AIDSSubstance Abuse Characteristics of injection drug users non-adherent to ART (Moatti 2000) Younger age Active IDU (5 fold higher) Alcohol abuse or use Stressful life events
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Mental Health & HIV/AIDSSubstance Abuse Treatment Detoxification: complicated by HIV illness & withdrawal from multiple substances Chronic opioid users Refer to methadone maintenance programs Certain ARV medications may decrease methadone levels Integrated settings most effective Directly Observed Therapy (DOT) may assist ART adherence
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Mental Health & HIV/AIDS Summary Changing epidemic with significant impact Challenging illness & patient population Team approach, multidisciplinary care Remember to look up medication interactions! www.madisonclinic.org http://hivinsite.ucsf.edu/arvdb?page=ar-00-02