Mental Health & HIV/AIDS Murray Bennett, MD, FRCPC Clinical Assistant Professor Psychiatry University of Washington Director Psychiatry Madison Clinic Harborview Medical Center 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 Mental Health & HIV/AIDS • I Changes In HIV AIDS Epidemic • II Psychiatric Epidemiology • III Medication Interactions • IV Challenging Patients • V Substance Abuse 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 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 Changes in the HIV/AIDS Epidemic New Infections USA • Men 70% – 60% MSM – 25% IDU – 15% Heterosexual • Women 30% – 75% Heterosexual – 25% IDU 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 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 Changes in the HIV/AIDS Epidemic ARV 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) 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 Mental Health & HIV/AIDS Psychiatric Epidemiology Mental Health & HIV/AIDS Psychiatric 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 Mental Health & HIV/AIDS Depression • Prevalence estimated at twofold higher – Meta-analysis 10 studies • Risk factor for HIV Infection (Ciesla & Roberts 2001) (Regier 1990) • 2.5 fold increase when CD4 cell <200 cells/mm³ (Lyketsos 1996) Mental Health & HIV/AIDS Depression • Negative effects noted – – – – Adherence to ART Quality of Life Treatment outcomes Mortality & disease progression (Dimatteo 2000) (Lenz & Demal 2000) (Holmes & House 2000) (Ickovics 2001) • Personal Health Questionnaire 9 (PHQ9) – Patient completed survey – Research validated Primary Care Clinics (Spitzer 1999) – APA advocates implementation Mental Health & HIV/AIDS Depression #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%) Mental Health & HIV/AIDS Depression #2 Complexity Overlapping Symptoms 4 out of 9 Sx could be caused by physical illness: • • • • Appetite changes Sleep disruption Energy changes Slowed motor movement Mental Health & HIV/AIDS Depression • 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%) Mental Health & HIV/AIDS Depression • 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 Mental Health & HIV/AIDS Depression • 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 Mental Health & HIV/AIDS Depression • Psychotherapy – Many studies showing benefit with and without antidepressants • • • • Group therapy – prominent modality Cognitive Behavioral Therapy (CBT) Interpersonal Supportive – Themes of guilt, shame, anger Mental Health & HIV/AIDS PTSD • 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 – Higher levels of pain (Lutgendorf 1997) (Smith 2002) Mental Health & HIV/AIDS PTSD • 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) Mental Health & HIV/AIDS Panic 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 Mental Health & HIV/AIDS Panic 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) Mental Health & HIV/AIDS Social 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 Mental Health & HIV/AIDS Dementia • 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 Mental Health & HIV/AIDS Dementia • 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 Mental Health & HIV/AIDS Dementia • 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) Mental Health & HIV/AIDS Dementia • Risk Factors – Seroconversion illness – Anemia – Vitamin deficiencies (B6, B12) – Low CD4 count – High CSF HIV viral Load – ETOH, cocaine & amphetamine – Depression Mental Health & HIV/AIDS Dementia • 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 Mental Health & HIV/AIDS Dementia • Early signs & symptoms – Decreased attention & concentration – Psychomotor slowing – Reduced speed of information processing – Executive dysfunction • Abstraction • Divided attention • Shifting cognitive sets Mental Health & HIV/AIDS Dementia • Later signs & symptoms – Memory impairment – Language problems – Visual-spatial difficulties – Apraxias Mental Health & HIV/AIDS Dementia • Associated behavioral changes – Apathy – Depression – Sleep disturbance – Agitation & mania – Psychosis Mental Health & HIV/AIDS Dementia • Neurocognitive problems – 30-50% Subclinical Neuropsychological testing impaired ---------(threshold clinical significance)------------ – 20% MCMD Minor Cognitive Motor Disorder – 2-4% HAD HIV Associated Dementia Mental Health & HIV/AIDS Dementia • Mild Manifestation • Diagnostic Criteria – MCMD 1) At least 2 of: impaired attention, concentration, memory, mental & psychomotor slowing, personality change 2) Rule out other cause Minor Cognitive Motor Disorder • Severe Manifestation* – HAD HIV Associated Dementia *functional impairment • Diagnostic Criteria 1) Acquired cognitive abn* 2) Acquired motor abn* 3) No clouded LOC & rule out other cause Mental Health & HIV/AIDS Dementia • 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 Mental Health & HIV/AIDS Dementia • 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) Mental Health & HIV/AIDS Dementia • 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 Mental Health & HIV/AIDS Bipolar - 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 Mental Health & HIV/AIDS Bipolar - 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 Mental Health & HIV/AIDS Bipolar - 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 Mental Health & HIV/AIDS Bipolar - 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 Mental Health & HIV/AIDS Bipolar - 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 Mental Health & HIV/AIDS Schizophrenia • 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 Mental Health & HIV/AIDS Schizophrenia • 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 Mental Health & HIV/AIDS Schizophrenia • Substance-induced psychosis – Least studied & most resistant to treatment – Methamphetamine > cocaine > hallucinogen – Possibly increased susceptibility in patients with later stage HIV infection (C3) Mental Health & HIV/AIDS Medication Interactions Mental Health & HIV/AIDS Medication 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 Mental Health & HIV/AIDS Medication Interactions Hepatic metabolism – Phase I • Oxidation – Cytochrome P450 • Reduction • Hydrolysis – Phase II • Glucuronidation - UGT • Acetylation • Sulfation Mental Health & HIV/AIDS Medication 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 Mental Health & HIV/AIDS Medication 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…. Mental Health & HIV/AIDS Medication 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) Mental Health & HIV/AIDS Medication 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 Mental Health & HIV/AIDS Medication 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 Mental Health & HIV/AIDS Medication Interactions • Hepatic cytochrome P450 Most important cytochrome P450 enzymes: • 1A2 • 2C9 & 2C19 • 2D6 • 3A4* Mental Health & HIV/AIDS Medication Interactions • Phase II Glucuronidation H2O-soluble molecules conjugated = more easily excreted Uridine Glucuronosyltransferase (UGT) – 2 clinically significant subfamilies 1A & 2B Mental Health & HIV/AIDS Medication 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 Mental Health & HIV/AIDS Medication Interactions • Antiretrovirals Major culprit: ritonavir Most potent known inhibitor of 3A4! Mental Health & HIV/AIDS Medication Interactions • Antiretrovirals – 1A2 • Induction by ritonavir & nelfinavir – 2C9 • Induction by ritonavir & nelfinavir • Inhibition by delavirdine – 2C19 • Induction by efavirenz & nelfinavir • Inhibition by efavirenz & delavirdine Mental Health & HIV/AIDS Medication Interactions • Antiretrovirals – 2D6 • Inhibition by ritonavir – 3A4 • Induction by ritonavir, nelfinavir, efavirenz, nevirapine • Inhibition by ritonavir, fosamprenavir, indinavir, nelfinavir, saquinavir, tipranavir, delavirdine Mental Health & HIV/AIDS Medication 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 Mental Health & HIV/AIDS Medication 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 Mental Health & HIV/AIDS Medication 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 Mental Health & HIV/AIDS Medication 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 Mental Health & HIV/AIDS Medication Interactions • Antidepressants – Dual-action agents: • Venlafaxine (Effexor) & duloxetine (Cymbalta) • Well tolerated without adjusting dose – Mirtazipine (Remeron) • Well tolerated Mental Health & HIV/AIDS Medication Interactions • Anxiolytics – Mostly metabolized at 3A4 – Avoid Alprazolam (Xanax) Triazolam (Halcion) Midazolam (Versed) Mental Health & HIV/AIDS Medication 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) Mental Health & HIV/AIDS Medication Interactions • Antipsychotics – Typicals (first generation = D2 blockers) – Atypicals (second generation = multiple neurotransmitters) Both are mostly metabolized at 2D6 Mental Health & HIV/AIDS Medication 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) Mental Health & HIV/AIDS Medication 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 Mental Health & HIV/AIDS Medication 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 Mental Health & HIV/AIDS Challenging Patient Population Mental Health & HIV/AIDS Challenging 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…. Mental Health & HIV/AIDS Challenging 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 Mental Health & HIV/AIDS Challenging 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 Mental Health & HIV/AIDS Challenging 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 Mental Health & HIV/AIDS Challenging 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 Mental Health & HIV/AIDS Challenging 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 Mental Health & HIV/AIDS Challenging 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 Mental Health & HIV/AIDS Substance Abuse Mental Health & HIV/AIDS Substance 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 Mental Health & HIV/AIDS Substance Abuse • Substances – Alcohol – Amphetamines – Cocaine – Heroin – Club drugs: • GHB, MDMA (Ecstasy), Ketamine (Special K) Mental Health & HIV/AIDS Substance 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) Mental Health & HIV/AIDS Substance Abuse • Characteristics of injection drug users nonadherent to ART (Moatti 2000) – Younger age – Active IDU – Alcohol abuse or use – Stressful life events (5 fold higher) Mental Health & HIV/AIDS Substance 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 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