mental health & hiv/aids murray bennett, md, frcpc clinical assistant professor psychiatry...

Mental Health & HIV/AIDSMental Health & HIV/AIDS

Murray Bennett, MD, FRCPCMurray Bennett, MD, FRCPCClinical Assistant Professor PsychiatryClinical Assistant Professor Psychiatry

University of WashingtonUniversity of Washington

Director Psychiatry Madison ClinicDirector Psychiatry Madison Clinic

Harborview Medical CenterHarborview Medical Center


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


• I Changes In HIV AIDS Epidemic

• II Psychiatric Epidemiology

• III Medication Interactions

• IV Challenging Patients

• V Substance Abuse


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


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 EpidemicChanges in the HIV/AIDS EpidemicNew Infections USANew Infections USA

• Men 70%– 60% MSM– 25% IDU– 15% Heterosexual

• Women 30%– 75% Heterosexual– 25% IDU

Changes in the HIV/AIDS EpidemicChanges 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


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 EpidemicChanges in the HIV/AIDS EpidemicARV MedicationsARV Medications

• NRTIsAbacavir (Ziagen)Didanosine (Videx)Emtricitabine (Emtriva)Lamivudine (Epivir)Stavudine (Zerit)Tenofovir (Viread)Zalcitabine (Hivid)Zidovudine (AZT)

• NNRTIsEfavirenz (Sustiva)Nevirapine (Viramune)Delavirdine (Rescriptor)

• Protease inhibitorsAmprenavir (Agenerase)Atazanavir (Reyataz)Darunavir (Prezista)Fosamprenavir (Lexiva)Indinavir (Crixivan)Lopinavir/ritonavir (Kaletra)Nelfinavir (Viracept)Ritonavir (Norvir)Saquinavir (Fortovase)Tipranavir (Aptivus)

• Fusion InhibitorT20 (Fuzeon)


• Challenging Illness to Treat• >20 antiretroviral medications

• Challenging Patient Populations• Comorbid Psychiatric Disorders• Substance AbuseSubstance Abuse• PovertyPoverty• HomelessnessHomelessness• Social isolationSocial isolation


Psychiatric Epidemiology

Mental Health & HIV/AIDSMental Health & HIV/AIDSPsychiatric EpidemiologyPsychiatric Epidemiology

• Depression >2 fold increaseat risk populations high rate

• PTSD high-risk populationswomen/prisoners/minorities

• Dementia decreased with ARTPrevalence? MCMD?

• Bipolar primary & secondary10 x higher

• Schizophrenia at-risk population2- 10 x higher

Mental Health & HIV/AIDSMental Health & HIV/AIDSDepressionDepression

• Prevalence estimated at twofold higherPrevalence estimated at twofold higher– Meta-analysis 10 studies Meta-analysis 10 studies (Ciesla & Roberts 2001)(Ciesla & Roberts 2001)

• Risk factor for HIV Infection Risk factor for HIV Infection (Regier 1990)(Regier 1990)

• 2.5 fold increase when CD4 cell <200 cells/mm2.5 fold increase when CD4 cell <200 cells/mm³³

(Lyketsos 1996)(Lyketsos 1996)


• Negative effects notedNegative effects noted– Adherence to ART Adherence to ART (Dimatteo 2000)(Dimatteo 2000)

– Quality of Life Quality of Life (Lenz & Demal 2000)(Lenz & Demal 2000)

– Treatment outcomes Treatment outcomes (Holmes & House (Holmes & House 2000)2000)

– Mortality & disease progression Mortality & disease progression (Ickovics 2001)(Ickovics 2001)

• Personal Health Questionnaire 9 (PHQ9)Personal Health Questionnaire 9 (PHQ9)– Patient completed surveyPatient completed survey– Research validated Primary Care Clinics Research validated Primary Care Clinics (Spitzer 1999)(Spitzer 1999)

– APA advocates implementationAPA advocates implementation


#1 Complexity#1 Complexity– ““Patient has a good reason to be..” or Patient has a good reason to be..” or – ““Well, you would be to if you were....” or Well, you would be to if you were....” or – ““It’s reasonable to be depressed…”It’s reasonable to be depressed…”

– FactFact: The majority of patients with : The majority of patients with chronic medical illness are chronic medical illness are notnot depressed depressed

(prevalence is never (prevalence is never >50%)>50%)


#2 Complexity#2 Complexity

Overlapping Symptoms - Overlapping Symptoms - 4 out of 9 Sx could be caused by physical 4 out of 9 Sx could be caused by physical illness: illness:

• Appetite changesAppetite changes• Sleep disruptionSleep disruption• Energy changesEnergy changes• Slowed motor movementSlowed motor movement


• Inclusive Model for Diagnosis of Major Inclusive Model for Diagnosis of Major DepressionDepression– Count all physical symptoms unless they are Count all physical symptoms unless they are

clearly and fullyclearly and fully caused by physical or caused by physical or medical illnessmedical illness

(positive predictive (positive predictive value 54 – 80%)value 54 – 80%)


• Psychosocial StressPsychosocial Stress– High suicide ratesHigh suicide rates

• Initial HIV diagnosis & later stages of illnessInitial HIV diagnosis & later stages of illness

– Multiple comorbid factorsMultiple comorbid factors• Substance abuseSubstance abuse• PovertyPoverty• HomelessnessHomelessness• Social isolationSocial isolation

– Physical stigma of ARTPhysical stigma of ART• Lipoatrophy, lipodystrophy: disclosure of infectionLipoatrophy, lipodystrophy: disclosure of infection


• Multiple studies indicate almost all Multiple studies indicate almost all antidepressants are effectiveantidepressants are effective– Concern for P450 interactions with some Concern for P450 interactions with some

antiretroviral medications antiretroviral medications • Favor citalopram & sertraline over paroxetine & Favor citalopram & sertraline over paroxetine &

fluoxetine (2D6)fluoxetine (2D6)• Caution with nefazodone & fluvoxamine (3A4)Caution with nefazodone & fluvoxamine (3A4)

– Side effect profile guides choice of agentSide effect profile guides choice of agent• Mirtazipine favored for sedation and appetite Mirtazipine favored for sedation and appetite

stimulationstimulation


• PsychotherapyPsychotherapy– Many studies showing benefit with and Many studies showing benefit with and

without antidepressantswithout antidepressants• Group therapy – prominent modalityGroup therapy – prominent modality• Cognitive Behavioral Therapy (CBT)Cognitive Behavioral Therapy (CBT)• Interpersonal Interpersonal • SupportiveSupportive

– Themes of guilt, shame, angerThemes of guilt, shame, anger

Mental Health & HIV/AIDSMental Health & HIV/AIDSPTSDPTSD

• 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)

Mental Health & HIV/AIDSMental Health & HIV/AIDSPTSDPTSD

• 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/AIDSMental Health & HIV/AIDSPanic DisorderPanic 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/AIDSMental Health & HIV/AIDSPanic DisorderPanic 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/AIDSMental Health & HIV/AIDSSocial PhobiaSocial 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/AIDSMental Health & HIV/AIDSDementiaDementia

• 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


• 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


• 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)


• Risk Factors– Seroconversion illness– Anemia– Vitamin deficiencies (B6, B12)– Low CD4 count– High CSF HIV viral Load– ETOH, cocaine & amphetamine– Depression


• 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


• Early signs & symptoms– Decreased attention & concentration– Psychomotor slowing– Reduced speed of information processing– Executive dysfunction

• Abstraction• Divided attention• Shifting cognitive sets


• Later signs & symptoms– Memory impairment– Language problems– Visual-spatial difficulties– Apraxias


• Associated behavioral changes– Apathy– Depression– Sleep disturbance– Agitation & mania– Psychosis


• Neurocognitive problems

– 30-50% Subclinical Neuropsychological testing

impaired

---------(threshold clinical significance)------------

– 20% MCMDMinor Cognitive Motor Disorder

– 2-4% HAD HIV Associated Dementia


• Mild Manifestation– MCMDMinor Cognitive Motor Disorder

• Severe Manifestation*– HADHIV Associated Dementia

*functional impairment

• Diagnostic Criteria1) At least 2 of: impaired attention, concentration, memory, mental & psychomotor slowing, personality change

2) Rule out other cause

• Diagnostic Criteria1) Acquired cognitive abn*

2) Acquired motor abn*

3) No clouded LOC & rule out other cause


• 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


• 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)


• 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/AIDSMental Health & HIV/AIDSBipolar - ManiaBipolar - 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


• 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


• 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


• 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


• 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/AIDSMental Health & HIV/AIDSSchizophreniaSchizophrenia

• 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


• 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


• Substance-induced psychosis

– Least studied & most resistant to treatment

– Methamphetamine > cocaine > hallucinogen

– Possibly increased susceptibility in patients with later stage HIV infection (C3)


Medication Interactions

Mental Health & HIV/AIDSMental Health & HIV/AIDSMedication InteractionsMedication 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


Hepatic metabolism– Phase I

• Oxidation – Cytochrome P450• Reduction• Hydrolysis

– Phase II• Glucuronidation - UGT• Acetylation• Sulfation


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


• 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….


• 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)


• 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



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



Most important cytochrome P450 enzymes:

• 1A2• 2C9 & 2C19• 2D6• 3A4*


• Phase II Glucuronidation

H2O-soluble molecules conjugated

= more easily excreted

Uridine Glucuronosyltransferase (UGT)– 2 clinically significant subfamilies

1A & 2B


• 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


• Antiretrovirals

Major culprit: ritonavir

Most potent known inhibitor of 3A4!


• Antiretrovirals– 1A2

• Induction by ritonavir & nelfinavir

– 2C9• Induction by ritonavir & nelfinavir• Inhibition by delavirdine

– 2C19• Induction by efavirenz & nelfinavir• Inhibition by efavirenz & delavirdine


• Antiretrovirals– 2D6

• Inhibition by ritonavir

– 3A4• Induction by ritonavir, nelfinavir, efavirenz,

nevirapine• Inhibition by ritonavir, fosamprenavir, indinavir,

nelfinavir, saquinavir, tipranavir, delavirdine


• 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


• Antidepressants– Most metabolized at 2D6– Exceptions:

• Fluvoxamine (Luvox)– AVOID

• Nefazodone (Serzone)– AVOID or dose cautiously

• Bupropion (Wellbutrin, Zyban) – @ 400 mg, dose cautiously with ritonavir


• Antidepressants– SSRIs

• Fluoxetine (Prozac) & paroxetine (Paxil): – some interactions, but not clinically significant for most

antiretrovirals

• Citalopram (Celexa), escitalopram (Lexapro), & sertraline (Zoloft):

– have fewest 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


• Antidepressants– Dual-action agents:

• Venlafaxine (Effexor) & duloxetine (Cymbalta)• Well tolerated without adjusting dose

– Mirtazipine (Remeron)• Well tolerated


• Anxiolytics– Mostly metabolized at 3A4– Avoid

Alprazolam (Xanax)

Triazolam (Halcion)

Midazolam (Versed)


• Anxiolytics– Safest to use glucuronidated benzodiazepines:

• Lorazepam (Ativan)• Temazepam (Restoril)• Oxazepam (Serax)

– Caution with buspirone (Buspar), and dosing of other benzodiazepines with ART (3A4)


• Antipsychotics– Typicals (first generation = D2 blockers)

– Atypicals (second generation = multiple neurotransmitters)

Both are mostly metabolized at 2D6


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)


• 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


• 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


Challenging Patient Population

Mental Health & HIV/AIDSMental Health & HIV/AIDSChallenging Patient PopulationChallenging 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….


• 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


• 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


• 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


• 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


• 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


• 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


Substance Abuse

Mental Health & HIV/AIDSMental Health & HIV/AIDSSubstance AbuseSubstance 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


• Substances– Alcohol– Amphetamines– Cocaine– Heroin– Club drugs:

• GHB, MDMA (Ecstasy), Ketamine (Special K)


• 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)


• 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


• 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/AIDSMental Health & HIV/AIDS Summary 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

mental health & hiv/aids murray bennett, md, frcpc clinical assistant professor psychiatry...

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