266e_mental-health-and-hiv-aids.ppt

Mental Health & HIV/AIDS
Murray Bennett, MD, FRCPC
Clinical Assistant Professor Psychiatry
University of Washington
Director Psychiatry Madison Clinic
Harborview 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

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

New Infections USA
• Men 70%
– 60% MSM
– 25% IDU
– 15% Heterosexual
• Women 30%
– 75% Heterosexual
– 25% IDU

• 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

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)

• Challenging Illness to Treat
• >20 antiretroviral medications
• Challenging Patient Populations
• Comorbid Psychiatric Disorders
• Substance Abuse
• Poverty
• Homelessness
• Social isolation

Psychiatric Epidemiology

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

Depression
• 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)

Depression
• 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

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%)

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

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%)

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

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

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

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 (Lutgendorf 1997)
– Higher levels of pain (Smith 2002)

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)

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

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)

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

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

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

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)

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

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

Dementia
• Early signs & symptoms
– Decreased attention & concentration
– Psychomotor slowing
– Reduced speed of information processing
– Executive dysfunction
• Abstraction
• Divided attention
• Shifting cognitive sets

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

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

Dementia
• Neurocognitive problems
– 30-50% Subclinical
Neuropsychological testing impaired
---------(threshold clinical significance)------------
– 20% MCMD
Minor Cognitive Motor Disorder
– 2-4% HAD
HIV Associated Dementia

Dementia
• 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

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

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)

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

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

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

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

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

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

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

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

Schizophrenia
• 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

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

• 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

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

Substance Abuse
• Substances
– Alcohol
– Amphetamines
– Cocaine
– Heroin
– Club drugs:
• GHB, MDMA (Ecstasy), Ketamine (Special K)

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)

Substance 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

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

Summary
• Changing epidemic with significant impact
• Challenging illness & patient population
• Team approach, multidisciplinary care
• Remember to look up medication interactions!

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