Neuropsychiatric Aspects of HIV

University of Hawaii

James Dilley, MD and Emily Leavitt, LCSW

Prevalence of MH Disorders among People with HIV/AIDS

n = 1489

0%

5%

10%

15%

20%

25%

30%

Any MDD PanicAny Mood

Any Anxiety

PTSD

Vitiello et al. AJPsych 2003, 160:547-54

from “HIV Cost and Services Utilization Study—1996”

Depression in HIV

• Most common dx in outpt settings

• Concern re: diagnosis in medically ill

• Emphasize cognitive/affective vs. neurovegatative signs/sxs

• Assoc with CD4, soc support and phys limitations and HIV sx

• Excellent pharmacologic response

• Give benefit of the doubt

INITIAL MAX

1. SSRI'sFluoxetine (Prozac) 10 mg 40 mg/DParoxetine (Paxil) 10 mg/D 40 mg/DSertraline (Zoloft) 50 mg 200 mg/D

2. OthersBupropion SR (Wellbutrin) 100 mg BID 200 BIDMirtazapine (Remeron) 15 mg 30 mg/ HSTrazodone (Desyrel) 50 mg 300 mg/HS

3. TCA'sDesipramine 100 mg 300 mg/ HS or AMNortriptyline 50 mg 150 mg/HS

Pharmacotherapy of Depression in HIV

Depression & Testosterone

• 50% of men with Sx HIV/AIDS have deficiency and sx of hypogonadism:

– Fatigue– Decreased libido– Decreased appetite– Decreased mood

Screening Tests

• Total Serum Testosterone: <300-400ng/dl

• Serum Free testosterone: <5-7 pcg/ml

• Tx: depot IM injections q ii wks (100-200mg IM; max 400 mg/wk)

• Patch (5-10mg; 1-2 times daily)

• Gel (25-100 mg to skin daily)

• Can see mood improvement

CNS: HIV’s Most Important Sanctuary Site

• HIV produces at diff rates in CNS vs. plsma

• Diff phen/genotypes: esp later in disease

• All ARV’s not = in treating CNS cx

• May result in peripheral success (pVL) but central failure

HIV Neuropathogenesis

Early and continuous seeding

Importance of Blood Brain Barrier

HAD: A Diagnosisof Exclusion

• HIV antibody positive

• No other treatable disorder known to be associated with mental status changes (e.g., no other CNS OI’s, trauma, metabolic disorders, etc.

Diagnosis Requires (continued):

• “Clinical findings of disabling cognitive and /or motor dysfunction interfering with occupation or activities of daily living”

• Neuropsychological testing often needed, especially in early cases--

• (1 SD below age/education adjusted norms on 2/8 tests) AND

• Either impairment in lower ext or fine motor skills or selfreported depression interfering with function

Pseudo-Dementia• Depression in “dementia’s clothing”

• Index of suspicion high if: – unremitting and detailed c/o memory pblms

– “I don’t know” responses to cog questions: communicates distress/emphasizes disability

– Behavior often incongruent w/level of complaint

– In early stages of HIV disease

– Frequently has past hx of psychiatric pblms

Cognitive Functions

A. MemoryShort-term vs. delayed

B. Concentration, Calculation and Constructional Ability

C. Personality Change: alteration or accentuation of pre-morbid traits

D. Language

E. Judgement“Reasonable plans”

Early Manifestations of HAD

• Cognitive

Memory Loss (names, historical details, etc.)

Impaired Concentration (difficulty reading, loses track of conversation)

Mental slowing (“not as quick,” less verbal)

Confusion (time, especially)

• BehavioralApathy, withdrawal, “depression”Agitation, hallucination

• MotorUnsteady gaitBilateral leg weaknessTremorLoss of fine motor coordination

Early Manifestations of HAD (continued)

Late Manifestations

• Cognitiveglobal dementia in all spheresconfusion and distractabilityslow verbal responsiveness

• Behavioralvacant staredisinhibition and restlessnessorganic psychosis

Late Manifestations (cont.)

• Motor

general slowing

truncal ataxia

weakness: legs > armspyramidal tract signs: spasticity, hyperreflexia

Effect of HAART

• Significant changes in the epidemiology of CNS disorders since HAART

• In Sx illness– Studies are more consistent with subcortical

dementia

• In asx illness, NP findings are inconsistent– > Length of battery>NP deficits– Significance clinically is unclear

Pathological Findings in CNS of AIDS Patients at Autopsy N = 1597

1984-1987(No therapy)

1988-1994(monotherapy)

1995-1996(dual comb. therapy)

1997-2000(triple comb. therapy)

0%

10%

20%

30%

40%

50%

60%

1984-87

1988-94

1995-96

1997-00

54%

32%

18%

15%

Vago L., et al. AIDS 2002, 16:1925-28

Risk Factors for Cognitive Impairment in HIVCase Control: 90 HIV- ; 88 ASX; 94 SXCI = Scores of 2SD below the means of the control on 2 or more standard neuropsychological tests

RESULTS

OR Limits

Education <6 yrs cf. >6yrs 17.2 3.6 – 83.3

Antiviral Use Yes 0.1 0.0 – 0.3

CD4<200200-400

>500>500

8.66.9

1.0 – 71.01.0 – 48.4

De Ronchi D., et al. Arch. Neurology. 2002 May; 59(5):812-8

HAART Use & NP FunctionN = 130; Avg Age = 41; 42% NW; 82% AIDS

HAART

N 69

CD 4 254

UVL 42%

NPI 22%

Non-HAART

61

342

20% p<0.01

54% p<0.0001

Ferrando et al., AIDS, 1998, 12F 65-70

NOTE: IMP = 25D in the impaired direction of age-matched population-based norms

HAART= NRTI + Ritanavir, Indinavir or Nelfinavir

Median HIV RNA levels for brain (for all available brain regions) and peripheral tissues stratified by neurologic status:

non-demented, mild, and moderate/severe

0

1

2

3

4

5

6

7

8

9

10

Brain Only Peripheral Only

NoneMildModerate

p = 0.0128

p = 0.0002

McClernon D.R, et al. Neurology 2001, 57:1396-1401

Correlation of Plasma VL to CSF VLP CSF

< 200 >200

No No

No Yes*

No Yes

No Yes*

No No

CSF NP Status

< 200 >200

Yes No

Yes No

Yes No

Yes No

Yes No

Brew (Aus)

Ellis (US)

MacArthur (US)

Dore (US)

DiStephano (Italy)___________________________

* Correlation exists in ASX state

Favorable CNS Characteristics of ARVs

• % protein binding ( = better)

• lipid solubility ( = better)

• molecular weight ( = better)

• inhibitory concentration ( = better)

Medical Rx of HAD

1. Aggressive ARV: neuroprotective

2. Use combinations of 3, 4 or more

Should include:

• AZT, D4T, 3TC, Abac-NRTI

• Nevirapine, Efavirenz-NNRTI

• Indinavir - PI

(best BBB penetrance)

Factors Influencing Efficacy of ARV Rx:

• Stage of HIV disease

• Degree of CNS replication/resistance

• Integrity of BBB

• Specific treatment strategy/ARV choice

Some Neuroprotective Disappointments

Nimodipene interaction with CAH

Peptide T block gp-120

*Memantine NMDA antagonist/showing efficacy for ADV

*Deprenyl Anti-oxidant/anti-poptotic

Lexipafant PAF antagonist

*some benefits

Case History - “JC”

ID: 42 y/o GWM architect admitted for agitation,irritability, decreased sleep, and grandiose delusions. Brought in by lover of 7 yrs.

HPI Two mos intermittent confusion/ hypomania (rapid speech, disorganized thinking over last 3 days; focus on spiritual issues. Felt friends were trying to harm him, stated he had been cured of AIDS; claimed he was a millionaire.

PMH HIV infected x 10 years; current CD4 count = 70.

No OI’s. No previous psych hx.

Case History - “JC” (cont.)MS: Alert, mildly agitated, unable to sit still.

Speech: mildly pressured, loud, but interruptable.Thought process: overly inclusive, loose assns.Content: grandiose, “richest family in California,”had “cured himself of AIDS.” Some paranoia.Cognitive: 0 x 2. Memory: Imm = 4/4; 2/4 @ 5 mins. 3/4 with prompts.Attention: Serial 7’s = mult. Errors;

WORLD backwards, “d-l-o-w.”Abstraction: Some concreteness.Construction: OKInsight: noneJudgement: impaired

Case History - “JC” (cont.)

Diff Dx:

Axis 1: Delirium due to HIV disease (293.0).Dementia due to HIV disease (294.1)R/O BADR/O Toxic Psychosis

Axis II: Deferred

Axis III: AIDS

Hospital Course

LAB: MRI: Extensive cortical atrophy.LP: unremarkable

Rx: Trilafon 2mg p.o. BID and 4 mg @ HSValproic acid 250mg p.o. BID and 500 mg @ HSAtivan 0.5 mg p.o. BID and prn agitation

Psychotropic Medication Use

0.00%

5.00%

10.00%

15.00%

20.00%

25.00%

30.00%

Any Anti-Anx StimulantsAnti-D Anti-Psych

NOTE: Use among Af-Am was significantly lower than White or Hispanic.

Vitiello et al. AJPsych 2003, 160:547-54

from “HIV Cost and Services Utilization Study—1996”

Psychopharmacology in HIV Disease

Consider geriatric dosing - “start low and go slow”

Look for low-anticholinergic meds

ConsiderPay special attention to Ritonavir (NORVIR - strong CYP3A4 inhibitor)

Overall, anti-HIV meds are not problematic

Pharmacotherapy of Anxiety Disorders

1. “Reactive” Anxiety - Lorazepam 0.5 mg B/TIDMax: 4 mg q 4 hrs

2. Panic Disorders with or without Agoraphobia Paroxetine (Paxil) 10-40 mg/D Lorazepam for breakthrough

3. GAD - Paroxetine; Buspirone (Buspar) 5-10 mg BID - 20 mg TID

Note: Buspirone is the “does not” drug: cause tolerance, physical dependence or a withdrawal syndrome, have abuse potential (hypnotic, muscle relaxant activity), work right away

Ritonavir (Norvir)(Potent inhibitor of CP450, esp. 2D6 and 3A4)

1. Adjust Anti-depressants SSRI’s - initially by 1/2 TCA’s - initially by 1/2 to 1/3Nefazodone and St. John’s Wort

2. Avoid Benzodiazepines Anti-psychoticsClonazepam (Klonopin) ClozapineAlprazolam (Xanax) PimozideDiazepam (Valium)Flurazepam (Dalmane)Triazolam (Halcion)Zolpidem (Ambien)

2. AllowTemazepam (Restoril)Oxazepam (Serax)Lorazepam (Ativan)Bupropion (Wellbutrin)

Methadone

• Ritonavir and Nevirapine (and likely Efavirenz) has been shown to lead to significant withdrawal symptoms in stable methadone users

• Should follow serum meth levels before & after initiation; may need to increase by 25-30%

Other Pharm Issues

• Sildenafil levels may be significantly raised by Ritonavir, Saquinavir and Indinavir--potentially serious CV effects (DNE 25mg)

• Fatal case reports have been filed suggesting Ritonavir in combination with methamphetamine and Ecstasy (MDMA) was the cause of death

• St. John’s Wort: may decrease PI’s

ARV Classes

Fusin

Inhibitor

Reverse Integrase Protease

Fuseon Transcriptase Inhibitors

NRTI NNRTI

AZT Nevirapine*DDI DelavardineDDC DMP-266D4T Efavirenz*3TC

IndinavirRitonavirSaquinavirNelfinavir

*Induce CP450 3A4 and 2D6