Download - 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
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