ERA Series 6: Neuropsychiatry

11 Jul, 16

Depression: Screening and Diagnosis

Significance

Higher prevalence of depression reported in HIV-positive persons (20-40% versus 7% in general population)
Significant disability and poorer treatment outcomes associated with depression

Screening and Diagnosis

Who?

How to screen?

How to diagnose?

Screening of all HIV-positive persons recommended in view of the high prevalence of depression

Populations at particular

high risk

Positive history of depression in family
Depressive episode in personal history
Older age
Adolescence
Persons with history of drug addiction, psychiatric, neurologic or severe somatic co-morbidity
Use of EFV
Use of neurotropic and recreational drugs
As part of investigation of neurocognitive impairment

Screen every 1-2 years
Two main questions:

1. Have you often felt depressed, sad or without hope in the last few months?

2. Have you lost interest in activities that you usually enjoy?

Specific symptoms in men

- Stressed, burn out, angry outbursts, coping through work or alcohol

Rule out organic cause (such as hypothyroidism, hypogonadism, Addison’s disease, non-HIV drugs, vitamin B12 deficiency)

Symptoms – evaluate

regularly

A. At least 2 weeks of depressed mood

B. Loss of interest

C. Diminished sense of pleasure

PLUS 4 out of 7 of the following:

1. Weight change of ≥5% in one month or a persistent change of appetite

2. Insomnia or hypersomnia on most days

3. Changes in speed of thought and movement

4. Fatigue

5. Feelings of guilt and worthlessness

6. Diminished concentration and decisiveness

7. Suicidal ideation or a suicide attemptⁱ

i. EFV has been associated with a higher risk of suicidal ideation

Depression: Management

Degree of depression	No. of symptoms (A,B or + 4/7)	Treatment	Consultation with expert
No	<4	No
Mild	4	Problem-focused consultation Consider antidepressant treatmentⁱ Recommend physical activity	Always, if treating physician is unfamiliar with use of antidepressants If depression is not responding to treatment If person has suicidal ideation In case of complex situations such as drug addiction, anxiety disorders, personality disorders, dementia, acute severe life events
Intermediate	5-6	Start antidepressant Treatmentⁱ
Severe	>6	Refer to expert (essential)

i. See Drug-drug Interactions between Antidepressants and ARVs

If a person is diagnosed with depression, switching off EFV to another third ARV drug according to switch rules is recommended.

Algorithm for Diagnosis and Management of HIV-associated Neurocognitive Impairment (NCI) in Persons without Obvious Confounding Conditions

Abbreviations: CSF cerebrospinal fluid; GDR genotypic drug resistance test; HAD HIV-associated dementia; MND mild neurocognitive disorder; MRI brain magnetic resonance imaging; NP neuropsychological

i. Obvious confounding conditions:

1. Severe psychiatric conditions

2. Abuse of psychotropic drugs

3. Alcohol abuse

4. Sequelae from previous CNS-OIs or other neurological diseases

5. Current CNS-OIs or other neurological diseases

ii. The following 3 questions may be used to guide physician assessment:

1. Do you experience frequent memory loss (e.g. do you forget the occurrence of special events even the more recent ones, appointments, etc.)?

2. Do you feel that you are slower when reasoning, planning activities, or solving problems?

3. Do you have difficulties paying attention (e.g. to a conversation, book or movie)?

For each question, answers could be as follows: a) never, b) hardly ever, or c) yes, definitely. HIV-positive persons are considered to have an “abnormal” result when answering “yes, definitely” on at least one question.

iii. See Depression: Screening and Diagnosis

iv. NP examination will have to include tests exploring the following cognitive domains: fluency, executive functions, speed of information processing, attention/working memory, verbal and visual learning, verbal and visual memory, motor skills plus assessment of daily functioning.

v. Neurological examination, brain MRI and CSF examination are required to exclude other pathologies and to further characterize HIV-associated NCI, by including assessment of CSF HIV-VL level and, where appropriate, evidence for genotypic drug resistance (GDR) in a paired CSF and plasma sample.

vi. NCl includes

1. marked acquired impairment in cognitive functioning involving at least 2 cognitive domains, as documented by performance of at least 1 SD below the mean for age-education appropriate norms on NP tests

2. interference in daily functioning

3. no evidence of another pre-existing cause for the dementia

vii. CSF escape definition either CSF VL >50 and plasma HIV-VL <50 copies/mL- or both CSF and plasma HIV-VL >50 copies/mL, with CSF HIV-VL >0.5 log10 higher than plasma HIV-VL

viii. Including all situations that do not fulfil the CSF escape definition

ix. Definition of ‘potentially CNS-active’ drugs:

ARV drugs with either

1. demonstrated clear CSF penetration when studied in healthy HIV-positive populations (concentration above the IC90 in > 90% examined persons)

2. proven short-term (3-6 months) effi cacy on cognitive function or CSF HIV-VL decay when evaluated as single agents or in controlled studies in peer-reviewed papers

Drugs with demonstrated clear CSF penetration:
NRTIs: ZDV, ABC*
NNRTIs: EFV**, NVP
PI/r, IDV/r, LPV/r, DRV/r*
INSTI: DTG
Other classes: MVC
Drugs with proven clinical efficacy:
NRTIs: ZDV, ABC
PI/r: LPV/r

* When administered twice daily. Once-daily administration of these drugs, although common in clinical practice, has not been studied extensively with regard to CNS effects/CSF penetration and may have different CNS activity.

** EFV should be used cautiously in HIV-positive persons with NCI because of its detrimental effects on neurocognitive function in a RCT and potentially confounding CNS effects.

Classification, Doses, Safety and Adverse Effects of Antidepressants

Mechanisms & classification	Start dose	Standard dose	Lethality in overdose	Insomnia and agitation	Sedati-on	Nausea or GI effects	Sexual Dysfuncti-on	Weight gain
Mechanisms & classification	mg/day		Lethality in overdose	Insomnia and agitation	Sedati-on	Nausea or GI effects	Sexual Dysfuncti-on	Weight gain
Selective serotonin-reuptake inhibitors (SSRIs)ⁱ
Paroxetine	10-20	20-40	Low	+	-/+	+	++	++
Sertraline	25-50	50-150	Low	+	-/+	+	+	+
Citalopram	10-20	20-40	Low	+	-/+	+	+	+
Escitalopram	5-10	10-20	Low	+	-/+	+	+	+
Mixed or dual-action reuptake inhibitors
Venlafaxine	37.5-75	75-225	Moderate	++	-/+	+	+	-/+
Mixed-action newer agents
Mirtazapine	30	30-60	Low	-/+	++	-/+	-/+	++

- None

+ Moderate

++ Severe

i For many persons, SSRI induction may be associated with adverse effects (GI tract, dizziness, anxiety, panic attacks). Commencing at lower doses (i.e. 10, 25 & 10 mg for Paroxetine, Sertraline and Citalopram, respectively) and increasing to the above starting doses after 4 to 7 days, if tolerated, may reduce such effects.

Drug-drug Interactions between Antidepressants and ARVs

Antidepressants

ATV/r

DRV/c

DRV/r

LPV/r

EFV

ETV

NVP

RPV

MVC

DTG

EVG/c

RAL

SSRI

citalopram

↑^a

↑

↑^a

↓

↔

↑

↔

escitalopram

↑^a

↑

↑^a

↓

↔

↑

↔

fluvoxamine

↑

↔

↑

↔

fluoxetine

↑

↔

↑

↔

paroxetine

↑↓?

↓39%

↑↓?

↔

↑↓?

↔

sertraline

↓

↑

↓49%

↓

↓39%

↓

↔

↑

↔

SNRI

duloxetine

↑↓

↑

↑↓

↔

↑

↔

venlafaxine

↑

↓

↔

↑

↔

TCA

amitriptyline

↑^a

↑

↑^a

↔

↑

↔

clomipramine

↑^a

↑

↑^a

↓

↔

↑

↔

desipramine

↑^a

↑

↑5%^a

↔

↑

↔

doxepin

↑

↔

↑

↔

imipramine

↑^a

↑

↑^a

↓

↔

↑

↔

nortriptyline

↑^a

↑

↑^a

↔

↑

↔

trimipramine

↑

↔

↑

↔

TeCA

Maprotiline

↑

↔

↑

↔

mianserine

↑

↓

↔

↑

↔

mirtazapine

↑

↓

↔

↑

↔

Others

bupropion

↓

↔

↓

↓57%

↓55%

↔

↓

↔

↑?

↔

lamotrigine

↓32%

↔

↓

↓50%

↓

↔

nefazodone

↑

↓E

↔

↑

↔

St. John’s wort

D^b

↔

trazodone

↑

↓

↔

↑

↔

↑ potential elevated exposure of the antidepressant

↓ potential decreased exposure of the antidepressant

↔ no significant effect

D potential decreased exposure of ARV drug

E potential elevated exposure of ARV drug

A ECG monitoring is recommended

B The US Prescribing Information recommends that co-administration should be avoided as there are insufficient data to make dosing recommendations. Numbers refer to decreased AUC of the antidepressant as observed in drug-drug interaction studies.

SSRI selective serotonin reuptake inhibitors

SNRI serotonin and norepinephrine reuptake inhibitors

TCA tricyclic antidepressants

TeCA tetracyclic antidepressants

Reference

EACS Guidelines version 8.0 - October 2015