Review of psychopharmacology in infectious diseases and the neuropsychiatric side effects of antimicrobials

1. Psychopharmacology in
Infectious Diseases
M I C H A E L T . I N G R A M , M . S . , M . D .
F E L L O W ( P G Y - 5 )
C O N S U L T A T I O N - L I A I S O N P S Y C H I A T R Y
U C L A / C E D A R S / W L A V A

2. Neuropsychiatry and Infectious Diseases
 Human behavior (mobility, travel, sexual practices, substance use, etc.) interacts with Infectious
Disease risk and outcomes in complex ways
 Psychiatric symptoms are part of the clinical presentation of many systemic and central nervous
system infectious processes (examples, NOT all inclusive):
HIV/AIDS
Cysticercosis
Syphilis
Toxoplasmosis
West Nile Encephalitis
 Infectious diseases have been implicated in the pathogenesis of psychiatric disorders
Viral antibodies in Schizophrenia
Pediatric Autoimmune Neuropsychiatric disorder associated with streptococcal infection (PANDAS)
Lyme disease

3. Neuropsychiatry and Infectious Diseases
 Pre-existing Neurological Disease, Neurological Injury, Neurocognitive impairment, and Aging
render patients more vulnerable to
Neuropsychiatric effects of even limited infectious diseases
Simple URI or UTI in young healthy individual has no major neuropsychiatric effects
But in a 78 year old woman with history of multiple CVAs and Alzheimer’s  devastating delirium
Neuropsychiatric side effects of the antibiotics, antivirals, etc. used to treat infections
Reasons are unknown but thought to relate to permeability changes in blood brain barrier and
the effects of inflammatory mediators (cytokines, hormones, etc.)
An acute change in neuropsychiatric symptoms may be the first sign of impending sepsis and
may even precede the development of fever

4. Neuropsychiatry and Infectious Diseases
 Psychological factors significantly affect risk for and course of infectious diseases
In a large Danish cohort of patients hospitalized for infection, 30 day mortality rate was 52% higher for
those with history of severe mental illness than those without (Ribe et al. 2015).

5. Drugs in ID: Adverse
Psychiatric Effects and
Drug Interactions

6. Drug Neuropsychiatric Adverse Effects
Antibacterials
Cephalosporins
Dapsone
Procaine Penicillin
Quinolones
TMP-SMX
Gentamicin
Clarithromycin
Euphoria, delusions, depersonalization, illusions
Insomnia, agitation, hallucinations, mania, depression
Agitation, depersonalization, hallucinations, Fear
Psychosis, Paranoia, Mania, Agitation, Tourette’s Sxs
Delirium, psychosis
Delirium, psychosis
Delirium, mania

7. Drug Neuropsychiatric Adverse Effects
Antituberculous
Cycloserine
Isoniazid
Ethionamide
Agitation, depression, psychosis, anxiety
Psychosis, Mania, Agitation, depersonalization
Depression, hallucinations

8. Drug Neuropsychiatric Adverse Effects
Antivirals
Acyclovir, ganciclovir
Amantadine
Oseltamivir, zanamivir
Interferon-alfa
Interleukin-2
Psychosis, delirium, depression, anxiety
Psychosis, delirium
Psychosis, delirium
Irritability, depression, agitation, paranoia
Psychosis, delirium

9. Drug Neuropsychiatric Adverse Effects
Antifungals
Amphotericin Delirium, psychosis, depression
Antiparasitic
Antimalarials
Metronidazole*
Thiabendazole
Confusion, delirium, psychosis, mania, depression,
anxiety, aggression
Depression, delirium
Psychosis
*Metronidazole and Tinidazole can cause disulfiram-like reactions after alcohol ingestion

10. Neuropsychiatric Side Effects of Antiretrovirals

11. Antiretrovirals: NRTIs Neuropsychiatric Side Effects
Abacavir Depression, Mania, Suicidal ideation, Anxiety
Psychosis, Insomnia, Nightmares, Fatigue
Didanosine Nervousness, Agitation, Mania, Lethargy
Emtricitabine Depression, Odd dreams, Insomnia, Confusion, Irritability
Interferon-a-2a Depression, Suicidal ideation, anxiety, mania, psychosis,
insomnia, delirium, altered cognition
Lamivudine Depression, Insomnia, Dizziness, dystonia
Zidovudine Anxiety, Agitation, Restlessness, Insomnia, Mania, Psychosis

12. Antiretrovirals: NNRTIs Neuropsychiatric Side Effects
Delavirdine Anxiety, Agitation, Amnesia,
Lightheadedness/dizziness
Efavirenz Anxiety, Insomnia, Irritability, Depression
Suicidal ideation, psychosis, Nightmares, Vivid dreams
Lightheadedness/dizziness
Nevirapine Vivid dreams, Nightmares, Visual hallucinations
Delusions, Mood Instability
Lightheadedness/dizziness
Etravirine Insomnia, lightheadedness/dizziness
Rilpivirine Odd Dreams, Insomnia, lightheadedness/dizziness

13. Antiretrovirals: PIs Neuropsychiatric Side Effects
Atazanavir Depression, Insomnia
Fosamprenavir Depression
Indinavir Anxiety, Agitation, Insomnia
Lopinavir and Ritonavir Insomnia
Nelfinavir Depression, Anxiety, Insomnia
Ritonavir Anxiety, Agitation, Euphoria
Hallucinations, Taste changes
Decreased libido
Saquinavir Anxiety, Agitation, Euphoria
Depression, Hallucinations
Excessive dreaming
Tipranavir Depression

14. Antiretrovirals:
Integrase Inhibitors
Neuropsychiatric Side Effects
Raltegravir Depression, suicidal ideation, psychosis
Vivid dreams, nightmares, vertigo,
Lightheadedness/dizziness
Elvitegravir Depression, Insomnia, Suicidal ideation
Dolutegravir Insomnia, Fatigue
Fusion Inhibitors
Enfuvirtide Depression, Insomnia

15. Most Notable
• DELIRIUM/PSYCHOSIS
• Quinolones (ciprofloxacin)
• Procaine penicillins
• Mefloquine
• Cycloserine
• DEPRESSION
• Interferon
• DISULFIRAM-LIKE REACTIONS
• Metronidazole

16. DRUG-DRUG
INTERACTIONS

17. Drug-Drug Interactions
Pharmacokinetic Interactions
• Absorption
• Distribution
• Protein Binding
• Metabolism
• CYP450 Enzymes
• Excretion
• Drug Transport
Pharmacodynamic Interactions
• Synergism
• Antagonism

19. Antimicrobial-Psychotropic drug interactions
• Antimalarials
• Increase phenothiazine levels (chlorpromazine)
• Azoles
• Increase alprazolam, midazolam levels
• Increase buspirone levels
• Clarithromycin, Erythromycin
• Increase alprazolam, midazolam levels
• Increase carbamazepine levels
• Increase clozapine levels
• Increase buspirone levels

20. • Quinolones
• Increase clozapine levels
• Increase benzodiazepine levels but decreases benzodiazepine effects via
GABA receptor
• Isoniazid
• Increases haloperidol level
• Increases carbamazepine level
• If used with disulfiram can cause ataxia
• Linezolid
• Serotonin syndrome with serotonergic drugs
Antimicrobial-psychotropic drug interactions

21. Other notable interactions
• Erythromycin, Clarithromycin, and Ketoconazole
• QT prolongation and ventricular arrythmias with TCAs and
antipsychotics
• Linezolid is an irreversible MAO-A inhibitor
• Serotonin syndrome
• Hypertensive crisis
• Isoniazid is a weaker MAO inhibitor
• Reports of Serotonin syndrome and hypertensive crisis

22. HIV/AIDS

23. HIV/AIDS
 General Guidelines for prescription of psychotropic
medication to HIV patients
1. Start at lower doses and increase gradually based on tolerability
and response
2. Use the simplest possible regimen
3. Use drugs with a side effect profile that can be used as a
therapeutic advantage
4. Consider drug pharmacokinetics to minimize interactions

24. HIV/AIDS
 Patients at advanced stages of liver or HIV disease have physical and cognitive impairment that
increase sensitivity to side effects
Prolonged use of antiretrovirals may lead to metabolic syndrome
Increased risk for cardiovascular and cerebrovascular diseases
Psychotropics that induce similar metabolic changes should be avoided, if possible
Examples: Olanzapine, Clozapine, Quetiapine, Valproate, Mirtazapine
Patients with a current or past history of substance dependence have greater risk of abuse of many
psychotropic drugs
 Quetiapine (Suzie Qs)
 Gabapentin
 Bupropion (snorted)
 Benzodiazepines
HIV patients have alterations in brain neurotransmitter systems (DA, 5HT)
May explain the atypical course and responses to psychiatric medications

25. HIV/AIDS
 NRTIs are predominantly excreted at the kidney
 Minimal interactions with psychotropics
NNRTIs have extensive metabolism via CYP450
 Nevirapine, Efavirenz, Etravirine: Substrates and inducers of CYP3A4
Efavirenz and Etravirine inhibit CYP2C9 and CYP2C19
Protease Inhibitors also have extensive metabolism via CYP450
Ritonavir is most potent inhibitor of CYP3A4 > CYP2D6
CCR5 Blocker Maraviroc metabolized by CYP3A4 (not an inducer or inhibitor)
Fusion inhibitor enfuvirtide (cleared by kidney) and integrase inhibitor raltegravir (cleared via
glucuronidation) have minimal to no clinically significant interactions with psychotropics

26. HIV/AIDS and Benzodiazepines
2/3 of medications prescribed for anxiety among HIV-infected individuals are BZDs
Individuals with HIV infection are particularly sensitive to the amnesic and paradoxical effects
(disinhibition, confusion, agitation) if BZDs
Benzodiazepines of choice for HIV patients
Clonazepam
Lorazepam
Oxazepam

27. HIV/AIDS and Antidepressants
Antidepressants with the lowest CYP450 interactions are best first choice agents
Sertraline
Citalopram
Excitalopram
Venlafaxine (weak 2D6 inhibitor)
Mirtazapine
Trazodone
Bupropion (potent 2D6 inhibitor but data supporting efficacy and tolerability)

28. HIV/AIDS and Psychostimulants
Methylphenidate, Dextroamphetamine, Amphetamine salts
Used for apathy in depression
Neglect of self-care and nutrition in advanced HIV patients
Fatigue, pain, neurocognitive changes in HIV patients

29. HIV/AIDS and Mood Stabilizers
Lithium is best choice
Valproate has been used safely and has minimal CYP450 interactions
Avoid Carbamazepine
Lamotrigine has been used safely for BP depression and neuropathic pain
Metabolized by glucuronidation
Risk of SJS/TEN with rapid dose escalation
Gabapentin not a mood stabilizer but good for neuropathic pain
No hepatic metabolism
No protein binding
Pregabalin did not separate from placebo in treatment of painful HIV neuropathy

30. Gallego, L. Barreiro P, López-Ibor JJ. Psychopharmacological treatments in HIV
patients under antiretroviral therapy. AIDS Rev. 2012 Apr-Jun;14(2):101-11

31. HIV/AIDS and Antipsychotics
HIV patients (especially late-stage) more sensitive to Extrapyramidal Symptoms (EPS)
Avoid typicals (haloperidol, chlorpromazine) due to EPS and cardiac side effects
Avoid anticholinergic agents to “prevent” EPS
Delirium risk
Cognitive decline
First line for Psychosis: Atypical Antipsychotics
Start low, go slow
No depot formulations
No clozapine or pimozide with ritonavir (increases clozapine and pimozide levels dramatically)

32. Gallego, L. Barreiro P, López-Ibor JJ.
Psychopharmacological treatments in HIV
patients under antiretroviral therapy. AIDS Rev.
2012 Apr-Jun;14(2):101-11

33. HIV/AIDS and Substance Use
Opioid Dependence
Buprenorphine better choice than methadone
Naltrexone has no CYP450 metabolism and is not expected to interact with antiretrovirals
Alcohol
Avoid Disulfiram
Used Naltrexone or acamprosate
Naltrexone: Reduces cravings, rewarding effect, and amount of alcohol consumed at relapse
Give during heavy drinking to reduce heavy drinking days
Acamprosate: Reduces cravings and attenuates relapse
Give during abstinence or early relapse

34. Gallego, L. Barreiro P, López-Ibor JJ.
Psychopharmacological treatments in
HIV patients under antiretroviral therapy.
AIDS Rev. 2012 Apr-Jun;14(2):101-11

35. References
1. Stern, T. A., Freudenreich, O., Fricchione, G., Rosenbaum, J. F., & Smith, F. A.
(2018). Massachusetts General Hospital handbook of general hospital psychiatry. Edinburgh:
Elsevier.
2. S. J. Ferrando, J. L. Levenson, & J. A. Owen (Eds.), Clinical manual of psychopharmacology in
the medically ill (pp. 3-38). Arlington, VA, US: American Psychiatric Publishing, Inc.
3. Levenson, J. L. (2019). The American Psychiatric Association Publishing textbook of
psychosomatic medicine and consultation-liaison psychiatry. Washington, D.C.: American
Psychiatric Association Publishing.
4. Gallego, L. Barreiro P, López-Ibor JJ. Psychopharmacological treatments in HIV patients under
antiretroviral therapy. AIDS Rev. 2012 Apr-Jun;14(2):101-11.

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