Psychiatric and nervous system disorders
We observed two cases of psychiatric disorders, in particular “major
depression syndrome” and “psychotic crisis”, accompanied by
agitation, delirium, and aggressiveness. In these cases, the suspected
COVID-19 medications were HCQ, darunavir/cobicistat, and, for one
patient, tocilizumab. Considering the presence of co-administered
antidepressants, antipsychotics, and hypnotic and sedative agents, for
these patients a COVID-19 drugs-related reduction of the activity of
central nervous system medications could not be excluded. At the same
time, psychological and social distress linked to COVID-19 infection
should be taken into consideration
[33,
34]. In fact, a recent
systematic review and meta-analysis confirmed that SARS-CoV-2 might
cause depression, anxiety, neuropsychiatric syndromes, and delirium in a
significant proportion of patients in the acute stage
[35]. Of notice, psychiatric
ADRs are not commonly associated to HCQ
[36], darunavir/cobicistat
[37], and tocilizumab
[38].
Cases of episodes of manic behaviour with psychotic features,
persecutory delusions, anxiety, and reality detachment triggered by
chloroquine were described
[39-43]. Considering that HCQ
and chloroquine have similar pharmacological properties, their toxicity
profiles could be considered comparable. A meta-analysis
[44] and a pharmacovigilance
study on registry [45]
confirmed the association between HCQ and psychiatric events. The
mechanisms responsible for the psychiatric ADRs following HCQ exposure
are not fully clarified. Among proposed hypotheses, there are the
cholinergic imbalance related to the inhibition of acetylcholinesterase,
prostaglandin E antagonism, the accumulation of HCQ toxic metabolites in
lysosomes, and the down-regulation of Glycoprotein-P in the blood-brain
barrier [46]. Moreover, HCQ
seems to inhibit the serotonin transporter, increasing its levels in the
synapsis, and to act as N-methyl-d-aspartate agonist and γ-aminobutyric
acid antagonist [46]. In
general, psychiatric ADRs resolution follows HCQ withdrawal.
Among psychiatric ADRs, only “abnormal dreams” are reported in
darunavir/cobicistat summary of product characteristics (SPC)
[37], and, to date,
literature is lacking evidence on this topic. In general, protease
inhibitors have limited central nervous system penetration and therefore
less-pronounced neurological and psychiatric ADRs
[47]. Among this group,
ritonavir alone or in combination is more likely to produce psychiatric
ADRs, in particular mood changes, agitation, and anxiety. In a clinical
trial, HIV patients were randomized to darunavir/ritonavir or
darunavir/ritonavir in combination with two nucleoside/nucleotide
reverse transcriptase inhibitors
[48]. After 48 weeks of
therapy, grade 1-4 nervous system and psychiatric ADRs were seen in 16%
and 9% of patients in each treatment arm. Researchers reported the
following psychiatric manifestations: anxiety, depression,
obsessive-compulsive disorder, and psychotic crisis. Considering that
cobicistat is a CYP3A4 inhibitor and recommendations reported in its SPC
suggest reducing the dosages of concomitant central nervous system
medications, actually, there is no possibility of a drug therapeutic
failure of antipsychotics driven by the pharmacokinetic properties of
suspected protease inhibitors. Therefore, psychiatric ADRs observed in
our sample may have been mainly related to high-dose HCQ and to
underlying psychiatric comorbidities.
After a literature search, we ascertained the lack of evidence on
psychiatric ADRs related to tocilizumab
[38]. Nowadays, the
association between tocilizumab and psychiatric ADRs cannot be fully
explained. As for protease inhibitors, particularly
darunavir/cobicistat, psychiatric ADRs may have been mainly related to
high-dose HCQ and to pre-existing psychiatric disorders.
When diagnosis of a
psychiatric ADRs is made, the best solution is to discontinue any
suspected drug. Based on our clinical experience, depending on
psychiatric clinical manifestation and on QT interval values, the
administration of specific antipsychotic medications (i.e.,
chlorpromazine) could be considered. Usually, patient’s mental status
reverts to normal in a few days. In case of emergencies, emotional
distress is ubiquitous, but some groups may be more vulnerable than
others. In particular, people at heightened risk for COVID-19, those who
contract the disease, and people with pre-existing medical or
psychiatric conditions are at increased risk for adverse psychosocial
outcomes [49]. Particular
attention should also be given to mental health of people in conditions
of increased risk, such as women during pregnancy
[50] or post-partum
[51].