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].