The impact of COVID-19 on the society is enormous. Over past few months, COVID-19 infection resulted in significant morbidity and mortality globally. Till date, there is no specific treatment of vaccine available for management and prevention of COVID-19. There have been lots of trials that attempted to see the efficacy of various antiviral medications, antibiotics, antimalarial agents, and immune-modulators. Similarly, trials of vaccine are also in different stages of development. Despite the challenges, researchers found some beneficial role of several medications including hydroxychloroquine (HCQ)/chloroquine, azithromycin, ritonavir, ivermectin, doxycycline, and remdesivir in the prophylaxis and treatment.[1–7] These medications gained popularity and are being widely used in the management of COVID-19 over past several months, till date. The close contacts of patients with COVID-19, health-care professionals, marginalized population, elderly and people with comorbidities are considered as at-risk populations. Mortality rates are high among people with comorbidities and elderly.[8,9] The deleterious effects of the COVID-19 are intense and not limited to physical well-being alone. Evidence support that a large proportion of people during this pandemic experience anxiety, depression, panic, sleep disturbances, and several other mental health issues.[10,11] A large number of people are not able to cope with the challenges during this pandemic as a result of which psychiatric disorders emerge.[12] HCQ is the most commonly used medication for the management of COVID-19 patients as well as prophylaxis among health-care workers. HCQ has potential cardiac side effects like QTc prolongation,[13] which is also shared by many of the psychotropic medications.[14–17] Hence, combined use of HCQ and psychotropic medication may be a challenging situation for psychiatrists. Similar concerns are there with use of azithromycin, chloroquine, ritonavir ivermectin, doxycycline, and remdesivir with psychotropic medications commonly used in current psychiatric practice.[18,19] Various other medications (ritonavir-boosted nirmatrelvir, bebtelovimab, molnupiravir, interferons, and nitazoxanide) has been tried in the management of COVID-19, with different levels of evidence. Recently, the recommendation of the National Institute of Health possible no role of interferons (except hospitalized patients), ivermectin, nitazoxanide, chloroquine, HCQ, lopinavir/ritonavir, and systemic interferon beta in the management of COVID-19 due to lack of robust evidences in favor of benefit.[20] The various monoclonal antibodies that are recently approved by the US FDA are also found to be less effective in the management of newly emerging strains of COVID-19 like omicron.[21] There is mass vaccination against COVID-19 infection, globally. In the past 2 years, several vaccines have been developed and were used mostly in adult to elderly population. Recently, it has also been given to the adolescent population. Although vaccine is protective against COVID-19, it is also not free from adverse drug reactions. Many neuropsychiatric adverse effects have been reported with vaccines used against COVID-19.[22] Most of the neuropsychiatric adverse effects are associated with viral vector vaccine. However, these neuropsychiatric side effects are rarely reported and when they are reported, they mostly occur within 2 weeks of vaccine administration.[22] There are certain challenging situations that demand a deep understanding about the understanding of drug–drug interaction between psychotropic agents and medications used to treat COVID-19: When a patient with a psychiatric illness already receiving psychotropic medications develops COVID-19, what precautionary measures to be taken while prescribing medications used to treat COVID-19? When a patient undergoing treatment for COVID-19 develops a psychiatric illness, which psychotropic medication to be considered because of potential side effects? The article does not provide any conclusive guidance on the choice of medication to be started in a patient of COVID-19 who develops a psychiatric illness or a patient who, maintained on medications, reports reappearance of symptoms. Given the aforementioned issues, the following strategies may be of help to the clinician, especially mental health personnel in deciding a medication for a patient who is concurrently being treated for COVID-19 infection with HCQ or other approved medications. While choosing a drug for treating depressive disorders, anxiety disorders or obsessive–compulsive disorder, serotonergic drugs such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the first-line agents. SSRIs may be given relatively safely except citalopram and escitalopram in patients taking HCQ since both have the potential to cause QTc prolongation Consider avoiding SSRIs and SNRIs in patients with recent bleeding or high risk for bleeding (e.g., thrombocytopenia, concurrent anticoagulation therapy, and history of hemorrhage)[23] Safer options include nonserotonin reuptake inhibitors such as Bupropion.[23] It must be noted that bupropion itself can lower the seizure threshold and hence best avoided in patients with a comorbid seizure disorder There is likely an increased risk of hypoglycemia associated with concomitant use of SSRIs with antiviral medications and/or Chloroquine/HCQ SSRIs like fluoxetine and its metabolite have potential risk of causing serotonin syndrome when given along with ritonavir Drugs must be given at the lowest possible dose to avoid any potential interactions with drugs used to treat HCQ No interactions have been reported between SSRIs and ribavirin. Similarly, no interaction has been found between mirtazapine and HCQ, chloroquine, ribavirin, and interferons Among the SNRIs, duloxetine should be avoided because of its potential to cause liver injury Patients with new-onset anxiety symptoms may be managed by prescribing the lowest possible dose of the serotonergic drugs. Buspirone can be used for anxiety management considering its minimum interaction with HCQ. Antipsychotics used by themselves can cause blood count disturbances such as decreased white blood cell count and thrombocytopenia in certain cases. Some antipsychotics such as haloperidol, quetiapine, and ziprasidone can prolong the QTc interval. Therefore, medications that can expand QTc like HCQ may have a synergistic effect and should be used with caution. For patients of COVID-19 on antiviral medications who develop recent-onset psychosis, antipsychotics such as aripiprazole may be preferred keeping in view its minimal side effects and drug interactions Patients who are generally maintained on an antipsychotic may be asked to continue the same medication. The clinician might lower doses of such antipsychotics based on clinical judgment One might avoid antipsychotics especially clozapine, quetiapine, olanzapine, and first-generation neuroleptics in patients who have seizures Patients, who are maintained on clozapine must be educated and clinical assessment including absolute neutrophil count (ANC) for those with symptoms of infection In patients with symptoms of infection such as flu-like symptoms, consider reducing the dose of clozapine to half. One might consider discontinuing the drug if symptoms of toxicity emerge Total white cell count and ANC must be done regularly and even with increasing frequency Clinicians can use remdesivir, baricitinib, and anakinra with antipsychotics to treat delirium, agitation, or behavioural difficulties in COVID-19 patients as these drugs have minimal drug interactions. Although hematological risks have been associated with clozapine and baricinitib Only chlorpromazine and quetiapine should be avoided when taking favipiravir. Mood stabilizers are mainstay drugs for the treatment of patients with bipolar disorders in the acute and maintenance phase. Mood stabilizers (e.g., lamotrigine) causing skin rash and hematologic adverse effects should be closely monitored when administered with antivirals. Antivirals like ritonavir and lopinavir, decrease serum concentration levels of valproic acid which can lead to emergence of affective symptoms in a bipolar patient on maintenance treatment. Lithium is least likely to cause drug interactions when administered with antivirals. Other medications used in the management of COVID-19, too have potential cardiovascular side effects.[24] There is a need to consider the pharmacological management of comorbid psychiatric disorders cautiously, to prevent untoward mortality due to life-threatening side effects resulting from drug-drug interaction. Patients with pre-existing psychiatric illness or new-onset psychiatric symptoms but asymptomatic for COVID-19 infection. These patients need to adhere to the treatment recommendations and specific precautionary measures for COVID-19. Reassurance and counseling of the patient and family may be helpful.[12] The dose of the medications used for the treatment of psychiatric illness may be reduced to a minimum effective dose and the patient need to be monitored closely for side effects of HCQ and other antivirals with co-administered psychotropic medications. Patients with pre-existing psychiatric illness taking psychotropics with moderate-to-severe symptoms of COVID-19 and taking anti-COVID-19 medications: A reduction in dose to the minimum effective dose may be done if the patient is maintained well on medications for a significant duration and not reporting any significant psychopathology. Patients reporting symptoms status quo or a worsening of psychiatric symptoms may be given anti-COVID medications in the lowest possible doses with routine monitoring and blood investigations. Such patients should be routinely followed up and any possible interactions should be monitored. A higher or lower plasma concentration of medications might result in toxicity or lack of efficacy. Moreover, intensification of similar adverse effects might harm the patients. Patients may be shifted to a psychotropic that has minimal interaction with the drugs used to treat COVID-19. Several medications used in the treatment of COVID-19 (corticosteroids, antiviral agents, immunomodulators, and antiparasitic agents) have high propensity to cause neuropsychiatric manifestations.[25] Hence, patients with pre-existing psychiatric disorders may expect worsening of symptoms. Hence, there is need of close watch on the psychopathology in patients with psychiatric disorders, who develop COVID-19 and receive the above group of medications. Patients with new emergent psychiatric symptoms with moderate-to-severe symptoms of COVID-19 and taking anti-COVID-19 medications: Patients with new-onset psychiatric symptoms may be started on nonpharmacological management along with reassurance and counseling. In such situations, it is imperative to manage the physical condition of the patient. In cases of severe anxiety, agitation, or sleep disturbances, sedative/hypnotic drugs such as benzodiazepines may be administered in low doses. In cases of delirium, drugs with minimal interactions with medications used to treat COVID-19 such as melatonin agonists and zolpidem may be given. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.