Michael W. Jann, PharmD, FCP

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The goal of this activity is to inform readers about the latest research and clinical trials on psilocybin and outline its possible clinical uses.

1. Describe the active ingredient of psilocybin.

2. Discuss the pharmacology and pharmacokinetic profile of psilocybin.

3. Recognize the potential clinical applications of psilocybin for treatment-resistant depression and other psychiatric conditions.

4. Identify the psychedelic-assisted psychotherapy method for psilocybin treatment.

This continuing medical education (CME) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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 and psilocin are the main psychedelic agents of the psychoactive mushroom genus Psilocybe.

 Historical and cultural use of these psychoactive mushrooms dates back 3000 years in Mexico and the Southwestern regional areas of the present-day United States. Scientifically, psilocybin was isolated and identified in 1958, synthesized in 1959, and used in various experimental research studies in the early 1960s. During that time, psilocybin and other 

 such as lysergic acid diethylamide (LSD) generated considerable controversy. Outside of recreational use, could they be used safely as therapeutic interventions?

The pharmaceutical company Sandoz ceased LSD and psilocybin manufacturing in 1965, and in 1970, the Controlled Substances Act placed psilocybin, LSD, and other psychedelic drugs under the Schedule I designation.

 This action resulted in a cessation of research associated with these agents. The revival of research into psilocybin and LSD began 25 years later under strict restrictions, when preliminary findings displayed promising results for a variety of psychiatric disorders. In the past several years, there have been more research studies on psychedelics than at any previous time.

The FDA approved the psychedelic agent, esketamine nasal spray for treatment-resistant depression (TRD) in 2019; this opened the door to the novel therapeutic approaches of psychedelic agents. In 2018, the FDA designated psilocybin for TRD and 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for 

 Based on these recent studies and approvals, psilocybin may have a growing role in the treatment of TRD and other psychiatric disorders.

Psilocybin reportedly has a low abuse potential and yields no physical dependence, based on the 8 factors of the Controlled Substances Act. It was recommended to be rescheduled as a Controlled Substance Schedule IV drug with a 

 (REMS) if approved by the regulatory agencies.

The structures of psilocybin (O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine) and its active metabolite psilocin (4-hydroxy-N,N-dimethyltryptamine) are shown in the 

, and they bothbelong to the group of tryptamine/indolamine hallucinogens that are related to serotonin.

 Psilocybin can be considered a prodrug, as it is rapidly converted to psilocin in the gastrointestinal (GI) tract by alkaline phosphatase and nonspecific esterases, where 1.0 mol of psilocin is equal to 1.4 mol of psilocybin.

 Psilocin is the active molecule that produces the pharmacologic effects of a selective agonist of serotonin (5-HT) receptors, which include 5-HT

 Compared to other similar 4-OH substituted tryptamines, psilocin has the most potent binding affinity (Ki) for 5-HT

 receptors (10 nM), and to a lesser extent, 5-HT

 receptor activation in the cortical and subcortical structures is the unifying mechanism by which psychedelics exert their hallucinogenic and other assorted psychological actions.

 Depending upon the dose used, the specific psychedelic agent, and possibly, the 5-HT

 receptor density in the different neuronal areas, psilocybin and other psychedelic agents can exert different modulatory actions across the various cortical regions. The administration of ketanserin (a 5-HT

 receptor antagonist) in human clinical studies attenuated the psychological effects of psilocybin, psilocin, and LSD.

 receptors in human psilocybin studies remain to be elucidated.

Besides 5-HT receptors, psychedelic agents may possess other pharmacologic actions that contribute to their behavioral and psychological effects. LSD was reported to interact with considerable affinity at the 

 with stereospecificity, as d-LSD was 1000 times more potent than l-LSD.

 examined the use of psilocybin in healthy volunteers (N = 7) and its effects on in vivo D2 receptor binding using 11C-raclopride in the striatum. Dosed at 0.25 mg/kg orally, psilocybin produced changes in mood, thinking disturbances, illusions, and visual hallucinations.

 Psilocybin also significantly decreased 11C-raclopride binding potential bilaterally in the caudate nucleus (19%) and putamen (20%), which was consistent with a reciprocal increase in endogenous dopamine. These findings indicate that 5-HT

 receptor activation can be a factor for modulating striatal dopamine release in acute psychosis. Psilocybin may be a useful pharmacologic agent for examining the complex interactions between serotonin-dopamine systems and various psychiatric conditions, such as schizophrenia.

 by psilocybin is also believed to increase glutamate release by the subsequent activation of postsynaptic α-amino-٣-hydroxy-٥-methyl-٤-isoxazole propionic acid (AMPA) receptors.

 The prefrontal cortex (PFC) and other cortical areas that highly express 5-HT

 receptors receive excitatory glutamatergic input from thalamic projections, but also send output to both the cortical and thalamic regions. The activation of presynaptic 5-HT

 receptors in the thalamocortical afferents contributes to the psychedelic-induced modulation of glutamatergic transmission to the PFC. Thus, these dual actions from the presynaptic and postsynaptic 5-HT

 receptors form a cyclic feedback process for 5-HT

 receptor activation of glutamate effects in the central nervous system, leading to a complex cortical-thalamic neurocircuitry.

Psilocybin is rapidly converted to the active molecule, psilocin. Specific bioanalytical assay methods have been developed to quantify psilocin, to determine its pharmacokinetic (PK) profile. An early study with psilocybin was conducted in healthy volunteers (N = 7), in which each participant received an intravenous (IV) dose of 1 mg and an oral dose of 0.224 mg/kg (range 10 to 20 mg).

 The estimated mean oral bioavailability of psilocin was 52.7% ± 20%. The following mean PK parameters reported from the oral route were the time to maximum effect/concentration (T

) of 105 ± 37 min; peak plasma concentration (C

) of 8.2 ± 2.8 ng/mL; and elimination half-life (T

) of 163.3 ± 63.5 min. An almost immediate phosphorylation of psilocybin takes place, and results from the IV administration noted a mean psilocin T

 of 74.1 ± 19.6 min. The psychological effects reportedly began at 20 to 90 min, and within 2 min from the oral and intravenous routes, respectively.

 formed via glucuronidation is psilocin glucuronide (psilocin-G), as shown in the 

 Psilocin-G is primarily eliminated from the body by renal excretion. The amount of psilocin-G produced was determined in another healthy volunteer (N = 8) PK 

, by giving a single oral dose of psilocybin 10 to 18 mg (mean 14 ± 3 mg), and urine samples were collected over the following 24 hours.

 was 3.3 ± 0.6 hours (closely resembling the 

) with the additional findings of a mean free psilocin amount of 3.4% ± 0.9% and mean psilocin-G excretion of 60.6% ± 27.1%, supporting the renal pathway as the primary elimination route.

In a population PK study, healthy volunteers (N = 12) were given escalating single oral doses of psilocybin at 0.3, 0.45, and 0.6 mg/kg, with a minimum of a 4-week interval between dosage administrations.

 The final model developed from the PK analysis was a single compartment model with linear absorption and clearance. The median area under the concentration-time curve (AUC) for psilocin was linear at 140 mg-hr/L, 213 mg-hr/L, and 267 mg-hr/L, corresponding to the doses of 0.3 mg/kg, 0.45 mg/kg, and 0.6 mg/kg, respectively.

Once psilocin is formed, it is mainly metabolized to psilocin-G (90%), and a small portion is converted to psilocin (10%). This can partially explain the interpatient variability observed with psilocybin administration. The 

 only 1.7% of the psilocybin dose found as psilocin in the urine, with a calculated psilocin renal clearance of 1 mL/min/kg, which corresponds to
58% of the creatinine clearance.

 These findings suggest that psilocybin dosage reductions are not necessary in patients with mild to moderate renal impairment.

The metabolic profile of psilocybin is presented in the 

, several metabolic routes are possible. As noted, psilocin-G is the major pathway (bold arrow line) with 2 minor pathways.

 Psilocin-G formation occurs via phase 2 metabolism with hepatic uridine 5’-diphospho (UDP)-glucuronosyltransferase (UGT) 1A9 and the small intestine UGT1A10.

In the second minor pathway, psilocin can be metabolized to 4-hydroxy-indole-3-acetaldehyde by 2 enzymes: aldehyde dehydrogenase (ALDH) and monoamine oxidase (MAO). It should be noted that alcohol and MAO inhibitors such as phenelzine may suggest interesting questions regarding potential drug-drug interactions that can lead to pharmacokinetic and/or pharmacodynamic effects. The metabolite, 4-hydroxy-indole-3-acetaldehyde is then further converted to 4-hydroxyindole-3-acetic acid and 4-hydroxytryptophole.

The third minor metabolic pathway for psilocin takes place via the cytochrome oxidase enzymes (it is unknown whether this is related to the cytochrome P450 oxidase enzymes) and non-enzymatic Fe3+ to form psilocin iminoquinone.

Earlier PK studies established the initial parameters for psilocybin dosing and provided information on the onset of its psychological effects for drug and product development. The next steps are to correlate the psilocybin (psilocin) clinical PK effects with its pharmacodynamics. 

 conducted on healthy volunteers (N = 8) who were given oral psilocybin (doses ranging from 3 mg to 30 mg) evaluated plasma psilocin concentrations, while assessing 5-HT

 Participants self-assessed their intensity ratings for clinical effects using a Likert scale from 1 to 10 (1 = least intense and 10 = most intense). Plasma psilocin C

 values displayed a linear correlation with doses of 3 mg to 30 mg (2.3 mg/L to 19.3 mg/L, respectively). The 5-HT

 receptor occupancy (%) results displayed a sigmoidal relationship with doses of 3 mg (42.9%), 15 mg (63.2%), and 30 mg (65.2%). Investigators observed a wide interpatient variability in psilocin plasma concentrations. Generally, the intensity ratings > 5 occurred when receptor occupancy approached 60% and psilocin plasma concentrations > 7.5 ng/mL.

A phase 1 clinical trial with the psilocybin formulation COMP360 was conducted in healthy volunteers (N = 89), in which participants randomly received a single 10 mg or 25 mg dose of psilocybin or placebo.

 The study aimed to evaluate the emotional and cognitive responses of participants, along with the safety and tolerability under strict procedures. The study found that psilocybin was well tolerated, and mood alteration was the most frequently reported effect. The most notable adverse effects were hallucinations and illusions, with a slightly higher incidence in the 25 mg dose than the 10 mg dose. These adverse effects occurred in about 67% of the subjects on day 0 of drug dosing and were resolved with cessation of any remaining adverse effects by the next day. No significant changes were observed in vital signs.

These findings showed that COMP360 was well tolerated and the psychological effects were transient and consistent with those observed in previous studies. Although significant changes in vital signs were not found,

 8 to 12 mg: mydriasis, change in heart rate, hypotension or hypertension, nausea, reflex tendencies, and tremors.

 Furthermore, if participants experienced significant hallucinations, illusions, or other psychotic symptoms, treatment with second-generation antipsychotic agents, such as risperidone or olanzapine, was suggested.

 Haloperidol was reported to alleviate only the euphoric, depersonalization, or derealization effects and not the visual hallucinations.

 It would be interesting to deduce the actions of pimavanserin, an antagonist of 5-HT

 receptors. Pimavanserin is FDA-approved for 

, for which hallucinations (visual and auditory predominantly) and illusions occur.

Esketamine is a noncompetitive N-methyl D-aspartate (NMDA) receptor antagonist that is FDA-approved for treatment-resistant depression (TRD). Esketamine underwent a phase 2 proof-of-concept study and then proceeded to the phase 3 clinical trials.

 TRD was defined as a failure to adequately respond to 2 different antidepressants.

Esketamine is administered twice weekly at doses of 56 mg or 84 mg. Each clinical trial had treatment groups administered placebo nasal spray plus an oral antidepressant or esketamine nasal spray plus an oral antidepressant. Therefore, each patient continued to receive treatment with an antidepressant as the standard of care. From a safety perspective, esketamine was well tolerated. However, the incidence of dissociation reactions was reported to be about 23%.

 Esketamine is available via the REMS program; patients must be monitored for 2 hours after nasal spray administration for safety.

These findings regarding esketamine led to the development of psilocybin for TRD. The drug and product development process for psilocybin will likely take a similar approach. An 

 in patients with TRD (N = 12) was conducted using 2 psilocybin doses of 10 mg and 25 mg.

 The psilocybin doses selected for TRD are comparable to those for other psychiatric disorders under evaluation (

Table 1. Summary of Psilocybin Clinical Studies

 treatment-resistant was defined as Hamilton Depression Rating Scale (HAM-D) scores > 17 and a lack of improvement with 2 different classes of antidepressant medications for at least 6 weeks within the current episode. A single dose of psilocybin 10 mg, followed by 25 mg 7 days later was administered. Clinical assessments were obtained at baseline, at 7 days with administration of the second dose, and at 3 months after the second dose. The primary efficacy outcome was determined by the Quick Inventory of Depressive Symptomatology (QIDS), and the secondary outcomes were determined by the HAM-D and Beck Depression Inventory (BDI).

Psilocybin significantly reduced the mean (± SD) QIDS scores at 1 week (−11.8 ± 4.9, P = .002) and at 3 months (−9.2 ± 6.0, P = .003). The 

 also resulted in significantly reduced HAM-D and scores.

 At the 1-week mark, remission (defined as reduction in BDI score of ≤ 9) was achieved in 8 patients (67%). At the 3-month follow-up, remission (defined as a 50% reduction in BDI scores) was achieved in 7 patients (58%); 5 patients (42%) reached complete remission. Psilocybin was well tolerated, with only mild transient confusion (N = 12) and/or transient anxiety (N = 9). Transient nausea (N = 4) was noted during the day of drug administration and subsided 1 to 2 days thereafter.

Because of these findings and the FDA’s designation of psilocybin as a breakthrough therapy, a phase 2b clinical trial is underway in the United States and Europe (N = 216), with additional phase 3 clinical trials planned.

 The phase 2b study design uses psilocybin 1 mg (considered placebo), 10 mg, and 25 mg, and the Montgomery-Asberg Depression Ratings Scales (MADRS) scores are considered the primary outcome.

As the psilocybin pharmacologic mechanism of action involves 5-HT

 receptor agonist effects, the study design for patients with TRD may differ from that of the esketamine program, in which antidepressants were continued. For the 

s, the use of antidepressants or other medications may need to be discontinued for safety reasons and to prevent the possible development of serotonin syndrome.

Another reason for antidepressant discontinuation is the suggestion that selective serotonin reuptake inhibitors (SSRIs) obstruct potential psilocybin benefits, as the pharmacological actions of an antidepressant may downregulate 5-HT

 The clinical psilocybin study may need to include a 2-week (at least) antidepressant withdrawal and washout phase to place patients, caregivers, and providers in a state of heightened alert to monitor and detect any significant changes in the patient’s status. After psilocybin administration, the next question would be when to restart the antidepressant or other medications that were previously discontinued, with appropriate safety monitoring.

A summary of the other psychiatric disorders for which psilocybin has been assessed is shown in 

 These studies enrolled only a small number of patients. Patients with cancer often have comorbid depression and anxiety and are associated with a poorer prognosis.

 Patients with a variety of cancers in 3 clinical studies have been reported together. These 3 studies had a control group that used either psilocybin low-dose (1 or 3 mg) or niacin (250 mg), with a double-blind crossover or double-blind fixed-dose study design. In the 3 studies (shown in 

), each patient acted as their own control and had 2 treatment sessions in random order (either psilocybin 0.2 mg/kg first, and then niacin, or vice-versa) spaced several weeks apart.

The second study was a crossover design that used psilocybin 22 mg/70 kg or 1 to 3 mg psilocybin/70 kg (instead of niacin). The third study used a crossover design with a higher single dose of psilocybin (0.3 mg/kg) and the placebo niacin in a randomized order, given 7 weeks apart. All 3 studies reported consistent results, in which psilocybin (not the low-dose group) produced significant decreases from baseline in depression (≥ 50% HAM-D scores) and anxiety (≥ 50% HAM-A scores) symptoms after 5 weeks, which persisted throughout the 6-month follow-up. Remission HAM-D and HAM-A scores were achieved by 65% and 57% of the participants, respectively. Studies of psilocybin use for depression, anxiety, and mood disorders associated with end of life are planned for 

Patients (N = 9) with treatment-resistant obsessive-compulsive disorder (OCD) were given 3 different psilocybin doses in a pilot study. The results showed significant decreases in the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) for all doses without serious adverse effects.17 Testing for each dose was administered in a random order and conducted over 8 hours in a controlled environment, with a 1-week separation. The Y-BOCS and the visual analog scale (VAS) for overall OCD symptom severity were completed at baseline, 4, 8, and 24 hours post–drug administration. The Hallucination Rating Scale was given at the 8-hour time point, which showed a significant correlation with dose (P = .017) but lacked significant correlations with the Y-BOCS or VAS scores. Based upon these preliminary results, 2 ongoing randomized phase 2 clinical trials are underway to replicate these original findings.

Both tobacco and alcohol use disorders have few therapeutic options; thus, pilot studies are exploring the use of psilocybin or such conditions (

). Psilocybin has yielded significant improvements in abstinence, as measured by laboratory and behavioral assessments. In 1 pilot tobacco cessation clinical study conducted in 2017, participants entered a 15-week structured smoking cessation program and were given a single dose of psilocybin 20 mg at week 5, and 30 mg at week 7, with an optional 30 mg dose at week 13. Urinary cotinine levels (< 200 ng/mL) and exhaled carbon monoxide (≤ 6ppm) were used as the biomarkers for abstinence.

At the end of 6 months, 12 of the 15 (80%) participants remained abstinent; 10 (67%) participants remained abstinent at 1 year; and 9 (75%) at 2.5 years. This pilot study was expanded to enroll 95 individuals and is scheduled to be completed in 2021, depending upon enrollment.

 The other pilot study assessed psilocybin’s efficacy in alleviating alcohol dependence, which was defined as having at least 2 heavy drinking days in the previous 30 days. Participants received a total of 14 psychotherapy sessions. A single dose of psilocybin 0.3 mg/kg was given after the first 4 sessions, and a second single dose of 0.4 mg/kg was given after another 4 psychotherapy sessions. Each psilocybin administration session was completed under the Psychedelic-Assisted Psychotherapy procedure. (See the next section, Psychedelic-Assisted Psychotherapy Method and Microdosing.) Abstinence was based on self-reporting and was found to be significantly increased after the first psilocybin session. Moreover, abstinence was maintained for up to 9 months. The study was expanded to enroll up to 180 participants with completion scheduled for 2020 or 2021.

Additional psilocybin clinical trials have been conducted for cocaine and opioid disorders, anorexia nervosa, and depression in early Alzheimer disease.

 Another suggested therapeutic use of psilocybin may be for cluster headaches.

Unlike previous clinical trials in psychopharmacology, the use of psychedelic agents, such as psilocybin, LSD, and MDMA, will employ a therapeutic technique called “Psychedelic-Assisted Psychotherapy,” which is summarized in 

 This technique consists of 3 sections: preparatory, medication administration (1 to 3 sessions), and integration. In the preparatory section, the therapist or cotherapist team works with the patient to obtain a personal history, help the patient understand their symptoms, and prepare for the potential emotional or psychological impact of the agent.

Table 2. Summary of the Psychedelic-Assisted Psychotherapy Session

During the medication session, a female-male cotherapy team is present to maintain integrity and safety, with the patient reclined in a chair or bed. For the next 6 to 8 hours, the therapists listen to the patient, while maintaining safety and facilitating trust and openness. Afterward, the therapists in the integration session work with the patient to interpret the psychedelic experience that arose, with the goal of making meaningful long-term changes. If the patient becomes highly agitated during the 6- to 8-hour period after psilocybin administration, while responding to the hallucinations or other psychological effects, a physician or nurse should immediately assess the need for either a single low-dose second-generation antipsychotic (eg, risperidone) or pimavanserin as a rescue medication.

Microdosing is another technique for psilocybin use. With this technique, about one-tenth of the full dose is used. Psilocybin dosing ranges are as follows: microdose, < 1 mg; very low dose, 3 mg; low dose, 8 mg; medium dose, 15 mg; and high dose, 22 mg or greater.

 Although microdosing has been studied in small open-label studies with doses administered about once every 3 to 5 days, it is unclear how this technique differs from the full dose administered for depression and other psychiatric disorders.

Psilocybin has received considerable renewed interest over the past few years and has been investigated as a treatment for TRD and other psychiatric conditions. Exploring the use of psilocybin for TRD and other potential therapeutic applications will be exciting, and would offer unique challenges for patients, mental health clinicians, as well as third-party reimbursement and regulatory agencies.

is professor in the Department of Pharmacotherapy at the University of North Texas (UNT) System College of Pharmacy located at the UNT Health Science Center, Fort Worth, Texas.

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Psilocybin--summary of knowledge and new perspectives

The therapeutic potential of psychedelic drugs: past, present, and future

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The past and future of psychedelic science: an introduction to this issue

5. Johnson MW, Griffiths RR, Hendricks PS, Henningfield JE. 

The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act

Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance

Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders

8. McKenna DJ, Repke DB, Lo L, Peroutka SJ. 

Differential interactions of indolealkylamines with 5-hydroxytryptamine receptor subtypes

The dopamine receptor: differential binding of d-LSD and related agents to agonist and antagonist states

10. Vollenweider FX, Vontobel P, Hell D, Leenders KL. 

5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man--a PET study with [11C]raclopride

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Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels

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Psychedelic drugs-a new era in psychiatry?

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Articles

Psilocybin may be useful for examining interactions between serotonin-dopamine systems and various psychiatric conditions, such as schizophrenia.

Psilocybin Revisited: The Science Behind the Drug and Its Surprising Therapeutic Potential

Although we are almost a year into the coronavirus disease 2019 (COVID-19) pandemic, there is still much about the virus that we do not know. Post-recovery patients are likely to suffer substantial sequelae, but it is difficult to say exactly what these might be. To better understand and anticipate such, investigators are reviewing data from patients who recovered from sepsis. Research shows previously septic patients have increased mortality, physical disabilities, cognitive impairment, recurrent infections, and overall health deterioration for at least the following 2 years.

 The pandemic's impact will likely trigger enormous aftershocks in recovery and rehabilitation services. Anticipating possible scenarios now will help psychiatrists and other medical professionals prepare for effective treatment later.

Post–COVID-19 neuropsychiatric sequelae

Patients who recover from acute COVID-19 can experience a variety of neuropsychiatric manifestations.

 For individuals with mild to moderate infections, the most common symptoms include headache, altered smell and taste, cough, asthenia, and myalgia. Regarding smell and taste, these dysfunctions occurred at rates of 85% and 88%, respectively. When severe illness occurs, reports of encephalopathies, encephalitis, seizures, neuromuscular disorders, Guillain-Barré syndrome, and other neuropathies were reported in about 36% of patients.

 of patients who were admitted to the intensive care unit (ICU), researchers found a number of long-term effects.

 Patients in the ICU with acute respiratory distress syndrome (ARDS) and severe illness (91% on ventilation) had average global cognition scores 1.5 standard deviations (SD) below the age-adjusted mean population and were similar to patients with mild cognitive impairment. Of those patients, 26% had 2 SD below the normal. Patients with mild Alzheimer disease and repeated testing at 12 months later did not show significant improvement. Cognitive impairment was noted in 70% to 100% of discharged patients, 46% to 80% had impairment 1 year and even 5 years later, and 20% had residual cognitive dysfunction.

 If patients admitted to the ICU with COVID-19 follow these trends, they will feel the virus’ effects for years to come.

Patients who have recovered from COVID-19 experience a wide range of psychiatric issues, including posttraumatic stress disorder (PTSD), depression, insomnia, anxiety, and suicide.

 If we use data from patients with ARDS with ICU admissions as a predictive model, the incidence of psychiatric sequelae was found to be 22% to 24% for PTSD, 26% to 33% for depression, and 38% to 44% for generalized anxiety.

 A significant risk factor for these patients was the presence of premorbid psychiatric illnesses. Family members also can experience PTSD, depression, and anxiety while adjusting to their new roles as caregivers.

A recent study of patients who had COVID-19 (N=402) noted 55.7% had at least 1 psychiatric-related condition with the symptoms found in the 

 (these data are from self-reported questionnaires so we cannot assume these are actual DSM-5 diagnoses).

 A variety of inflammatory laboratory biomarkers (eg, C-reactive protein) results were obtained from the patient charts to determine any possible links with the psychiatric illnesses. 

 levels and inflammatory biomarkers were found not to be associated with any of the psychiatric symptoms, suggesting that the mental health consequences may not have been a manifestation of physical symptoms (ie, virus effects on the brain).

 that 0.9% to 4% of patients who had COVID-19 developed psychotic spectrum disorders, with appropriate antipsychotic treatment indicated.

 Psychotropic medications should be continued (where possible) or restarted in patients with preexisting psychiatric conditions. Medication selection should be based upon the existing guidelines associated with the various psychiatric illnesses. Finally, alcohol and 

 can emerge or be exacerbated in post–COVID-19 recovery, hence clinicians should monitor patients and their families for these.

Because of the acute and chronic stress conditions that accompany the mental health consequences for survivors and their families, the psychological sequelae may persist for months or years. Individuals who had COVID-19, and especially those who had severe COVID-19 illness, are at an increased risk of suicide.

 The suicide rate in the United States has been steadily increasing from 1999 to 2017

, and the COVID-19 pandemic adds a suicide risk factor that providers need to monitor. Factors that increase suicide risk in context of COVID-19 include economic problems, social isolation, and uncertainty about the future, as shown in 

. Suicide assessment should be included in the short- and long-term treatment of survivors.

It is unknown whether COVID-19 can exacerbate or increase risk for other neuropsychiatric effects. A 

 described a patient who was treated with haloperidol decanoate and 3 weeks after injection developed neuroleptic malignant syndrome. The patient recovered and was treated with dantrolene and bromocriptine.

 Another case report portrayed a previously healthy man in his 60s living with family members who had COVID-19.9 He became confused, slowed, and forgetful, and tested positive for the virus. During the next 2 weeks, his disorientation became much worse, and he was admitted to the hospital. He received a complete laboratory assessment in which the CSF RT-QuIC, 14-3-3, and T-tau protein results confirmed Creutzfeldt-Jakob disease (CJD). The patient died 2 months after the initial onset of symptoms, and it is not clear whether the COVID-19 infection accelerated the course of the CJD. As COVID-19 increases risk of neuropsychiatric sequelae, it is possible that other neurological consequences may emerge and providers should be vigilant.

Patients with COVID-19 and severe respiratory impairment must remain on mechanical ventilators for longer time periods than the typical ICU admission.

 Recovery from the ICU can lead to short- and long-term consequences that stem from the post-intensive care syndrome (PICS). A summary of the PICS risk factors and neuropsychiatric and physical impairments are presented in 

 During a prolonged stay in the ICU, sedation and mechanical ventilation increases the PICS risk. About 33% of patients recovering from PICS do not return to work and another 33% do not go back to their pre-ICU job or a job with a pre-ICU salary. At least 25% of these individuals have substantial loss of independent living and 

 with daily activities for at least 1 year post-ICU admission.

 from severe COVID-19 illness can be categorized into 2 other main areas: critical illness polyneuropathy (CIP) and critical illness myopathy (CIM).

 The CIP is a mixed sensorimotor neuropathy with an occurrence reported to be about 46% in ICU patients. It is associated with neuropsychiatric impairment, pain, muscle weakness, fatigue, dysphagia, and incontinence. CIM occurs in 48% to 96% of patients in the ICU and is a non-necrotizing diffuse myopathy with fatty degeneration, atrophy, and fibrosis. The CIM clinical presentation is similar to CIP but with more distal weakness and sensory preservation and may be associated with use of paralytic agents, steroids, and sepsis. Patients recover more completely and quickly from CIM than CIP. However, 

 and quality of life from both conditions can linger for 2 years or longer.

 Based on the Medicare data from sepsis, about 50% of recovered patients will need additional facility-based care and home health care.

 Given the challenges from quarantine measures required by COVID-19, this presents additional issues that must be faced in the short- and long-term recovery programs.

Practical applications for managing symptoms

As patients recover and are discharged from hospitals, they face many challenges in the short- and long-term management of their mental and physical rehabilitation. Interdisciplinary team treatment approaches will be necessary. The medical sequelae from COVID-19 will determine initial short-term rehabilitation needs (eg, respiratory system) and its comorbidities (eg, hypertension, diabetes) and form the treatment plans. At discharge, clinicians should establish treatment plans that can be continued at another facility or with home health services. Mental health services should be an integral aspect of the patient’s overall treatment plan with continued assessments during physical rehabilitation. The presence of PTSD, depression, anxiety, or other psychiatric symptoms should be detected as early as possible with appropriate treatment programs incorporated for at least the first 2 years following infection.

Learning from past disasters, psychiatrists are taking center staet in helping patients, family members, first responders, and other health care professionals affected by the COVID-19 pandemic.

Michael W. Jann, PharmD, FCP

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