Michael W. Jann, PharmD, FCP

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.

 may persist for years after recovery from COVID-19. Improving these symptoms will require a collaborative approach between family members and health care professionals. The stressful psychological impact of quarantine cannot be underestimated.

 Upon discharge from the hospital or facility, the survivor and their family members face fears of infection, reinfection, frustration, helplessness, boredom, and uncertainty about what the future holds. Historically, alonger period of quarantine duration was associated with worse mental health, specifically PTSD.

 Finally, financial stressors and the stigma of quarantine influence rates of acceptance and adherence. Once people accept that quarantine is necessary for public health reasons and not a political choice, then it becomes easier to endure psychologically.

Access to physical and mental health care services for patients who have recovered from COVID-19 is a major concern. This is particularly true for minority populations, as COVID-19 infections disproportionally affect African-American and Latino patients.

 These 2 populations are 2 to 3 times more likely to know someone who died from COVID-19 than white individuals. Their recovery and rehabilitation should include culturally competent services along with technological support for internet, smart phones, or tablets necessary for telemedicine.

The COVID-19 pandemic has revealed significant weaknesses in our health care system, from public health preparedness to the structure of our medical facilities and the need for long-term rehabilitation.

 A rational systematic approach to a pandemic with lessons learned from the past can provide guidance. Mental health services play a vital role in treating patients, family members, first responders, and health care professionals.

The impact of COVID-19 will reverberate for many years. For example, PTSD, depression, anxiety, and other disorders remain among post-9/11 first responders and individuals in New York City nearly 20 years after the attacks.14 Identifying disaster-related stressors that predict physical and mental health adversity after natural disasters such as Hurricane Katrina can also be applied to the COVID-19 environment.

 One to 4 years post-Katrina, lack of medications, medical care, safety, and bereavement were the main stress predictors for PTSD, psychological distress, and physical symptoms. The belief that an individual’s life was in danger continued to predict PTSD at 12 years after the disaster.

Both 9/11 and Hurricane Katrina were acutely short in duration, yet they had long-term health consequences. The COVID-19 pandemic began in late 2019 and will continue for the foreseeable future. Learning from past disasters, health care systems need to minimize any lapses in services for medical care, mental health care, and medications. Policy makers need to provide infrastructure support for the economic and technological sustenance of our society for years, as COVID-19 has changed our way of life. Psychiatrists and other mental health professionals should be prepared for the short-term (less than 2 years) and long-term (more than 2 years) management of patients and others affected by the pandemic. Psychiatry has faced unusual tasks during the COVID-19 pandemic, with increasing distress among our society that has led to increasing rates of depression, anxiety, and other mental health conditions. This trend will likely continue, and close collaboration between primary care providers and mental health professionals will be needed.

is professor of pharmacotherapy at the University of North Texas System College of Pharmacy and founder of Jann Medical Writing

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Neuropsychiatric aspects of COVID-19 pandemic: a selective review

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Anxiety and depression in COVID-19 survivors: role of inflammatory and clinical predictors

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Neuroleptic malignant syndrome in a COVID-19 patient

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10. Brooks SK, Webster RK, Smith LE, et al. The psychological impact of quarantine and how to reduce it: rapid review of the evidence. Lancet. 2020; 39: 912-920.

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12. Tandon R. COVID-19 and mental health: preserving humanity, maintaining sanity, and promoting health. Asian J Psychiatry. 2020; 51:102256.

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16. Öngür D, Perlis R, Goff D. Psychiatry and COVID-19. JAMA. 2020;324(12):1149-1150. ❒

Articles

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.

Neuropsychiatric & Medical Sequelae of COVID-19 

is Professor of Pharmacotherapy at the University of North Texas System College of Pharmacy and founder of Jann Medical Writing.

Videos

Pharmacists are here for you, through the thick and thin of this pandemic, and can provide assistance to those who have lost their jobs or need help acquiring medications.  

Pharmacies Are Here For You

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common chronic medical condition that affects between 6% to 9% of children with clinically significant symptoms carrying on into adulthood in about 60% of the cases.

 Data from the 2016 National Survey noted that 9.4% of children in the United States aged 2 to 17 years had a diagnosis of ADHD.

 The worldwide epidemiologic prevalence of adults with ADHD is estimated to be 4%.

 Boys are 2 to 4 times more likely than girls to be diagnosed with ADHD.

Treatment approaches for ADHD include education, psychotherapy, and pharmacotherapy, irrespective of age.

 Among children and adolescents with ADHD, about two-thirds received pharmacotherapy, and about half have received psychotherapy. Combined pharmacotherapy and psychotherapy commonly occurs but not in every person. Interestingly, nearly 25% of the persons 

The stimulant medications, such as methylphenidate and amphetamines, are the mainstay of pharmacotherapy for persons with ADHD and have been used for over 30 years.

 A variety of formulations for methylphenidate and amphetamine are available as oral tablets, capsules, and transdermal patches.

 The tablet and capsule products exist as immediate-release (IR) preparations that requires administration of 2 to 3 times per day and extended-release (ER) formulations taken only once daily. There are several non-stimulant agents that include atomoxetine, clonidine ER, and guanfacine ER.

 The benefits, risks, and safety profiles of these agents are well known.

Numerous studies clearly demonstrate that stimulants significantly improve attention, concentration, behavior, visual short-term memory, and driving performance. An epidemiologic parameter that offers a magnitude of improvement on functional outcomes is the statistical number needed to treat (NNT) where the lower the number, the more effective the treatment. The theoretical NNT = 1 means that every person treated will be benefit. If a medication has a low NNT, this finding would likely have high a clinical and public health impact. An NNT of 2.5 means that the treatment is effective.

 a stimulant’s NNT was reported to be “3” to prevent disruptive behavioral disorders and repeating a grade in school, whereas the NNT = 4 for preventing motor vehicle accidents (MVAs). These findings convey that stimulants are effective agents in preventing disruptive behaviors, lessens the possibility of a child or adolescent repeating a grade at school while also reducing the prospects of MVAs compared with untreated ADHD. For adolescent teens and young adults, preventing MVAs can be a significant public health factor.

Unfortunately, poor adherence to and premature termination of stimulants continue to undermine their benefits. 

 reported that the adherence rates in children whose ADHD symptoms were treated with stimulants ranged from 56% to 75% with greater than 50% ceasing treatment despite their efficacy. The accuracy of adherence studies relies on the study methodologies. Adherence studies with stimulants in children with ADHD typically utilized methods that included prescription fills and refills picked up by the parents and parental verbal reports. A prescription fills or refills and parental verbal reports may not necessarily indicate actual medication adherence by the child.

Measurement of saliva drug concentrations as a surrogate biomarker for adherence was compared with parental verbal reporting in the MTA Cooperative Study.

 All participants (N = 254) were placed on methylphenidate (MPH) during the 14-month study. Subjects were assessed to be verbally adherent if the parent reported their child took medication 80% or more asked at each monthly visit. Four saliva samples were collected at months 2, 6, 9, and 14 where detectable MPH measurements specifies physiological adherence as drug was taken that day (detection limit was > 3 ng/mL).

Due to the variable saliva samples obtained per child, subjects were noted to be adherent if greater than 50% of a person’s saliva samples contained detectable MPH concentrations. Parents verbally reported MPH was taken on the day for all children when saliva samples were obtained with 89.8% of their children taking medications on all occasions. Results from the saliva MPH levels showed that 24.8% of subjects were physiologically non-adherent (≤ 50% of samples below 3 ng/mL) and 12.2% of subjects were non-adherent for all four collected saliva samples. Only 53.5% of subjects were physiologically adherent for all four saliva samples. This study indicates that the parent’s verbal report to the provider may overestimate adherence while underestimating non-adherence in their children.

, the pattern of adherence in children with ADHD (N=166) was examined that include these factors: sex, ADHD severity, and higher socioeconomic status (SES).

 The data were obtained from Longitudinal Study of Australian Children (LSAC) between May 2002 and March 2015. Children (average age 9.7 years ± SD = 2.7 years) that were started with methylphenidate, dexamphetamine, or atomoxetine and followed continuously with data collected every 2 years. The data collected was prescription redemption via the Pharmaceutical Benefit Scheme (PBS) and the total number of prescriptions redeemed throughout the study. The total time on medication was defined as the time between the first and last redeemed prescription.

The results reported that only just over half (54%) had a single continuous use of medication; 21.6% had one interruption; and 25.4% had two or more time periods of interruptions. The only variable found predictive of medication coverage was SES as higher SES was associated with higher medication coverage. The prescription redemption pattern over time showed that coverage was relatively high during the first year, progressively decreased for 3 to 4 years, and increased for those who remained on medication after 5 years (U-shaped curve).

A subset of children (N=89) was analyzed where the median medication coverage was 81% for the first 90 days and decreased to 54% beyond the first 90 days. This study suggests that psychiatrists and other health professionals need to be consistently engaged with the children and their parents for extended time periods for commitment to long-term treatment. Additionally, approximately 90% of children and adolescents with ADHD responded effectively to either methylphenidate or dexamphetamine.

Yet, these two different studies conducted about 10 years apart using different methods reported similar findings of non-adherence in about 50% among the participants.

Many rationales are offered to account for non-adherence. These include the “stigma” of taking medications by the child and adolescent; parental explanations for taking medications; lifestyle factors; busyness; forgetfulness; and SES. Medication adverse effects and multiple drug administrations can add to non-adherence. Careful stimulant monitoring and products with once-daily dosing can maximize benefits and minimize potential risks.

The updated clinical practice guidelines for children and adolescents with ADHD have strong recommendations for medications in children (greater than 6 years) and adolescents (12 to 18 years) with dosing titrations to achieve maximal benefits.

 The guidelines have a number of areas for future research that include developing methods to involve children, adolescents, and parents to improve adherence to psychotherapy and pharmacotherapy and development of electronic means (apps) to assist in monitoring. Stimulants have demonstrated vibrant benefits for persons with ADHD and every effort should be utilized to lessen non-adherence.

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2. Wolraich ML, Hagan JF, Allan C, et al. 

Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents

3. Markowitz JS, Yu G. Stimulants and other non-stimulants for attention deficit/hyperactivity disorder. In. 

Applied Clinical Pharmacokinetics and Pharmacodynamics of Psychopharmacological Agents.

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4. Biederman J, DiSalvo M, Fried R, et al. 

Quantifying the protective effects of stimulats on functional outcomes in attention-deficit/hyperactivity disorder: a focus on number needed to treat statistic and sex effects

5. Pappadopulos E, Jensen PS, Chait AR, et al. 

Medication adherence in the MTA: saliva methylphenidate samples versus parent report and mediating effect of concomitant behavioral treatment

6. Efron D, Mulraney M, Sciberras E, et al. 

Patterns of long-term ADHD medication use in Australian children. 

: (21, March 2020). doi:10.1136/archdischild-2019-317997.

Despite proven efficacy of ADHD treatments, adherence remains a challenge.

Adherence Challenges With Medications in Patients With ADHD

The Buzz on Long-Acting Injectable Antipsychotics

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

The goal of this activity is to provide an understanding of long-acting injectable antipsychotics and how they can benefit treatment adherence.

After engaging with the content of this CME activity, you should be better prepared to:

• Identify the formulation differences between oral and long-acting injectable (LAI) antipsychotics.

• Assess the efficacy and safety profiles of LAI second-generation antipsychotics.

• Discuss LAI antipsychotics as they relate to treatment adherence.

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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This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership Physicians’ Education Resource®, LLC and 

. Physicians’ Education Resource®, LLC is accredited by the ACCME to provide continuing medical education for physicians

Physicians’ Education Resource®, LLC designates this enduring material for a maximum of 1.5 

™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is funded entirely by Physicians’ Education Resource®, LLC. No commercial support was received.

This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical education purposes only and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic or treatment options for a specific patient’s medical condition.

The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians’ Education Resource®, LLC.

FACULTY, STAFF, AND PLANNERS’ DISCLOSURES

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 have no relevant financial relationships with commercial interests.

John J. Miller, MD, external peer reviewer, reports that he is on the Speaker Bureaus for Sunovion, Otsuka, Allergan, Teva, Neurocrine, and Janssen; and he is on the Advisory Board for Janssen and Align2Action.

Eric Achtyes, external peer reviewer, reports that he has received research support from Alkermes, Astellas, Biogen, Boehringer-Ingelheim, Janssen, Neurocrine Biosciences, Otsuka, Pine Rest Foundation, Takeda, and Vaguard Research Group; and he has served as a consultant or on advisory boards for Alkermes, Indivior, Janssen, Neurocrine Biosciences, and Roche.

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Patient nonadherence to long-term antipsychotic therapy presents clinicians with unique unmet needs but also opportunities for promoting the realistic benefits of consistent treatment. According to the World Health Organization, adherence is defined as “the extent to which a person’s behavior-taking medication, following a special diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a health care provider.” However, nonadherence typically implies a situation in which a patient cannot follow a specific medication regimen. Both adherence and nonadherence can be imprecise terms in a patient’s clinical management where the lack of a defined threshold exists. Clinicians who prescribe oral antipsychotics may overestimate adherence and underestimate nonadherence.

“John” is a 24-year-old male who 6 months ago received a diagnosis of schizophrenia. After successful initial treatment with an oral antipsychotic, he felt no further need to take his medications. Subsequently, over the next several months, his family noticed that delusional symptoms began reappearing and withdrawal behaviors from current activities increased.

At his next outpatient appointment, the prospect of a long-acting injectable antipsychotic was introduced. Initially, John refused the injectable antipsychotic saying that he can take oral medications. Over the next 2 weeks, his family noticed that only part of his medication was taken and, when looking over the number of tablets, it appeared that John was taking about half of his medication. His clinician told him that if inconsistent adherence to treatment continues, the symptoms likely will not get better and could get worse. If the symptoms and his thinking get worse, he may need to be hospitalized.

The option of a LAI was reintroduced. Although John was seemingly reluctant, he was convinced by the treatment team and agreed to give the LAI a try for the next few months. His family whole-heartedly supported the LAI option knowing that this option would eliminate gaps in his pharmacotherapy.

Long-acting injectable (LAI) antipsychotics address both adherence and nonadherence issues. Fluphenazine enthate, a first-generation antipsychotic, became available as a LAI in the US in the 1960s; fluphenazine decanoate LAI became became available in the 1970s; and haloperidol decanoate LAI became available in the 1980s.

The first second-generation antipsychotic LAI, risperidone microsphere, was FDA approved in 2003. Only three other LAI second-generation antipsychotics are currently available: olanzapine pamoate, paliperidone palmitate, and aripiprazole (available as monohydrate and lauroxil formulations). Paliperidone palmitate has two formulations for monthly or three-month injection intervals. Aripiprazole lauroxil also has formulations that allows for monthly, a 6-week, or 8-week administration intervals.

Formulation, pharmacokinetics, and dosing

The process to develop LAI antipsychotic formulations represents significant technological challenges and opportunities. Based on their chemical structure, not all antipsychotics are available as a LAI formulation. LAI formulations impose their pharmacokinetic profiles, initial dosing requirements, storage conditions, and utilization methods as well as the ability to slowly release in the body over an extended time period.

LAI fluphenazine and haloperidol are basically esters that are dissolved in sesame oil. LAI second-generation antipsychotics are aqueous preparations with different formulations. Only risperidone microspheres are given at 2-week intervals; the other LAI second-generation antipsychotics are administered from monthly to as long as every 3 months (olanzapine pamoate microcrystals, paliperidone palmitate Nanocrystals, and two aripiprazole preparations: a lyophilized monohydrate and a prodrug approach with the N-acyloxymethyl molecule). These formulations account for their different pharmacokinetic profiles and dosing practices. The common thread is that the dosing interval is extended beyond daily oral dosing.

The key concept for LAI antipsychotics is that the time to reach steady-state conditions takes longer than an oral formulation as the drug is gradually released from the deltoid (also the gluteus maximus) muscle injection site. Because of this, oral antipsychotics are typically needed for about 2 to 3 weeks when LAIs are started. However, there are exceptions:

Paliperidone palmitate dosing starts at 234 mg followed by a 156 mg second administration one week later and reaching therapeutic plasma concentrations within a few days.

 Olanzapine pamoate reaches peak plasma concentration 2 to 4 days after injection with an elimination half-life of 2 to 4 weeks.

 Aripiprazole lauroxil has a 1-day treatment initiation option where the patient can receive a single 662-mg aripiprazole lauroxil injection plus 30-mg oral aripiprazole followed by either 441-mg or 882-mg aripiprazole lauroxil injection.

After initiation, LAI antipsychotics can be administered monthly or every 4 weeks. Paliperidone palmitate can be given every 3 months, but only after the patient has been stabilized with the monthly formulation for at least 4 months-with the last two injections at the same dose. Monthly LAI aripiprazole lauroxil has two additional formulations with administration every 6 or 8 weeks.

To provide further dosing flexibility for patients and providers, LAI antipsychotics can be administered +/- 1 week for the monthly dosing intervals allowing for possible changes in the patient’s appointment schedule. This also applies to the 3-month paliperidone palmitate preparation with a +/- 2-weeks for the every 3-months dosage schedule. (For more information on dosing, missed doses, and switching strategies see Samtani et al.

There is a large body of clinical studies on LAI second-generation antipsychotics including those leading to regulatory agency approval as well as real-world studies. The latter study types provide clinicians with a comprehensive look at various clinical situations.

LAI second-generation antipsychotics are FDA approved for the acute and/or maintenance treatment of schizophrenia. The LAI formulations have several additional indications: monthly paliperidone palmitate is FDA approved for schizoaffective disorder; risperidone and aripiprazole monohydrate are FDA approved for bipolar disorder.

Clinical studies designed for regulatory agency review typically follow a specific design methodology. For example, patients are randomly assigned to a placebo control group and compared to one or more doses of the antipsychotic. LAI antipsychotic doses are usually fixed doses to accurately determine the drug’s efficacy and safety profiles. The study duration for acute exacerbation of schizophrenia is about 12 weeks. The primary efficacy outcome measure uses the Positive and Negative Syndrome Scale (PANSS) where the total score decreases from baseline to the study endpoint and demonstrates a statistical significance from the placebo group.

The study design for a maintenance study with a LAI antipsychotic is more complex with two main phases in a trial: an open-label phase and a double-blind phase. At a minimum, the open-label phase consists of different stages where patients are switched to the LAI formulation of the antipsychotic being studies, and then to a tolerability phase. The next step is being stabilized on either the oral formulation or directly to a LAI antipsychotic (plus an oral dosing overlap if needed). The subsequent stage proceeds with LAI administration with the study agent with continued stabilization. These stages can last from 9 weeks up to 36 weeks depending on study design. Finally, LAI second-generation antipsychotics are evaluated in a 52-week, double-blind, and placebo control phase.

The primary outcome measure is the time for patient relapse. In the monthly paliperidone palmitate study, relapse was defined as hospitalization, an increase in total PANSS or an increase on any specified PANSS item (eg, delusions) for two consecutive assessments, and deliberate self-injury or aggressive behavior and suicidal or homicidal ideation deemed significant by the clinician.

For the 400 mg aripiprazole monthly dose study, the primary outcome was time to relapse of psychotic symptoms and/or impending relapse defined as any or all 4 criteria on the Clinical Global Impression Scale (CGIS), risk of suicide as defined by the CGIS, an increase on any individual PANSS item (eg, hallucinatory behavior), hospitalization, or violent behavior.

The study design was similar for the 3-month paliperidone palmitate preparation; however, the trial consisted of the monthly formulation (transitional phase) followed by one injection of the 3-month formulation (maintenance phase), and finally the double-blind, placebo-controlled phase.

 The primary outcome was relapse where relapse rates and time to first relapse were calculated. Relapse was defined as hospitalization, an increase level of care, an increase of 25% in the total PANSS score, or an increase of 10 points if the baseline total PANSS was less than 40. Clinical situations such as deliberate self-injury, suicidal or homicidal ideations, violent behavior or property damage, or a change in the CGIS score to 6 or 7 were also included in the relapse criteria.

These complex study designs are necessary to establish objective and subjective patient stability prior to the testing conducted in the double-blind, placebo-control phase. Therefore, when a relapse episode takes place, its occurrence is defined and scored by a binary process (eg, yes/no).

Each of the studies with monthly LAI second-generation antipsychotics showed efficacy. Patients had significantly fewer (

 < .05) relapse and hospitalization rates. LAI antipsychotics with a longer than monthly administration interval have unique qualities when undergoing efficacy analysis. The 3-month paliperidone palmitate clinical trial interim analysis for delaying time to relapse was significantly in favor of the active agent compared with placebo (

 < .001) with the median time to relapse of 274 days. The relapse rate for 3-month paliperidone palmitate compared with placebo group was substantially lower (9% versus 29%, respectively).

LAI first-generation versus second-generation

LAI risperidone was not available to providers until 2003. Yet, the question of comparing a first-generation antipsychotics with a second-generation antipsychotic presented clinicians with an intriguing issue. For example, how to design a study that can equally compare a first-generation to a second-generation antipsychotics. A double-blind clinical study (funded by Janssen, the manufacturer of risperidone) evaluated oral risperidone (mean [± SD] dose 4.9 ± 1.9 mg) versus oral haloperidol (mean dose 11.7 ± 5.0 mg).6 The study was undertaken to examine relapse prevention in outpatients with schizophrenia or schizoaffective disorder (N = 397) with an extensive criteria defined for relapse. The results indicated a higher relapse rate for haloperidol (risk ratio = 1.93, 95% CI = 1.33 – 2.80, 

Another study compared LAI risperidone with a psychiatrist’s choice of oral antipsychotics in unstable schizophrenia or schizoaffective disorder.

 A total of 382 patients were enrolled in the study and randomized to receive LAI risperidone or continue on their oral antipsychotic. The findings indicate that LAI risperidone was not superior to the oral antipsychotics in preventing hospitalizations rates (39% after 10.8 months versus 45% after 11.3 months (respectively), hazard ratio (HR) = 0.87, 95% CI = 0.63 - 1.20). Moreover, there were no significant differences in survival and health service use.

The ACLAIMS clinical trial compared 1-month paliperidone palmitate with haloperidol decanoate in patients with schizophrenia or schizoaffective disorder.

 The primary criteria for efficacy failure included psychiatric hospitalization, need for crisis stabilization, increased frequency of outpatient visits, ongoing or repeated need for adjunctive oral antipsychotic medications, and several other reasons regarding transitioning from previous oral to injectable antipsychotics. No statistically significant differences between 1-month paliperidone palmitate and haloperidol decanoate in efficacy failure (HR = 0.98, 95% C.I. = 0.65 – 1.47) were found, which indicates that the antipsychotics were equally effective in preventing relapse.

Taken together, the results of these comparative studies of first-generation versus second-generation antipsychotics are reasonable given their pharmacologic profiles for dopamine receptor subtype 2 antagonism. The addition of serotonin 5-HT2A antagonism for risperidone and paliperidone is representative of most second-generation antipsychotics.

The overall outcomes from the LAI second-generation antipsychotics studies found no new concerns regarding safety information. The only exception where a LAI second-generation antipsychotic differs in the safety profile from its oral counterpart is olanzapine pamoate. Approved by the FDA in 2009, olanzapine pamoate has a warning regarding post-injection delirium sedation syndrome, which occurs when the drug is inadvertently administered into a blood vessel, which leads to rapid drug release. The resulting symptoms are delirium, ataxia, confusion, or altered consciousness, thus the FDA requires that patients remain at their treatment facility for 3 hours post-injection.

For second-generation LAI antipsychotic usage, after establishing tolerability with the corresponding oral antipsychotic, the long-term safety monitoring should be ascertained using recommended guidelines where available. Providers should exercise their clinical assessments balancing benefits versus risk especially when LAI second-generation antipsychotics are prescribed. (For detailed information on adverse effects, the reader is referred elsewhere.

When treating with LAI second-generation antipsychotic, long-term monitoring is needed for metabolic syndrome, extrapyramidal effects (especially tardive dyskinesia), and hyperprolactinemia. For metabolic syndrome guidelines include monitoring of weight, fasting blood glucose, Hb1Ac, and lipid profiles at various treatment intervals.

Findings suggest a relatively low occurrence of akathisia with LAI second-generation compared with LAI first generation antipsychotics. The incidence of akathisia was significantly greater for haloperidol decanoate compared with once-monthly paliperidone palmitate (10.6% versus 2.8% respectively, 

 The incidence was comparable to that of LAI aripiprazole lauroxil.

A baseline Abnormal Involuntary Movement Scale (AIMS) exam is recommended before any antipsychotic medication is initiated; it should be repeated at least every 6 months with first-generation antipsychotics and annually with second-generation antipsychotics. Another safety difference reported in the clinical trial between haloperidol decanoate and 1-month paliperidone palmitate was the elevation of prolactin concentrations, but the incidence of sexual adverse effects, galactorrhea, and gynecomastia was not different.

There were significant differences in serum prolactin concentrations (mean, 95% CI) between haloperidol decanoate and 1-month paliperidone palmitate in men (15.41 Î¼g/L, 10.73 - 20.08 versus 34.56 Î¼g/L, 29.75 - 39.37; respectively, 

 < .001) and women (26.84 Î¼g/L, 13.29 - 40.40 versus 75.19 Î¼g/L, 63.03 - 87.36; respectively, 

 < .001). However, no clinical significant differences were found on sexual dysfunction scores (≥ 19) using the Arizona Sexual Experiences scale in men (39.4% versus 37.8%; respectively, 

 = .77) and women (73.1% versus 72.7%; respectively, 

Elevated prolactin levels are known to occur with risperidone and paliperidone, but the long-term consequences remain to be elucidated. Prolactin levels remain relatively neutral with aripiprazole.

Communication strategies and considerations

Theoretically, any patient needing long-term maintenance antipsychotic treatment is a candidate for LAI antipsychotics. A pro and con summary of antipsychotics versus oral antipsychotics is presented in the 

, which can help when discussing treatment decisions with patients. LAI second-generation antipsychotics are typically more expensive than oral antipsychotics.

 describes the initial challenges for treatment providers and the need to collaborate with the patient in offering a LAI antipsychotic. LAI second-generation antipsychotics are preferred over first-generation antipsychotics because of fewer extrapyramidal adverse effects.

 There are advantages for LAI antipsychotics because the clinician has reliable information on how much medication was given during treatment. Moreover, patient adherence with oral antipsychotics can be overestimated and nonadherence underestimated by providers and caregivers.

Patients should be asked about adherence at every visit in a respectful manner without placing blame on any missed doses. Patients often decline the first opportunity for LAI antipsychotics. This should not discourage providers, the treatment team, or family caregivers. Over time, understanding and respecting the reasons for a patient’s nonadherence assists in building trust with the patient and his or her family or caregivers. Although, there are no guarantees with LAI antipsychotics about adherence- the patient may miss an appointment-clinicians have time to work with the patient on adherence.

After establishing initial tolerability with an oral antipsychotic that is available in a LAI preparation, the patient can be successfully transitioned. The efficacy of LAI antipsychotics are at least as comparable to the oral antipsychotics. Recent real-world designed large studies comparing LAI antipsychotics to oral antipsychotics demonstrated superiority of the injectable medications in preventing hospitalizations or relapse.

LAI antipsychotics have been available to providers for more than 40 years yet they appears to be underutilized. LAI second-generation antipsychotics have been well-studied in clinical situations and in regulatory trials their adverse effects are well understood. LAI antipsychotics offer providers a viable option to help with medication adherence and reduce any potential gaps in treatment.

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Patient nonadherence to long-term antipsychotic therapy presents clinicians with unique unmet needs but also opportunities for promoting the realistic benefits of consistent treatment.