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 is a leading cause of suffering and disability worldwide, affecting about 1% of the global population, community services for those with chronic schizophrenic illness are lacking in many areas. As a result, the emergency department (ED) often becomes a primary location for care of this severe mental disorder.

With our combined experience as an emergency medicine physician with interest in the management of acute psychiatric presentations (Furiato) and a psychotherapist with interest in the psychotherapy of schizophrenia (Ruffalo), we believe a psychologically (and psychodynamically) informed guide to the management of schizophrenia in the ED that incorporates relevant research from pharmacotherapy, psychology, and 

 can be very useful in the acute care of these patients.

Attempts to distinguish schizophrenia from the psychotic symptoms that occur in other mental and medical disorders date at least to Kraepelin’s pioneering work in the late 1800s. Another German psychiatrist, Kurt Schneider, proposed the “first-rank symptoms” of schizophrenia in 1939, and his theory held widespread popularity throughout the 20th century (

). A recent Cochrane review of Schneider’s first-rank symptoms (FRS) concluded that FRS correctly identifies individuals with schizophrenia 75% to 95% of the time.

 While reliance on FRS alone may not be sufficient to diagnose schizophrenia,

 recognition of FRS can aid ED physicians and mental health workers in the triage and care of patients presenting with psychotic disturbance.

Patients presenting to EDs may be well-known to ED staff; the course of schizophrenia is generally chronic and, in many geographic regions of the United States, comprehensive mental health systems are sorely lacking. In cases wherein the patient is a poor historian, or past records are otherwise unable to be obtained, reliance on clinical skill, such as knowledge of FRS, is necessary to ascertain the diagnosis of 

In certain instances, such as a clinical suspicion of new-onset schizophrenia or abnormal neurologic exam findings, use of brain imaging may be necessary to rule out organic disease of the nervous system. While a comprehensive review of brain imaging in psychosis is outside of the scope of this paper, Coentre et al

 note that neuroimaging is particularly useful in first-episode psychosis when patients are elderly, have neurological symptoms, or have an atypical clinical picture.

In the ED setting, the first and most important consideration upon presentation of the acutely agitated patient with psychosis or schizophrenia is the level of risk of harm they pose to themselves and staff.

 The resulting answer will help determine the route and type of medication for the specific patient. Speed of onset can dictate the route of administration, as those who are violent will need more rapid calming. These therapies should be used with verbal de-escalation techniques or directly after such attempts have failed.

Benzodiazepines, which are pharmacologically active on the gamma-aminobutyric acid (GABA) receptors, act on the central nervous system and are among the most common medications used for calming and sedation in the ED.

 The largest concentrations exist in the thalamus, cortex, and cerebellum. There are many different subclasses of GABA receptors, including the main α- and β- subunits. The biochemical neurotransmitter effects include reversable binding of the excitatory neuroreceptors and neuronal firing. The primary clinical effects are anxiolysis, 

 are also commonly used as the first-line agent of emergency treatment of seizure disorders and epilepsy.

 Potential adverse events include respiratory depression, hypoxia, hypotension, and paradoxical excitation reaction in those with organic brain disease. Depending on the lipid solubility of the agent and route of metabolism with patient comorbidities, half-lives vary widely (

Patients who are successfully verbally calmed and de-escalated can be considered for therapy with oral management with benzodiazepines alone or in combination with antipsychotics. Intramuscular medications combined with antipsychotics, often with the help of physical restraints, are used for those patients who cannot be de-escalated and pose a risk of injury to themselves and staff.

The 2 main categories of antipsychotics in the emergency setting are first-generation (typical) and second-generation (atypical) agents. The class distinctions are mostly important because of the associated adverse effects.

 First-generation antipsychotics were developed for the treatment of schizophrenia; they act on the multiple dopaminergic receptor, anticholinergic, and histamine pathways. Each drug has its own mechanism of action and level of antagonism of those pathways.

The hallmark first-generation drug is haloperidol, commonly used in the ED. It has been used with great success in treating the positive symptoms of schizophrenia. One of its main limitations, and ultimately a reason that prompted the development of the second-generation drug class, consists of extrapyramidal symptoms such as tremor, slurred speech, akathisia, dystonia, and 

The second-generation class of medications further treats the negative symptoms of schizophrenia and improves upon the adverse event profile of the first-generation group.

 Olanzapine and ziprasidone are common second-generation antipsychotics used in the ED. Significant adverse event of the second-generation drugs include sedation, hypotension, 

Many of the antipsychotics can be administered by mouth to those who are receptive to such and calm enough for safe administration. Antipsychotics can also be administered by intramuscular and intravenous injection for those who are severely agitated.

 Careful observation of the patient’s respiratory status by cardiac monitoring and continuous pulse oximetry must be done after administration, as adverse event can also include respiratory depression and hypoxia. The regular combination of benzodiazepines and antipsychotics can compound this risk. In addition, many of the antipsychotics can have adverse cardiac electrophysiologic effects, including prolonged QT intervals and the development of ventricular tachycardic arrythmias, necessitating electrocardiogram screening once the patient is chemically calmed.

 and antipsychotics used in the ED include lorazepam plus haloperidol or ziprasidone; and midazolam plus haloperidol or ziprasidone. The addition of the antihistamine diphenhydramine is also sometimes added to the aforementioned 2-drug cocktail for patients who are extremely violent. This practice is falling out of favor as seen in a recent retrospective cohort study.

 has also been examined for the acute management of the violently agitated patient.

 Ketamine is a dissociative agent that works at the N-methyl-D-aspartate (NMDA) receptor, which is thought to play a partial role in the development in schizophrenia. Ketamine, when given intramuscularly, can produce more rapid de-escalation and sedation vs the more traditional method of benzodiazepines plus an antipsychotic.

 The drawback to the use of ketamine is the theoretical possibility of exaggerating schizophrenic episodes due to activity on the NMDA receptors. There does not appear to be an increased need for inpatient psychiatric admission or ED psychiatric evaluation vs the traditional therapy.

 More research is needed to further assess the use of ketamine in the acute agitated schizophrenic patient.

Schizophrenia is a complex, multidimensional problem that requires appreciation of both biomedical and psychosocial aspects of disease management. This is true not only in the psychiatric treatment setting but also in the ED, since patients with schizophrenia may exhibit the most severe symptoms in the acute care setting.

Of greatest importance, perhaps, is the recognition that the patient’s heightened state of 

 has contributed to their current psychotic disintegration.

 The patient with schizophrenia often feels alone and afraid, isolated, and without any sense of basic trust or security. The threat of interpersonal contact is too much for them to bear, so they escape even deeper into their psychotic world. Care must be taken to avoid any unnecessary situations in which the patient’s anxiety is increased, as this will only worsen the psychotic symptoms.

Any attempt to challenge or question the validity of delusional themes will result in utter failure, so the ED clinician must avoid these types of confrontations. At the same time, the clinician should not tacitly agree with the patient’s deluded ideas but instead explain empathically that there are reasons they are experiencing things differently. Again, the clinician must do everything they can to foster an environment in which some semblance of trust can be established. For the patient who is mute or otherwise difficult to engage in an interview, speaking about neutral subjects, such as the weather or sports, may help alleviate anxiety and open up the patient to answering some basic questions.

While it is, of course, necessary to gather some information from the patient to establish a history and determine appropriate disposition, the patient with schizophrenia may experience too many questions as an imposition. As Silvano Arieti, MD, noted, “The request for information is often interpreted by the patient as ‘an attempt to take something from him.’”

 The aim of the ED interview should be less the collection of detailed information and more of a process of relating to the patient, while gathering an assessment of current symptoms, an attempt to relay a sense of warmth, security, and trust which will serve as the foundation for ongoing treatment.

As previously discussed, the administration of psychotropic medications in the ED is sometimes necessary to stabilize an aggressive or violent patient. In these cases, the ED physician and mental health professional should maximize the patient’s sense of autonomy and self-determination; for example, the staff can allow the patient to choose the route of administration. Most likely, the patient feels that they have been violated in some way—either due to intrusive voices, paranoia, somatic delusions, or some other terrifying symptom—so the ED clinician should attempt to avoid coercion to the greatest degree possible.

Lastly, in many cases of schizophrenia, psychotic symptoms are ongoing, sometimes in spite of good pharmacological and psychotherapeutic management. The mere presence of psychotic symptoms in a patient who experiences such symptoms at baseline does not warrant 

, and it is unlikely that any such admission would do anything to improve the patient’s chronic illness.

Schizophrenia is a complex, disabling condition that presents a challenge to psychiatric and emergency medicine providers alike. Due in part to the lack of a comprehensive mental health system in the United States, patients with schizophrenia frequently present to the ED for diagnosis, treatment, and acute stabilization. Knowledge of diagnostic, pharmacological, and psychosocial elements of schizophrenia is essential for competent ED care. Of chief importance is the recognition that the patient with psychosis is in a psychologically vulnerable state, worsened by anxiety, and improved with understanding, empathy, and evidence-based symptom management.

 is the program director of the emergency medicine residency at Brandon Regional Hospital and an assistant professor of emergency medicine at the University of South Florida Morsani College of Medicine in Tampa, Florida. He currently practices emergency medicine and specializes in substance use disorder care in the emergency department setting in Brandon, Florida.

is an instructor of psychiatry at the University of Central Florida College of Medicine in Orlando, and an adjunct instructor of psychiatry at Tufts University School of Medicine in Boston, Masschusetts. He is a psychoanalytic psychotherapist in private practice in Tampa.

1. Soares-Weiser K, Maayan N, Bergman H, et al. 

2. Coentre R, Silva-Dos-Santos A, Talina MC. 

Retrospective study on structural neuroimaging in first-episode psychosis. 

Rosen’s Emergency Medicine: Concepts and Clinical Practice.

4. Griffin CE III, Kaye AM, Rivera Bueno F, Kaye AD. 

Benzodiazepine pharmacology and central nervous system-mediated effects.

5. Abou-Setta AM, Mousavi SS, Spooner C, et al. First-generation versus second-generation antipsychotics in adults: comparative effectiveness. In: 

Comparative Effectiveness Reviews, No. 63. 

Agency for Healthcare Research and Quality (US); 2012. Accessed August 11, 2021. 

https://www.ncbi.nlm.nih.gov/books/NBK107237/

6. Campillo A, MacDonald KS, Vilke GM, Wilson MP. The B52 combination is not frequently used in emergency departments and causes a high proportion of patients to fall asleep. 

7. Lebin JA, Akhavan AR, Hippe DS, et al. 

Psychiatric outcomes of patients with severe agitation following administration of prehospital ketamine.

9. Arieti S. Individual psychotherapy of schizophrenia. In: Arieti S, ed. 

Schizophrenia in the Emergency Department: Psychologically and Psychodynamically Informed Practices

 is not a disease, but rather a variation of normal human experience. This view arguably originated with the writings of the 1960s antipsychiatrist R.D. Laing and is now echoed by some within the existential, sociological, and psychological communities. For instance, a recent report published by the British Psychological Society

 suggests that schizophrenia is not an illness. This view has obvious implications for psychiatric patients and for the discipline of psychiatry itself. I wish here to provide a brief refutation of this notion and an examination of schizophrenia as a pathology that differs in kind from normal human experience.

It has been known for more than a century that psychotic symptoms are widely distributed among the general population.

 One European study showed that roughly 25% of people experience hypnopompic hallucinations (those occurring at sleep onset), and about 7% experience hypnagogic hallucinations (those occurring upon waking), with about half of these psychotic symptoms being associated with specific pathologies.

 Similarly, transient paranoid experiences may result under extreme stress and are also commonly found in nonpsychotic psychiatric disorders, such as the borderline personality. Those writing from a trauma-informed perspective have noted that individuals who have endured abuse and other traumas are more prone to psychotic disturbance.

For these and other reasons, it has been alleged that schizophrenia exists on the same continuum as these nonpathological or nonschizophrenic experiences and represents a difference only of degree, not of kind. From this perspective, schizophrenia is viewed not as a disease, but as an extreme variation of normality. Those associated with the anti- or critical psychiatry movement go on to assert that antipsychotic treatment and even psychotherapies aimed at treating schizophrenia are misguided at best, and abuses at worst; to these authors, there can be no treatment for a disease that “does not exist.”

It must be clarified at this point that schizophrenia as a single, unitary disease has been disputed since the age of Bleuler,

[emphasis added].” It is now generally accepted that what we call schizophrenia is likely a grouping of many different disease processes, perhaps upwards of 200. But this heterogeneity does not repudiate the pathological nature of the human conditions we now refer to as “schizophrenia.”

Quantity of Symptoms and Qualitatively Different Nature

All differences that occur in nature are essentially quantitative ones, but it is the difference in quantity that produces the qualitative or categorical difference. A normal person may experience hypnagogic or hypnopompic hallucinations; an anxious individual may believe that their boss is talking behind their back, or a jealous spouse may have a fit of paranoid rage. But as long as these experiences are quantitatively so minimal that the individual can keep them in check (ie, the experiences do not produce any impairment), then we do not consider them schizophrenia.

 of the symptoms reaches a certain level—when the symptoms gain the upper hand, creating dysfunction and impairment in the individual’s life, and when, as the late psychiatrist Silvano Arieti, MD, so aptly put it, “the way of living of the patient expresses itself not in contrast to, but in accordance with, the symptoms”

Thus, at different quantitative levels, we have such dramatic changes in the experience of the symptoms, their persistence, and the degree of impairment caused by them that the total picture (schizophrenia) acquires a truly qualitatively different nature and is ruled by different mechanisms. Hypertension remains pathological despite the fact that all living persons have a blood pressure; likewise, schizophrenia remains pathological despite the fact that all persons have a mind that, at times, may be prone to transient psychotic aberrations.

This basic misunderstanding of the relationship between quantitative and qualitative differences—ie, that the quantity or degree of symptoms can transform the entire picture from a normal to a pathological one—forms the basis of much of the confusion regarding the nature of schizophrenia and psychiatric disorder in general. The same faulty argument has been made against the conceptualization of depression as a pathology: Because all human beings experience periods of sadness, it is alleged that depression is not a disorder.

Yet, anyone who has ever treated, or even interacted at length with, a person with schizophrenia or severe depression knows that these conditions differ in significant ways from ordinary human experience. The patient with schizophrenia cannot be convinced of the irrationality of his or her delusional beliefs, and the melancholic cannot be willed into a state of happiness or joy. The degree of impairment caused by these symptoms has produced a state that is governed by a different set of rules; the condition takes on a life of its own,so that it is so qualitatively different from normal mental functioning as to be unrecognizable to those who have not observed the situation in others before. This is the very essence of pathological states.

This point also underscores the fact that disease is most accurately defined as a state that characteristically produces some combination of suffering and dysfunction, regardless of whether it is associated with any known or putative biological abnormality. That is to say that schizophrenia exists as a disease entity despite the fact that there remain no biological tests for it, because the quantity of its symptoms produces a state that differs qualitatively from normal. Indeed, schizophrenia will remain indefinitely classified as a disease even if no biological cause or causes are ever discovered for it.

 note, “The lack of a universally clear boundary between the normal and abnormal does not mean that the concept of discrete illness becomes invalid.”

Despite the obfuscations of those who deny the pathological nature of schizophrenia, many of whom are driven by antipsychiatry motives, schizophrenia can rightly be considered a disease in so far as it represents a state that differs in kind from normal human mental life.

 is Instructor of Psychiatry at the University of Central Florida College of Medicine in Orlando, FL, and Adjunct Instructor of Psychiatry at Tufts University School of Medicine in Boston, MA. He is a psychoanalytic psychotherapist in private practice in Tampa, FL.

Understanding psychosis and schizophrenia

Dementia Praecox or the Group of Schizophrenias.

Prevalence of hallucinations and their pathological associations in the general population

Trauma and psychosis: an analysis of the National Comorbidity Survey

Schizophrenia: the sacred symbol of psychiatry

Recent conceptions and misconceptions of schizophrenia

On myths and countermyths: more on Szaszian fallacies

Letter to the editor: schizophrenia does not represent the extreme of a normally distributed trait

How does schizophrenia as a pathology differ from normal human experience?

Schizophrenia: A Difference of Kind

“Ms Patterson” was a 57-year-old Caucasian female with a history of chronic schizophrenia since her 20s. Her psychotic disorder has been stable on ziprasidone, with no psychiatric hospitalizations in the past 10 years. She smoked 2+ packs of cigarettes per day over 30 years.At age 49, Ms Patterson was hospitalized due to a ruptured cerebral aneurysm. Thereafter, she quit smoking for about 3 months, but then returned to 

 2 packs per day. She also had comorbid hypertension and chronic obstructive pulmonary disease. After seeing the same psychiatrist for 11 years, Ms Patterson moved to another state to live with 1 of her adult children. Approximately 1 year later, she returned to her previous residence. Prior to her outpatient appointment with her long-time psychiatrist, she died at the age of 57 from another cerebrovascular event.

Severe mental illness (SMI)—including schizophrenia, schizoaffective disorder, and bipolar disorder—is associated with decreased life expectancy.

 An increased prevalence of cigarette smoking is a likely contributor to this burden of premature mortality. More than half of patients with schizophrenia and more than a third of patients with bipolar disorder are cigarette smokers.

 Smokers in the general population have a 7- to 10-year shorter life expectancy than non-smokers.

 No previous studies have investigated the effect of 

 on life expectancy in patients with mental disorders, which would inform on the potential impact of smoking cessation interventions.

 investigated the life expectancy at birth according to 

smoking status in patients with schizophrenia

, schizoaffective disorder, and bipolar disorder.The authors obtained data from a large electronic secondary mental health care database: the South London and Maudsley NHS Foundation Trust Biomedical Research Centre Case Register, which contained anonymized data on more than 400,000 patients.

The study population included all patients with an SMI diagnosis (ICD-10 schizophrenia, schizoaffective disorder, and bipolar disorder) between January 2007 and December 2018, reached age 15 before the end of the observation period in 2018, and had information on smoking status. Deaths were identified using the NHS Care Records Service, which records every death in the United Kingdom. Smoking status was classified into current smokers, past smokers, and non-smokers (based on the most frequently recorded smoking status). Past smokers (n=470) and patients with unclear smoking status (n=963) were excluded. Life expectancy at birth based on smoking status was calculated using Chiang’s method of abridged life tables.

 Cox regression models were used to estimate mortality hazard ratios (HR), controlling for multiple potential confounding factors.

The authors identified 20,155 patients for inclusion in the cohort (83% current smokers and 17% non-smokers). In females, life expectancy was 67.6 years in current smokers and 74.9 years in non-smokers (a difference of 7.3 years), corresponding to an adjusted HR of 1.42. In males, life expectancy was 63.5 years in current smokers and 68.5 years in non-smokers (a difference of 5.0 years), corresponding to an adjusted HR of 1.49.

The authors concluded that in patients with SMI, the gap in life expectancy between current smokers and non-smokers was 7 years in females and 5 years in males. Based on life expectancy in the United Kingdom general population in 2012,

 the life expectancy gap for females was 15.1 years for current smokers and 7.8 years for non-smokers. The life expectancy gap for males was 15.2 years for current smokers and 10.2 years for non-smokers. Thus, smoking accounts for about half of the life expectancy gap in women and one-third of the gap in men. The mortality risks associated with smoking were similar to comorbid alcohol and 

. Study strengths included the large sample size, use of clinical registry data, and consideration of multiple potential confounding factors.

Smoking is associated with decreased life expectancy in patients with SMI. Given the high prevalence in patients with SMI, smoking makes a substantial contribution to premature mortality. Therefore, comprehensive implementation of effective smoking cessation interventions could have a substantial impact on improving life expectancy in this patient population.

is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for 

The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

Risks of all-cause and suicide mortality in mental disorders: a meta-review.

2. Mitchell AJ, Vancampfort D, Sweers K, et al. 

Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders-a systematic review and meta-analysis.

3. Royal College of Physicians, Royal College of Psychiatrists. Smoking and mental health. RCP. March 28, 2013. Accessed November 5, 2021. 

https://www.rcplondon.ac.uk/projects/outputs/smoking-and-mental-health

Impact of smoking on mortality and life expectancy in Japanese smokers: a prospective cohort study.

The impact of cigarette smoking on life expectancy in schizophrenia, schizoaffective disorder and bipolar affective disorder: an electronic case register cohort study.

6. Perera G, Broadbent M, Callard F, et al. 

Cohort profile of the South London and Maudsley NHS Foundation Trust biomedical research Centre (SLaM BRC) case register: current status and recent enhancement of an electronic mental health record-derived data resource.

8. Office for National Statistics. Life expectancy at birth and at age 65 by local areas, UK. December 11, 2019. Accessed November 5, 2021. 

https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/healthandlifeexpectancies/datasets/lifeexpectancyatbirthandatage65bylocalareasuk

Put out your cigarette. Researchers performed a cohort study of the impact of cigarette smoking on life expectancy in schizophrenia, schizoaffective disorder, and bipolar disorder.

Cigarette Smoking and Life Expectancy in Schizophrenia

“Mr Harris” is a 30-year-old male with a 5-year history of schizophrenia. His primary psychotic symptoms included auditory hallucinations and persecutory delusions. In the first year after the onset of his illness, he developed an obsessive fear of contamination and compulsive hand washing and bathing. He failed trial (adequate dose and duration) of 2 different second-generation and 1 first-generation antipsychotic. During a psychiatric hospitalization, he was subsequently started on clozapine, which was titrated to 300 mg/day. His auditory hallucinations remitted, and his persecutory delusions were significantly reduced. However, his compulsive hand washing and bathing worsened within 3 months of clozapine treatment. He was aware that his fears of contamination were excessive, but he was unable to resist acting on them. Adjunctive treatment with clomipramine 50 mg/day significantly decreased his obsessive thoughts and compulsive behaviors.

Many patients with schizophrenia have comorbid obsessive-compulsive symptoms (OCS) or 

 (OCD), with a pooled prevalence of 30% and 12%, respectively.

 There is some evidence that a greater duration of illness may be associated with a higher prevalence of comorbid OCS or OCD.

 Furthermore, OCS or OCD may be present as a prodromal symptom or co-occurring symptom in schizophrenia, or as an adverse effect of 

. Cross-sectional studies are limited by their inability to investigate the temporal relationship between antipsychotic exposure and OCS/OCD.

 investigated the association between antipsychotic use and the risk of new-onset OCD in patients with schizophrenia using a nationwide cohort in Korea.

The authors used a nationwide medical claims database that covers about 98% of the Korean population. Patients aged 15 to 60 with a first diagnosis of 

 between January 2010 and December 2018 (index date) were included. Patients with a diagnosis of schizophrenia or exposure to any antipsychotic within 2 years before the index date were excluded. Patients diagnosed with OCD before schizophrenia or within 2 weeks of the first schizophrenia diagnosis were also excluded, as were patients without an antipsychotic prescription during the observation period.

The authors used a nested case-control design to avoid potential biases (eg length bias due to antipsychotic exposure). 

, but without OCD were matched to patients with schizophrenia and OCD in a 4:1 ratio based on age, sex, date of schizophrenia diagnosis, observation period, location, and level of medical facility. Age of schizophrenia diagnosis was trichotomized into early-onset (age 15 to 20), intermediate-onset (age 21 to 44), and late-onset (age 45 to 60). The authors analyzed the 9 most frequently prescribed antipsychotics in Korea: 

, risperidone, quetiapine, aripiprazole, clozapine, haloperidol, chlorpromazine, amisulpride, and paliperidone. Logistic regression analysis was used to estimate the risk of newly diagnosed OCD, calculating odds ratios (ORs) and 95% confidence intervals (CIs), with haloperidol set as the reference, and adjusting for type of health insurance and presence of previous psychiatric illness.

Among approximately 50,000 patients newly diagnosed with schizophrenia during the study period, 775 cases of new-onset OCD and 3100 matched controls were identified. The mean subject age was 31, and the sample was 54% male. Compared to haloperidol, 

 was associated with significant increased odds of OCD (OR=2.9, 95% CI 1.6-5.0). Furthermore, risks of clozapine and new-onset OCD were significant in the early- and intermediate-onset groups, but not the late-onset schizophrenia group (although there were only n=3 subjects in this group). Among the 35 patients prescribed clozapine with new-onset OCD, the mean time from clozapine initiation to OCD diagnosis was 1.9 years, and the mean clozapine dose was 146 mg. There was no difference in the risk of OCD between all other antipsychotics and haloperidol.

The authors concluded that clozapine was associated with almost threefold increased odds (versus haloperidol) of new-onset OCD inpatients with schizophrenia, with no significant difference in risk for other antipsychotics. Strengths of the study include the population-based representative sample. Study limitations include the inability to assess the frequency of subthreshold OCS, which are more common than OCD and may require clinical attention. Data on other potential risk factors, such as genetics/family history of OCD and severity of psychotic symptoms, were not available.

There is reliable evidence for the risk of OCD associated with commonly prescribed antipsychotics, particularly clozapine (and within the first 2 years of treatment).

1. Swets M, Dekker J, van Emmerik-van Oortmerssen K, et al. 

The obsessive compulsive spectrum in schizophrenia, a meta-analysis and meta-regression exploring prevalence rates. 

2. Schirmbeck F, Swets M, de Haan L. Epidemiology: prevalence and clinical characteristics of obsessive-compulsive disorder and obsessive-compulsive symptoms in patients with psychotic disorders. In: de Haan L, Schiirmbeck F, Zink M, eds. 

Obsessive-Compulsive Symptoms in Schizophrenia

A nationwide nested case-control study of new-onset obsessive-compulsive disorder following antipsychotic use in schizophrenia.

Comorbidity or medication adverse effect? Researchers performed a nested case-control study of new-onset obsessive-compulsive disorder following antipsychotic use in schizophrenia.

Antipsychotics and New-Onset Obsessive-Compulsive Disorder in Schizophrenia

“Ms Rose” is a 63-year-old African-American female with schizoaffective disorder. Her psychotic disorder has been stable on ziprasidone, venlafaxine, and zolpidem as needed. She had surgical repair of a torn rotator cuff and was prescribed opioids (oxycodone) for postoperative pain. Two weeks later, her husband found her on the porch, unresponsive and not following commands. She was brought to the local 

 by ambulance. Work-up for acute stroke and other causes of altered mental status was negative/unremarkable. Her discharge diagnosis was orthostatic hypotension secondary to medication polypharmacy, and she was advised to discontinue opioids.

 in the United States are filled by patients with comorbid mental health disorders, including patients with concomitant antipsychotic use.

 Compared to the general population, patients with severe mental illness are 2.5 times more likely to be treated with opioids for chronic pain.

 In 2016, the US Food and Drug Administration (FDA) issued a black-box warning about the combined use of opioids and antipsychotics due to risks of respiratory depression.

 However, there is substantial heterogeneity amongst individual antipsychotics in regards to sedative properties and the potential for respiratory depression, which is mediated through antagonism of histamine-1 receptors.

 Risks of overdose in patients co-prescribed opioids and sedating versus nonsedating antipsychotics has not been investigated.

 investigated this association in a population-based cohort. The authors studied patients aged 15 to 85 who filled an opioid prescription between 2004 and 2017, nested in the IBM MarketScan Commercial and Medicare supplemental claims database.

The investigators identified all individuals who filled a prescription for an antipsychotic (index date). Other inclusion criteria were continuous medical and prescription drug benefit coverage for 180 days before the index date, no evidence of 

, and at least 1 opioid prescription filled within 14 days preceding the index date. Antipsychotics were classified as sedating (eg, chlorpromazine, clozapine, olanzapine, and quetiapine) and nonsedating (eg, aripiprazole, haloperidol, lurasidone, risperidone, and ziprasidone) based on histamine-1 receptor affinity (

The primary outcome measure was emergency department visit or 

 due to an overdose even within 30 days of the index date. Patients were followed until the occurrence of the outcome, death, end of the study, or 30 days, whichever came first. Szmulewicz et al compared baseline characteristics between patients receiving opioids and sedating versus nonsedating antipsychotics using propensity score matching. Incidence rates (IRs) and their 95% confidence intervals (CIs) were calculated for each exposure group. Hazard ratios (HRs) and 95% CIs were estimated with Cox proportional hazard models. 

After 1:1 propensity score matching, the cohort consisted of 62,604 patients newly exposed to a sedating antipsychotic plus opioids (“exposed”) and an equal number of patients newly exposed to a nonsedating antipsychotic plus opioids (“referent”). Mean patient age was 50, and 33% of the cohort was male. The most commonly prescribed opioids were hydrocodone, oxycodone, tramadol, and buprenorphine. The IR of overdose was 35 events per 1000 person-years in the exposed group, and 26 events per 1000 person-years in the referent group, corresponding to an adjust HR of 1.34 (95% CI 1.07-1.68). In sensitivity analyses, there was evidence for a dose-response relationship based on antipsychotic dosage. Findings were consistent across a number of other sensitivity and subgroup analyses.

The authors concluded that among patients receiving prescription 

, sedating antipsychotics are associated with an increased risk (up to 60%) of unintended overdose compared to nonsedating antipsychotics. Findings support the FDA black-box warning about the combined use of opioids and antipsychotics.

Strengths of the present study include the large sample size, consideration of many potential confounders, use of an active comparator, and multiple sensitivity analyses. Limitations include the observational study design, the potential for medication nonadherence during the follow-up period, and the use of a commercially insured population, and that fatal unintentional overdoses prior to hospitalization would have been missed.

Clinicians should consider the risk of unintentional overdose when prescribing 

 to patients taking opioids. Depending on the clinical situation, use of nonsedating antipsychotics may help mitigate this risk.

Prescription opioid use among adults with mental health disorders in the United States.

2. FDA Drug Safety Communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. FDA. March 2019. Accessed October 26, 2021. 

https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-about-serious-risks-and-death-when-combining-opioid-pain-or

Receptor-binding profiles of antipsychotics: clinical strategies when switching between agents.

4. Szmulewicz AG, Bateman BT, Levin R, et al. 

Risk of overdose associated with co-prescription of antipsychtoics and opioids: a population-based cohort study.

Unintentional overdose with antipsychotics plus opioids. Researchers performed a population-based cohort study of the risk of overdose associated with co-prescription of antipsychotics and opioids.

Risk of Overdose with Antipsychotic and Opioid Co-Prescription

“Ms Washington” is a 52-year-old African-American female with schizophrenia and no previous suicide attempts. Her psychotic disorder has been stable on quetiapine 200 mg at bedtime, with no psychiatric hospitalizations in the past 20 years. She has a history of episodic 

, which is currently treated with quetiapine and trazodone. In response to multiple recent stressors—including financial, transportation, and medical work-up for possible colon cancer—and in consultation with her psychiatrist, her quetiapine was increased over 1 month to 400 mg at bedtime due to worsening paranoia and insomnia. Subsequently, she overdosed on multiple, unspecified medications at home in a 

. She woke up the next morning, did not seek any medical attention, and did not tell anyone about the overdose until she revealed this information to her psychiatrist at an outpatient visit about 6 weeks after the attempt.

Insomnia and suicide ideation/behavior/death (SIB) are common in psychiatric disorders. Among psychotropic medications, there is evidence that clozapine and 

 have antisuicidal properties. Clozapine is the only antipsychotic with an indication for suicide prevention in schizophrenia from the US Food and Drug Administration (FDA).

 In the International Suicide Prevention Trial (InterSePT),

 insomnia was significantly less common in patients treated with clozapine versus olanzapine, consistent with evidence that sedation is a common adverse effect of clozapine.

 Similarly, there is evidence for antisuicidal properties of lithium.

 Although sedation is reported less frequently with lithium compared with other psychotropics, there is evidence for potential beneficial effects of lithium on sleep.

 Although the mechanisms underlying antisuicidal properties of clozapine and lithium remain unclear, effects on insomnia and sleep behavior may play a role. No previous studies have investigated associations between insomnia and SIB in patients taking antipsychotics and mood stabilizers.

 investigated the prevalence of spontaneously reported psychiatric 

 (ADRs) of insomnia and SIB in adults for other second-generation antipsychotics (SGAs) and mood stabilizers compared to clozapine and lithium.

The authors included all reports in the US FDA Adverse Event Reporting System (FAERS) publicly available database from inception in 1968 through February 2021, for which either a second-generation antipsychotic or mood stabilizer was the suspected agent of a psychiatric adverse event in adults aged 18 to 64. Data on total psychiatric adverse events, as well as insomnia and SIB adverse events were extracted. Data were combined for both generic and brand formulations, as well as oral and long-acting injectable forms of each SGA.

For each agent, the authors calculated the proportion of ADRs for insomnia and SIB by dividing the number of insomnia and SIB ADRs by the total number of psychiatric ADRs, respectively. They then calculated reporting odds ratios (rORs) and 95% confidence intervals (95% CIs) for insomnia and SIB ADRs relative to clozapine (for SGAs) and lithium (for mood stabilizers). Finally, they calculated bivariate correlations between the insomnia rOR and the SIB rOR.

Ten different SGAs (clozapine, olanzapine, paliperidone, risperidone, lurasidone, brexpiprazole, aripiprazole, asenapine, ziprasidone, and 

) and 5 different mood stabilizers (lithium carbamazepine, 

, oxcarbazepine, and lamotrigine) with at least 500 psychiatric ADRs were included in the analyses. For SGAs, insomnia ADRs comprised 11% and SIB ADRs comprised 23% of the total psychiatric ADRs. Compared to 

, all of the other SGAs were associated with a significantly increased reported odds of insomnia (rOR=2.41-9.70) and SIB (rOR=1.18-2.72). After excluding 1 extreme outlier (quetiapine), the insomnia and SIB rORs for each SGA were correlated at the trend level (r=0.66, p=0.053).

For mood stabilizers, insomnia ADRs comprised 7% and SIB ADRs comprised 32% of the psychiatric ADRs. Compared to lithium, there was a significantly increased reported odds of insomnia (rOR=1.66) for lamotrigine, a nonsignificantly increased reported odds of insomnia for the other mood stabilizers (rOR=1.06-1.23), and a significantly increased reported odds of SIB (rOR=1.17-1.70) for all other mood stabilizers. The insomnia and SIB rORs for each mood stabilizer were significantly, positively correlated (r=0.97, p=0.005).

The authors concluded that, compared with clozapine and 

, other SGAs and mood stabilizers, respectively, were associated with increased reported odds of insomnia and SIB, and the insomnia and SIB rORs were positively correlated for each medication class. Limitations of public pharmacovigilence data include that the FDA does not verify reports submitted to FAERS. Also, given the prevalence of insomnia and SIB in patients taking SGAs and/or mood stabilizers, it is also possible that some adverse events were misattributed to the drug rather than the illness itself. Individual level data in the FAERS database are limited, which could shed light on other potential confounding or moderating factors.

The present study is consistent with previous evidence for antisuicidal properties and potential beneficial effects on sleep for clozapine and 

. Findings raise the possibility that beneficial effects on sleep as one potential pathway underlying the antisuicidal properties for these agents, which warrant investigation in longitudinal studies. Findings also affirm the use of clozapine and lithium in relevant patient populations at high risk for suicide.

Managing suicide risk in patients with schizophrenia.

2. Meltzer HY, Alphs L, Green AI, et al. International Suicide Prevention Trial Study Group. 

Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT).

Clozapine in the treatment of refractory schizophrenia: a practical guide for healthcare professionals.

4. Antolín-Concha D, Lähteenvuo M, Vattulainen P, et al. 

Suicide mortality and use of psychotropic drugs in patients hospitalized due to bipolar disorder: a Finnish nationwide cohort study.

All in a good night’s sleep? Researchers performed a pharmacovigilance study of second-generation antipsychotics and mood stabilizers as the suspected agent of psychiatric adverse drug reactions (insomnia and suicide/ideation/behavior/death).

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