Hero

Videos

Slideshows

Articles

Podcasts

Poll

Although cognitive difficulties may not be the primary symptom addressed in patients with schizophrenia, these impairments are a 

 that can contribute to social and functional disability.

 Cognitive dysfunction in schizophrenia affects not only attention, verbal memory, reasoning, and processing speed, but also social 

 Thus, the topic has received increased attention. (For more information, see the 

A growing body of research results indicates viruses may play a role in both schizophrenia and cognitive difficulties. One in particular, Epstein-Barr virus (EBV), has received notable attention in the possible pathophysiology of schizophrenia as well as of associated cognitive dysfunction, although findings have been inconsistent. For instance, in 

y of 229 patients with schizophrenia, the data did not indicate an association between EBV seropositivity and cognitive performance.

 Importantly, previous studies have generally measured exposure by reactivity to a single EBV protein, rather than to a panel of proteins or EBV virions. EBV, also known as human herpesvirus 4, is a lymphotropic virus that can produce acute and latent infections.

Using the MATRICS Consensus Cognitive Battery (MCCB), 

 tested their hypothesis that antibodies to various EBV proteins may be associated with different levels and domains of cognitive functioning in patients with 

 Patients with schizophrenia or schizoaffective disorder were enrolled at the Stanley Research Program at Sheppard Pratt in Baltimore, Maryland, in 1 of 3 trials of adjunctive medications for adults with schizophrenia that were conducted between 2014 and 2019.

Across the 3 trials, inclusion criteria were: receiving outpatient (vs inpatient) treatment; aged > 18 years; diagnosis of schizophrenia/schizoaffective disorder confirmed by structured clinical interview; and current stable antipsychotic treatment. Patients were excluded from the study if they had clinically significant or unstable medical disorders; were pregnant or breastfeeding; had current or recent substance use disorder; or were found to have an intellectual disability or IQ below 70 (

 In addition to the MCCB, the psychopathology of each patient was assessed using the Positive and Negative Syndrome Scale (PANSS). The total sample size was 84 (

Blood was assayed for immunoglobulin G antibodies to EBV antigens derived from intact virions using enzyme immunoassay. Assay values for patients were compared with a standard score based on the reactivity of controls without psychiatric disorders. Reactivity to herpes simplex virus type 1 (HSV-1) was also measured by immunoassay. In all studies, blood samples and cognitive testing were completed before the administration of any study medication. Linear regression models were used to determine whether EBV antibodies (to the whole virion and to specific proteins) were associated with MCCB composite and domain scores (

), controlling for age, sex, race, education, smoking, and HSV-1 serology.

The authors found a significant association between the lower MCCB overall percentile composite score (ie, worse cognition) and higher levels of antibodies to the whole EBV virion, to the EBV nuclear antigen-1 (EBNA-1), and to the EBV viral capsid antigen (VCA). There was also a significant association between lower MCCB social cognition and higher level of EBV virion, EBNA-1, and VCA antibodies. Lower MCCB processing speed was associated with higher EBV virion antibodies at a trend level. Lower MCCB working memory was also associated with higher EBNA-1 antibodies at a trend level.

The authors concluded that worse cognitive functioning in schizophrenia was associated with specific patterns of reactivity to EBV, including global and social cognition. Dickerson and colleagues acknowledged both strengths and limitations of their study. For instance, the present study includes the comprehensive cognitive battery (MCCB) and the measurement of EBV reactivity to specific EBV proteins. The investigators noted that the biological basis for the association between cognitive functioning and immune response to EBV is unknown. However, this study included a relatively small sample size, so the results may not be generalizable to other samples of patients with schizophrenia. Similarly, there may be possible residual confounding effects (eg, diet, genetics).

Exposure to EBV may contribute to cognitive impairments in patients with schizophrenia, which may have clinical implications. In particular, certain antiviral medications may be relevant to the prevention and treatment of EBV-associated cognitive impairment.

Regardless of these findings, it is important for clinicians to remain vigilant in the identification and assessment of cognitive impairment in schizophrenia, given its impact on social and functional disability. Although there are not any approved medications, clinicians can potentially improve cognitive outcomes by optimizing antipsychotic dosing based on symptoms and adverse effects, treating underlying depression, facilitating treatment of medical comorbidities (eg, hypertension, diabetes), and utilizing other therapies (eg, cognitive remediation) as available and appropriate.

is a professor in the Department of Psychiatry and Health Behavior of Augusta University in 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, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.

1. Dickerson F, Boronow JJ, Ringel N, Parente F. 

Neurocognitive deficits and social functioning in outpatients with schizophrenia

3. Dickerson FB, Boronow JJ, Stallings C, et al. 

Association of serum antibodies to herpes simplex virus 1 with cognitive deficits in individuals with schizophrenia

. Arch Gen Psychiatry. 2003;60(5):466-472.

4. Dickerson F, Katsafanas E, Origoni A, et al. 

Exposure to Epstein Barr virus and cognitive functioning in individuals with schizophrenia

5. MCCB [MATRICS Consensus Cognitive Battery] Neuropsychological Assessment. MATRICS Assessment Inc. Accessed February 4, 2021. 

A growing body of scientific literature makes the case.

Is Epstein-Barr Virus to Blame for Cognition in Schizophrenia?

Lyndra Therapeutics announced the positive outcome of an end-of-phase 2 meeting with the US Food and Drug Administration (FDA) suggesting a clear path to approval for its weekly risperidone for the treatment of schizophrenia, LYN-005. This treatment is designed as the first-ever oral, ultra-long-acting, extended-release therapy.

The company plans to initiate its pivotal program for LYN-005 in early 2022.

“We are grateful to the FDA for their guidance as we design this pivotal program. Transforming the patient experience via oral therapies that achieve consistent plasma drug concentrations at target therapeutic levels for an entire week is one of our key goals,” said Patricia Hurter, PhD, Chief Executive Officer of Lyndra Therapeutics. “This pivotal program allows us to deliver swiftly on the unmet need for ultra-long-acting oral therapies that have the potential to have an enormous and positive impact for patients and caregivers. We hope that the availability of an oral, once-weekly risperidone product will provide a valuable option for those who struggle with adherence but prefer an oral formulation.”

Lyndra and the FDA agreed on the necessity of 2 key elements of this program: 1) a 90-person pharmacokinetic comparability study that builds on the previously established safety and efficacy profile of risperidone, and 2) a 6-month double-blind safety study to characterize the safety profile of the dosage form. Both studies will evaluate LYN-005 at weekly doses ranging from 2 to 6 mg daily, and will support indications in schizophrenia, bipolar mania, and bipolar 1 disorder.

“The FDA provided valuable feedback during the end-of-phase 2 meeting on trial design, manufacturing and control strategy and Lyndra’s path forward as we pursue the pivotal program,” said Chief Medical Officer of Lyndra Therapeutics, Richard Scranton, MD, MPH. “The productive and collaborative nature of these meetings has allowed us to develop a clear and direct course of action as we pursue the tremendous potential of LYN-005.”

To read more on previous studies of LYN-005, see 

Extended-Release Risperidone Capsule Making Waves

1. Lyndra Therapeutics announces positive outcome of end-of-phase 2 meeting with the FDA for Lyndra’s weekly risperidone (LYN-005) for the treatment of adults with schizophrenia and other indications. News release. July 19, 2021. 

https://www.businesswire.com/news/home/20210719005181/en/Lyndra-Therapeutics-Announces-Positive-Outcome-of-End-of-Phase-2-Meeting-with-the-FDA-for-Lyndra’s-Weekly-Risperidone-LYN-005-for-the-Treatment-of-Adults-with-Schizophrenia-and-Other-Indications

2. Kuntz L. Extended-release risperidone capsule making waves. 

https://www.psychiatrictimes.com/view/extended-release-risperidone-capsule-making-waves

An extended release, ultra-long acting antipsychotic takes another step forward in the approval process.

Positive End-Of-Phase 2 Meeting for Extended-Release Risperidone Capsule 

A disruption in blood clotting and the first line immune system could contribute to the development psychosis, according to a recent scientific review published in 

“Early identification and treatment significantly improves clinical outcomes of psychotic disorders. Our theory may provide a further step to biomarkers of psychosis and allow the identification of therapeutic targets for early and more effective treatment,” said Melanie Föcking, PhD, joint first author on the paper and Lecturer in Psychiatric Neuroscience at RCSI Department of Psychiatry.

Investigators at RCSI University of Medicine and Health Sciences, Cardiff University, and the UCD Conway Institute led the research. Their findings resonate with other recent studies, which have identified blood proteins and blood clotting networks as instrumental in psychosis development. The researchers developed their new theory after analyzing these studies, proposing the imbalance of these systems leads to inflammation, which in turn contributes to the development of psychosis.

“While the idea of psychosis resulting from some form of inflammation and immune activation is not new, our data suggest a new understanding and change of focus towards a combined function of the innate immune complement system and coagulation pathways to the progression to psychotic disorder,” said joint first author Meike Heurich, PhD, lecturer at School of Pharmacy and Pharmaceutical Sciences at Cardiff University.

The new theory builds upon the “two-hit” hypothesis. In this hypothesis, early genetic and environmental factors disrupt the developing central nervous system, or the “first-hit,” and thus increases the individual’s vulnerability to subsequent, late environmental disruptions, or the “second-hit.”

“The works builds on our recent studies, which increasingly implicate dysregulation of the complement and coagulation pathways both in and preceding psychotic disorder,” said David Cotter, PhD, senior author of the paper and professor of Molecular Psychiatry at RCSI Department of Psychiatry.

1. Heurich M, Föcking M, Mongan D, et al. Dysregulation of complement and coagulation pathways: emerging mechanisms in the development of psychosis. 

2. RCSI. New theory suggests blood immune and clotting components could contribute to psychosis. News release. July 16, 2021. 

https://www.eurekalert.org/pub_releases/2021-07/r-nts071621.php

New research may help better understand psychosis etiology as well as provide potential biomarkers for psychosis. 

Do Blood Clotting and Immune System Contribute to Psychosis? 

The rise in synthetic cathinone and cannabinoid use has been linked to a wide range of 

, including agitation, psychosis, and delirium.

 Managing and stabilizing the complex toxic effects of these drugs can be challenging.

Colloquially known as spice, these designer synthetic cannabinoid receptor agonists have potent 

 at the cannabinoid (CB) 1 and 2 receptors.

 The compounds were originally developed to study the endocannabinoid system, but they emerged as a drug of abuse in 2008.

 Initially designed to mimic the effects of 9-tetrahydrocannabidiol, synthetic cannabinoids are 2 to 100 times more potent than marijuana at the CB1 and CB2 receptor, resulting in a range of adverse neuropsychiatric symptoms (

 Furthermore, synthetic cannabinoids are often adulterated with ingredients to either enhance or attenuate the drug high, resulting in clinically unpredictable toxicological profiles.

 As a consequence, no specific toxidrome is associated with synthetic cannabinoid intoxication, and patients will typically present with a constellation of sympathomimetic, anticholinergic, and marijuana toxic effects (

 The most common sympathetic nervous system cardiovascular effects are tachycardia (46%) and hypertension (21%). The anticholinergic effects closely overlap with signs and symptoms of a sympathomimetic toxidrome. Distinguishing symptoms specific to anticholinergic toxicity include dry skin, “cotton mouth,” absent bowel sounds, blurred vision, and urinary retention. Patients may also present with marijuana intoxication symptoms (eg, ataxia, delayed reaction time, and conjunctival injection). Laboratory studies are indicated in cases of severe intoxication with agitation or seizures; the potential metabolic derangements that can result may be life-threatening.

Colloquially known as bath salts, these agents are synthetic psychostimulants structurally related to cathinone, a monoamine alkaloid found in the khat plant. They are commonly abused for their euphoric, empathogenic, and stimulating effects. As substituted phenethylamines, synthetic cathinones are structurally and pharmacologically similar to amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). The 

 synthetic cathinones are 4-methylmethcathinone (mephedrone), 3,4-methylenedioxy-N-methylcathinone (methylone), and 4-methylenedioxypyrovalerone.

Synthetic cathinones produce major effects on the central nervous system and are linked to adverse neuropsychiatric complications (

 stimulate the release of dopamine and inhibit the reuptake of epinephrine, norepinephrine, and serotonin, inducing a broad range of sympathomimetic, serotonergic, and hallucinogenic adverse toxidrome effects (

 The most frequent sympathetic nervous system cardiovascular effects are tachycardia (46%) and hypertension (21%). The hallucinogenic effects (ie, perceptual distortions, depersonalization, synesthesia) can be highly distressing, often prompting emergency psychiatric care. Ancillary lab studies should be ordered in cases of severe agitation because of the increased risk for acute kidney injury, rhabdomyolysis, lactic acidosis, stroke, and intracranial hemorrhage.

The diagnosis of intoxication is based on a history of exposure and presence of characteristic signs and symptoms. Patients may unknowingly or inadvertently administer synthetic cannabinoids and cathinones, as these compounds are often adulterated with 

 Patients will typically present with signs and symptoms of adrenergic neurohumoral activation.

 The neurotoxic symptoms (eg, aggression, confusion, and psychosis) may overlap with a primary mental illness; psychiatrists should rely on the clinical history and physical exam findings for an accurate diagnosis. In the setting of acute intoxication, urine immunoassay testing has a low positive predictive value for synthetic cannabinoids and cathinones.

 The molecular geometry of synthetic cannabinoids and cathinones is ever changing, making it increasingly difficult to identify these compounds via gas chromatography/mass spectrometry, which may not be readily available to assist in the diagnosis process.

 An atypical onset of psychosis and agitation alongside hypersympathetic activation and a mixed toxidrome is strongly suggestive of intoxication.

Psychiatrists should strongly consider the possibility of intoxication in any patient with no known psychiatric history, a negative urine drug screen, and no known contributing medical mimickers presenting with a mixed toxidrome. Patients will not necessarily fit neatly into a particular toxidrome; rather, they present with overlapping signs and symptoms from multiple toxidrome classes. Consequently, differentiating synthetic cannabinoid and synthetic cathinone toxicity can be challenging. Regardless, supportive care and symptom management is the mainstay of the treatment. Benzodiazepines are considered the first line of treatment to reduce the 

 (eg, hypertension, agitation, and seizures).

Agitation is the most common neuropsychiatric complication associated with synthetic cannabinoid and cathinone ingestion. In fact, according to one report, 40% of intoxicated patients evaluated in an ED will experience severe agitation.

 The spectrum of psychomotor agitation can be objectively measured and identified with a standardized rating scale such as the Behavioral Activity Rating Scale (BARS). For patients with mild-to-moderate agitation (BARS score = 5 or 6), the patient may initially be calmed with verbal de-escalation techniques and environmental modification. For patients with moderate-to-severe agitation (BARS score > 6), benzodiazepines remain the first-line treatment.

Among the benzodiazepines, midazolam and lorazepam are considered the initial drugs of choice for decreasing agitation because of their rapid onset of action, short half-life, and parenteral route of administration availability.

 Antipsychotics are commonly administered with benzodiazepines to manage the psychotomimetic effects.

 However, risks associated with antipsychotics in acute poisoning settings must be carefully considered since they may increase the risk of seizure induction, have anticholinergic effects, impair thermoregulation mechanisms, and prolong the QTc interval.

 Serotonergic sedatives such as fentanyl should be avoided because of the increased risk of serotonin toxicity associated with synthetic cannabinoids and cathinones.

A systematic review reported that 25% to 94% of patients diagnosed with excited delirium were recently exposed to synthetic cannabinoids and/or cathinones. The American College of Emergency Physicians has provided guidance on evaluating excited delirium, for which a minimum of 6 of 10 clinical criteria are required to make a diagnosis. If undertreated, the case-fatality rate is estimated to be 20%, partly due to catecholaminergic cardiorespiratory failure. The cornerstone of treatment is rapid sedation to reduce the sympathomimetic outflow and facilitate lifesaving treatments.

To date, no large-scale randomized controlled trials have evaluated pharmacological treatments for excited delirium. Nonetheless, the standard of care is to administer benzodiazepines and antipsychotics to decrease psychomotor agitation. In the emergency setting, intramuscular (IM) ketamine (4-5 mg/kg) is increasingly used for sedation of agitated patients with excited delirium. Initial studies in the prehospital setting (emergency medical services) reported that intubation rates following ketamine administration were as high as 60%. Emerging literature supports that IM ketamine administration in the hospital setting (ie, ED) is a safe and effective treatment for excited delirium while not significantly affecting the cardiopulmonary system.

 reported that more patients required intubation after ketamine administration in the prehospital setting (30%) compared with the hospital setting (1.8%). Prospective studies conducted in the ED have demonstrated that there is no significant difference in incidence of complications between IM ketamine and IM haloperidol.

 The adverse effects of single doses of IM ketamine for agitation are generally transient and self-limiting; they include emesis, hypersalivation, recovery agitation (also known as emergence reaction), hypertension, and tachycardia. Moreover, ketamine has other potential benefits, including a faster onset to sedation compared with benzodiazepines and antipsychotics.

 There are observational reports of ketamine exacerbating psychosis in susceptible patients. Larger studies, however, have concluded that acute- and short-term ketamine administration for agitation does not increase psychiatric inpatient admissions or ED psychiatric evaluations.

 Physical restraints should be used as a last resort, primarily as a bridge to pharmacologic treatment, as prolonged use of physical restraints is likely to worsen delirium and rhabdomyolysis, as well as lead to renal failure, electrolyte abnormalities, and arrhythmias.

Synthetic cannabinoids have been linked to psychotic reactions, such as paranoia, catatonia, and dissociation, as well as auditory and/or visual hallucinations.

 Longitudinal studies have reported that consumption of potent cannabinoids quintuples the risk of a psychotic episode.

 The psychotomimetic effects are usually transient and resolve within 5 to 8 days; however, up to one-third of patients will transition to schizophrenia.

 Although there is no established antidote, preliminary reports suggest that cannabinol, an allosteric modulator at the CB1 receptor, may reverse the neurotoxic effects.

Similarly, synthetic cathinones have propsychotic effects, potentially triggering a psychotic state in vulnerable patients. An observational study reported that synthetic stimulants were implicated in approximately 25% of ED visits involving drug-related psychosis. Specifically, mephedrone was the most common synthetic cathinone involved, accounting for approximately 20% of stimulant-related psychotic cases.

 Synthetic cathinone-induced psychosis is typically brief and resolves within days to weeks; however, 25% of patients will transition to a schizophrenia spectrum disorder.

The psychotomimetic symptoms can be controlled with first- and second-generation antipsychotic medications with careful consideration of adverse effect profiles. Among the first-generation antipsychotics, the butyrophenone neuroleptics IM haloperidol and IM droperidol are reasonable pharmacotherapeutic options.

 In comparison with IM haloperidol, IM droperidol has a faster onset of action; it rapidly prevents and treats emergent psychotic agitation within 5 to 10 minutes of IM administration.

 Some expert panels have recommended avoiding butyrophenone neuroleptics in cases of substance-induced psychosis due to its proconvulsant properties, cardiotoxic effects, and extrapyramidal symptoms.

Among the second-generation antipsychotics, po olanzapine has a track record of treating NPS-induced psychosis, and prodrug websites have touted olanzapine as the ideal medication to terminate “bad trips.”

 In spite of its efficacy, olanzapine has anticholinergic and central thermoregulatory effects that impair core temperature regulation. In theory, po or IM aripiprazole and ziprasidone are probably the safest antipsychotics to administer because of their relatively favorable safety profile and negligible anticholinergic and seizurogenic effects.

Despite the infamous concerns about QTc prolongation, epidemiological studies do not support a correlation between ziprasidone and torsades de pointes. In many instances, detoxification with benzodiazepines and rest will often quell the substance-induced symptoms without the added need for antipsychotics. Given the risks associated with neuroleptics, especially in patients who are antipsychotic naïve, it may be best to consider a benzodiazepine as the first-line agent to reduce the psychotic agitation. Antipsychotics can be initiated if the psychosis continues to persist after the detoxification period, or if the patient has an underlying primary psychotic illness.

Synthetic cannabinoid and cathinone harms are increasing. Synthetic cannabinoids and cathinones have propsychotic and agitative effects, and the toxic reactions can mimic a primary mental illness. Because no definitive diagnostic test differentiates primary vs secondary drug-induced mental illness, psychiatrists must rely on the history and physical examination.

 is an assistant professor of medical education and psychiatry at California University of Sciences and Medicine, Arrowhead Regional Medical Center, in San Bernardino.

 is a core faculty member for the Internal Medicine Residency Program at Arrowhead Regional Medical Center, San Bernardino. The authors have no relevant financial disclosures to report.

1. Cohen K, Weinstein AM. Synthetic and non-synthetic cannabinoid drugs and their adverse effects—a review from public health prospective. Front Public Health. 2018;6:162.

2. Tai S, Fantegrossi WE. Pharmacological and toxicological effects of synthetic cannabinoids and their metabolites. Curr Top Behav Neurosci. 2017;32:249-262.

3. Wiley JL, Marusich JA, Huffman JW, et al. Hijacking of basic research: the case of synthetic cannabinoids. Methods Rep RTI Press. 2011;2011:17971.

4. Castaneto MS, Gorelick DA, Desrosiers NA, et al. Synthetic cannabinoids: epidemiology, pharmacodynamics, and clinical implications. Drug Alcohol Depend. 2014;144:12-41.

5. Zuba D, Byrska B. Prevalence and co-existence of active components of ‘legal highs.’ Drug Test Anal. 2013;5(6):420-429.

6. Bilici R. Synthetic cannabinoids. North Clin Istanb. 2014;1(2):121-126.

7. Weinstein AM, Rosca P, Fattore L, London ED. Synthetic cathinone and cannabinoid designer drugs pose a major risk for public health. Front Psychiatry. 2017;8:156.

8. Baumann MH, Walters HM, Niello M, Sitte HH. Neuropharmacology of synthetic cathinones. Handb Exp Pharmacol. 2018;252:113-142.

9. Oliver CF, Palamar JJ, Salomone A, et al. Synthetic cathinone adulteration of illegal drugs. Psychopharmacology (Berl). 2019;236(3):869-879.

10. Riederer AM, Campleman SL, Carlson RG, et al; Toxicology Investigators Consortium (ToxIC). Acute poisonings from synthetic cannabinoids – 50 U.S. Toxicology Investigators Consortium registry sites, 2010-2015. MMWR Morb Mortal Wkly Rep. 2016;65(27):692-695.

11. Arntson A, Ofsa B, Lancaster D, et al. Validation of a novel immunoassay for the detection of synthetic cannabinoids and metabolites in urine specimens. J Anal Toxicol. 2013;37(5):284-290.

12. Moeller KE, Kissack JC, Atayee RS, Lee KC. Clinical interpretation of urine drug tests: what clinicians need to know about urine drug screens. Mayo Clin Proc. 2017;92(5):774-796.

13. Bonaccorso S, Metastasio A, Ricciardi A, et al. Synthetic cannabinoid use in a case series of patients with psychosis presenting to acute psychiatric settings: clinical presentation and management issues. Brain Sci. 2018;8(7):133.

14. Katz KD, Leonetti AL, Bailey BC, et al. Case series of synthetic cannabinoid intoxication from one toxicology center. West J Emerg Med. 2016;17(3):290-294.

15. Nordstrom K, Zun LS, Wilson MP, et al. Medical evaluation and triage of the agitated patient: consensus statement of the American Association for Emergency Psychiatry Project BETA Medical Evaluation Workgroup. West J Emerg Med. 2012;13(1):3-10.

16. Hui D. Benzodiazepines for agitation in patients with delirium: selecting the right patient, right time, and right indication. Curr Opin Support Palliat Care. 2018;12(4):489-494.

17. Roberto AJ, Lorenzo A, Li KJ, et al. First-episode of synthetic cannabinoid-induced psychosis in a young adult, successfully managed with hospitalization and risperidone. Case Rep Psychiatry. 2016;2016:7257489.

18. Gonin P, Beysard N, Yersin B, Carron P-N. Excited delirium: a systematic review. Acad Emerg Med. 2018;25(5):552-565.

19. Li M, Martinelli AN, Oliver WD, Wilkerson RG. Evaluation of ketamine for excited delirium syndrome in the adult emergency department. J Emerg Med. Published online November 14, 2019.

20. Mankowitz SL, Regenberg P, Kaldan J, Cole JB. Ketamine for rapid sedation of agitated patients in the prehospital and emergency department settings: a systematic review and proportional meta-analysis. J Emerg Med. 2018;55(5):670-681.

21. Heydari F, Gholamian A, Zamani M, Majidinejad S. Effect of intramuscular ketamine versus haloperidol on short-term control of severe agitated patients in emergency department: a randomized clinical trial. Bull Emerg Trauma. 2018;6(4):292-299.

22. Lebin JA, Akhavan AR, Hippe DS, et al. Psychiatric outcomes of patients with severe agitation following administration of prehospital ketamine. Acad Emerg Med. 2019;26(8):889-896.

23. Annas GJ. The last resort—the use of physical restraints in medical emergencies. N Engl J Med. 1999;341(18):1408-1412.

24. Hurst D, Loeffler G, McLay R. Psychosis associated with synthetic cannabinoid agonists: a case series. Am J Psychiatry. 2011;168(10):1119.

25. Di Forti M, Marconi A, Carra E, et al. Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study. Lancet Psychiatry. 2015;2(3):233-238.

26. Murrie B, Lappin J, Large M, Sara G. Transition of substance-induced, brief, and atypical psychoses to schizophrenia: a systematic review and meta-analysis. Schizophr Bull. 2020;46(3):505-516.

27. Hudson R, Renard J, Norris C, et al. Cannabidiol counteracts the psychotropic side-effects of delta-9-tetrahydrocannabinol in the ventral hippocampus through bidirectional control of ERK1-2 phosphorylation. J Neurosci. 2019;39(44):8762-8777.

28. Martin Vallersnes O, Dines AM, Wood DM, et al; Euro-DEN Research Group. Psychosis associated with acute recreational drug toxicity: a European case series. BMC Psychiatry. 2016;16:293.

29. Calver L, Drinkwater V, Gupta R, et al. Droperidol v. haloperidol for sedation of aggressive behavior in acute mental health: randomized controlled trial. Br J Psychiatry. 2015;206(3):223-228.

30. Thomas H Jr, Schwartz E, Petrilli R. Droperidol versus haloperidol for chemical restraint of agitated and combative patients. Ann Emerg Med. 1992;21(4):407-413.

31. Valeriani G, Corazza O, Saverio Bersani F, et al. Olanzapine as the ideal “trip terminator”? analysis of online reports relating to antipsychotics’ use and misuse following occurrence of novel psychoactive substance-related psychotic symptoms. Hum Psychopharmacol. 2015;30(4):249-254. ❒

Cannabis has been heralded as a treatment for many conditions, but what about its psychiatric risks? 

The Rise in Synthetic Cannabinoids and Cathinones

“Hilda” is a Black female aged 42 years, with a history of schizophrenia and catatonia. She was aged 26 years at the onset of her psychotic illness. She had several inpatient psychiatric hospitalizations during the first 3 years of her illness but none in the past 14 years. Hilda has experienced prolonged remission of catatonia and of positive symptoms of psychosis, and she has minimal residual negative symptoms following treatment with a long-acting injectable antipsychotic medication. She has hypertension and diabetes but no substance use disorder comorbidity. For the past 5 years, Hilda has had full-time employment, bought a vehicle, has been in a romantic relationship, and lives independently. She is planning to pursue online coursework toward completion of a bachelor’s degree and feels satisfied with her life.

Would this scenario be the same if Hilda were Harry? In other words, do women with schizophrenia have more favorable disease courses and overall 

 Several studies have examined sex-outcome differences in patients with first-episode psychosis (FEP), with inconclusive results. However, no studies have specifically explored long-term differences in male vs female patients with FEP after being discharged from a psychosis early intervention service (EIS).

In general, it is believed that short- and long-term outcomes in schizophrenia may 

 To explore long-term sex differences in patients with FEP, Ayesa-Arriola and 

 looked at several outcomes (clinical, functional, cognition, and treatment), as well as sex differences in the maintenance of benefits of EIS treatment after patients were transferred to regular care.

Ayesa-Arriola et al obtained data from the First Episode Psychosis Clinical Program (Program of Attention and Intervention First-Episode Psychosis [PAFIP] and PAFIP-10) 

 which are incidence and 10-year follow-up studies of participants with FEP who presented to a local catchment area with an EIS service in Cantabria, Spain, after February 2001. Patients received 3 years of evidence-based, phase-specific early intervention for psychosis: low-dose antipsychotic medication, patient and family psychoeducation, and support for functional recovery. All participants had experienced their first episode of nonaffective psychosis as classified by DSM-IV; were aged between 15 and 60 years; lived in the catchment area; and had a total lifetime antipsychotic treatment of < 6 weeks. Individuals with drug or alcohol dependence, intellectual disability, or a history of neurological disease or head injury were excluded.

The same senior consultant psychiatrist interviewed patients at baseline and at follow-up intervals of 1, 3, and 10 years post baseline. Clinical symptoms were assessed using the Scales for the Assessment of Positive and Negative Symptoms (SAPS and SANS), the Brief Psychiatric Rating Scale, and the Calgary Depression Scale for Schizophrenia. Global functioning was measured using the Disability Assessment Scale. An assessment of global cognitive function was also performed. Recovery, defined as symptomatic remission and adequate psychosocial function at 1, 3, and 10 years following FEP, was determined based on SANS and SAPS scale scores. Data on relapses, mean antipsychotic daily doses, and extrapyramidal symptoms were also obtained. General linear models with repeated measures of analysis of covariance were conducted to test longitudinal outcomes of males vs females. Kaplan-Meier survival analysis was used to examine the relationship between relapse and time.

Baseline PAFIP measures were available for 379 patients (male, n = 179; female, n = 128). Of these, 297 were retested by in-person interview at 1 year post baseline; 259 at 3 years post baseline; and 209 between approximately 8 and 16 years post baseline (for 26 of the 209, interviews were completed by mail or telephone). Individuals who did not complete the study had significantly lower education, lived in urban areas, were unemployed, and used cannabis. There was a trend toward higher participation by women vs men in the 10-year reassessment.

When comparing baseline characteristics for those who completed the 10-year reassessment, females were significantly older at illness onset than males (mean age, 31 vs 27 years); had higher premorbid functioning, IQ, and education; and were more likely to be living independently of parents, be employed, and have a partner and children. Schizophrenia diagnosis and alcohol and cannabis use were more frequent among men (

Clinical, functional, neuropsychological, and antipsychotic treatment information over the 10-year follow-up period were available for 151 patients (male, n = 66; female, n = 85). Women showed greater improvements in negative symptoms than males. No sex differences were found in Disability Assessment Scale or Global Cognitive Functioning scores. Survival curves showed that most relapses occurred during the first 3 years of follow-up, with no significant differences between females and males. Symptomatic and functional recovery was significantly more likely in females at 1 year and 3 years, but not at 10 years (

). Women used significantly lower therapeutic antipsychotic dosages, but antipsychotic doses increased over time following discharge from EIS. Males and females did not significantly differ in the occurrence of extrapyramidal symptoms.

The authors concluded that better outcomes for women were found after 3 years of treatment at an EIS were underpinned by more favorable premorbid and baseline characteristics. After an average of 10 years of treatment, they found that outcomes for women and men converged, except for the course of negative symptoms. Dose size of antipsychotic medications increased in both sexes once patients were discharged from the EIS program and moved into community-based services.

No other published longitudinal studies have explored sex differences in long-term outcomes, which is a strength of this investigation. However, relative contributions of biological (eg, estrogen), psychosocial, and environmental factors on sex differences and their interplay were not explored, which is a limitation the authors noted.

Better outcomes seen among women during the first 3 years after FEP occurred in the context of more favorable premorbid and baseline characteristics. After an average of 10 years of follow-up, with the exception of negative symptoms, outcomes for women approximated those for men.

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

1. Wils RS, Gotfredsen DR, Hjorthøj C, et al. Antipsychotic medication and remission of psychotic symptoms 10 years after a first-episode psychosis. Schizophr Res. 2017;182:42-48.

2. Morgan C, Lappin J, Heslin M, et al. Reappraising the long-term course and outcome of psychotic disorders: the AESOP-10 study. Psychol Med. 2014;44(13):2713-2726.

3. Gotfredsen DR, Wils RS, Hjorthøj C, et al. Stability and development of psychotic symptoms and the use of antipsychotic medication – long-term follow-up. Psychol Med. 2017;47(12):2118-2129.

4. Ayesa-Arriola R, de la Foz VO-G, Setién-Suero E, et al. Understanding sex differences in long-term outcomes after a first episode of psychosis. NPJ Schizophrenia. 2020;6(1):33.

5. Longitudinal long-term study (10 years) of the sample of first episode of non-affective psychosis: PAFIP (10PAFIP). ClinicalTrials.gov. Updated December 16, 2020. Accessed February 4, 2021. https://clinicaltrials.gov/ct2/show/NCT02200588 ❒

Does Sex Make a Difference? Exploring Long-Term Outcomes After First-Episode Psychosis

VanMeter and Cichetti define resilience as “a dynamic developmental process that encompasses an individual’s capacity to adapt positively following significant adversity.”

 While some researchers have conceptualized resilience as 

 many clinicians and researchers view it as a multidimensional and transactional process unfolding across the lifespan. When considering resilience in individuals recovering from a first episode of psychosis (FEP), it is important to remember that this condition usually develops over an extended period of time and culminates in a psychotic disorder that may further languish for months or even years before proper treatment is procured. Even when effective treatment for FEP is obtained, it rarely eliminates all the symptoms and dysfunction. Individuals are still left struggling to cope with an often chronic and unpredictable illness and, while trying to make sense of their experiences, they must struggle to put their lives back together as best as they can. Therefore, understanding the nature of resilience in individuals with FEP is a uniquely complex undertaking.

Researchers have found that resilience in individuals with FEP is 

 While there is no single measure of resilience, certain findings can help clinicians better understand resilience in this population. First, resilience is associated with greater improvements in functioning for individuals with FEP as well as with multiple-episode psychosis.

 Furthermore, no strong evidence suggests that individuals with FEP are more or less resilient than those experiencing a more prolonged course of schizophrenia. Second, little evidence indicates that greater resilience is associated with less severe positive symptoms. Conversely, resilience does appear to be related to negative symptoms and mood difficulties, meaning that higher resilience is associated with lower negative symtpoms.

 This evidence suggests that targeting resilience could improve functioning. Similarly, it shows that improving mood and reducing negative symptoms could promote resilience. While pharmacological treatments target positive symptoms, treating negative symptoms requires interventions that address mood, negative emotions, and motivation.

Recovery from FEP can mean more than reduction of positive symptoms. It also offers an opportunity to cultivate resiliency. Early intervention programs such as NAVIGATE, which incorporate strengths-based and resilience-focused principles, are anchored by the view that recovery transcends the alleviation of symptoms and aims at the experience of positive emotions, satisfaction, and promotion of 

 A core intervention component of the NAVIGATE program is Individual Resiliency Training (IRT).

IRT is a module-based approach to treatment that specifically aspires to promote self-efficacy and self-determination, hope for the future, meaning in life, and personal well-being in the context of teaching information and 

 Modules within IRT—and the NAVIGATE model more broadly—foster resiliency in individuals with FEP by providing guidance and training in numerous areas: enhancing positive emotions; cultivating an internal locus of control through shared decision-making; increasing cognitive flexibility and adaptive coping skills; increasing a sense of meaning and purpose through motivational enhancement and collaboration with natural supports (eg, relationships within family, school, work, and community environments); and fostering growth through cultivating a framework for understanding and processing the psychotic episode.

Throughout IRT, modules help patients develop their own personal resiliency story. This narrative of cultivating resilience is woven across the standard and individualized modules and creates opportunities for individuals to identify their own resilient qualities, highlight past personal stories of resiliency, build resilience through enhancing personal strengths, and identify the good things that happen every day.

 Similarly, these modules foster growth and resiliency by helping the patient to process their psychotic experiences and learn positive coping strategies.

The concept of resiliency in IRT is based on the broaden-and-build theory, which posits that the experience of positive emotions broadens an individual’s awareness, increases their cognitive flexibility, facilitates adaptive coping strategies, counteracts negative emotions, and encourages novel and exploratory thoughts and actions. Together, this leads to increased resources and opportunities to 

 Based on positive psychology interventions, the skills and strategies learned in IRT emphasize a behavioral approach, which increases the experience of positive emotions and focuses on building gratitude, prolonging pleasure through savoring, enhancing positive relationships, increasing kindness, and improving well-being.

Integrating Resiliency Into Clinical Practice

The implications of incorporating resiliency strategies into treatment could be wide-reaching. Environments that foster self-determination may promote motivation, well-being, and overall growth in 

 We will discuss 3 opportunities to build resiliency and self-determination within clinical encounters: shared decision making, establishing and following up on goals, and incorporating strengths into treatment.

Shared decision making is critical to empowering individuals with mental illness to become knowledgeable and participate in managing their illness.

 In the NAVIGATE model, prescribers use shared decision-making to select medications based on 

 This approach promotes autonomy and supports resiliency by facilitating choice, hope, and collaboration.

 The shared decision-making process begins by including the individual in the treatment discussions. During the process, practitioners should encourage opportunities for individuals to express their concerns about treatment, learn and discuss treatment options, ensure that patients are happy with the treatment decision, and provide time to review the treatment decision.

By identifying goals and taking the necessary steps toward achieving these goals, positive behaviors are fostered and meaningful outcomes become possible. In fact, the achievement of personal goals is associated with increases in 

 Practitioners provide opportunities for patients to reengage in their lives and promote recovery by developing goals that are personally relevant and challenging, and that focus on proximal outcomes. Patients have greater opportunities for recovery when practitioners provide ongoing feedback on goals that is structured and timely.

 In addition, clinicians who ask about and support goal progress promote self-efficacy in their patients and increase their expectations for success.

 In early-intervention treatment, clinicians can ask patients to share their goals, ask about progress toward a goal, or problem-solve a challenge or obstacle. Role-playing can help patients practice for success and increase their motivation to pursue a goal.

One of the best ways to foster resiliency is by building on existing strengths. Character strengths are defined as positive trait-like capacities associated with thinking, feeling, and behaving in ways that benefit an individual and others

 These strengths are associated with fulfillment and the pursuit of happiness, and they are a key feature of 

 The Brief Strengths Test can be used to assess character strengths, and it has successfully been implemented in IRT sessions with individuals with FEP.

 Ascertaining patients’ strengths can help make their relapse prevention plan more potent, by assisting them in identifying coping skills as well as crafting response strategies for early warning signs or triggers. These strengths can also foster engagement in healthy lifestyle strategies.

For example, if among a patient’s strengths is their ability to see beauty in nature, a helpful coping strategy could be taking a walk outside and paying close attention to the living things in the natural world. Since many coping strategies associated with character strengths have been compiled, clinicians can readily share these with their 

Additionally, character strengths can present opportunities to address difficulties and challenges, such as medication adherence.

 For example, if a patient’s strength is hope, the clinician can discuss how to cultivate a positive attitude about long-term mental health and explain how taking medication will contribute to their overall well-being in the future.

“Leroy” is a man with schizophrenia, aged 24 years. He struggles with delusional beliefs that the government is watching him and spying on him. He also hears voices that tell him he is a bad person and will never succeed in life. He currently lives at home with his parents and is a part-time college student. He is engaged in treatment with a coordinated specialty care program for individuals with FEP that includes therapy, supported employment and education, and antipsychotic medications. Leroy’s parents also participate in family education.

Leroy is currently participating in IRT with a therapist, who has begun IRT’s Assessment and Goal Setting Module. When Leroy completed the Brief Strengths Test, he identified his top 5 strengths as creativity, spirituality, love of learning, appreciation of beauty, and gratitude. Afterward, Leroy became increasingly paranoid about cars driving past his house; he began spending more time alone in his room, and he reported that the voices became louder.

In IRT, the therapist worked with Leroy to develop some coping skills to decrease his distress and support his goal of completing college. The therapist noted that listening to music and talking to a supportive friend are helpful coping strategies, and suggested that Leroy use one or more of his identified strengths to pinpoint other possible strategies. Leroy had discussed his interest in creative writing and exploring different religious beliefs. Thus, in collaboration with the therapist, Leroy developed a plan to try writing every day to engage his creativity. Leroy also said that he was interested in writing poetry and short stories about his spiritual beliefs and practices, which would engage his strength of spirituality.

Simple but powerful strategies for drawing on patients’ existing character strengths and long-term goals. 

Schizophrenia/Psychosis

Is Epstein-Barr Virus to Blame for Cognition in Schizophrenia?

Positive End-Of-Phase 2 Meeting for Extended-Release Risperidone Capsule

Do Blood Clotting and Immune System Contribute to Psychosis?

The Rise in Synthetic Cannabinoids and Cathinones

Does Sex Make a Difference? Exploring Long-Term Outcomes After First-Episode Psychosis

Promoting Resiliency After First-Episode Psychosis

New Directions in Addressing Motivational Deficits in Schizophrenia and Depression

Varenicline and Tardive Dyskinesia in Schizophrenia

FDA Approves a New Atypical Antipsychotic With Less Adverse Effects

Dreaming of New Treatments