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Although the clinical symptoms of psychotic disorders are dramatic and are what most clinicians focus on as their treatment targets, impairments in a wide range of cognitive function are observed in these illnesses.

Common Neural Abnormalities in Psychotic Disorders

 in patients with schizophrenia that can adversely affect treatment response and functional outcomes.

 for significant pro-cognitive effects for antipsychotics and other pharmacologic approaches.

 Therefore, treatment of cognitive impairment in schizophrenia represents a tremendous area of unmet need.

Regarding non-pharmacological treatments, there has been significant research on the 

 on brain structure and functional performance.

 A meta-analysis found that aerobic exercise exerted a positive effect on global cognition and some cognitive domains, but not others, in patients with schizophrenia, but findings are limited by small samples, as well as variable types and intensity of exercise and study designs.

 performed a 12-week randomized controlled trial of the effects of aerobic walking on cognitive function in patients with schizophrenia, and whether the intensity of aerobic walking is associated with changes in cognition. Patients were randomized 1:1 based on age and sex to usual treatment with antipsychotics with or without aerobic walking. Inclusion criteria were aged 20 to 60 years, DSM-5 diagnosis of schizophrenia, stable antipsychotic dose for at least 1 month, Positive and Negative Syndrome Scale (PANSS) total score < 95, no history of major physical illness, and no physical disability that caused difficulty walking.

The program comprised 150 minutes/week of outdoor walking, typically divided over 3 to 5 sessions and each with a 5-minute warm-up, followed by a 5-minute cool-down. Transportation was provided to the exercise sessions if needed. Participants wore a Fitbit to monitor heart rate and exercise intensity. Research staff supervised each participant and provided guidance based on heart rate. The patients could rest if needed. Participants were stratified into high- and low-intensity groups based on the average in-session heart rate reserve. 

 was evaluated with the Brief Assessment of Cognition in Schizophrenia (BACS).

Data were analyzed using intention-to-treat and per-protocol analyses. Multivariate general linear model repeated measures were used to investigate the effects of time, group, and the time x group interaction on cognition, controlling for illness duration. The authors randomized 67 patients to treatment-as-usual (TAU, n = 34) or aerobic walking (n = 33) who completed the baseline assessment. Thirty-three patients in the TAU and 31 in the 

The mean age was 42 years; mean BMI was 27; mean PANSS total score was 79; and 42% were male. Importantly, at baseline, subjects in the aerobic walking group scored approximately 0.5 standard deviations lower on global cognition than the TAU group. The mean duration of aerobic walking was 129 minutes/week. Eleven patients achieved high-intensity walking and 22 maintained low-intensity. In the entire intent-to-treat sample, the authors found a trend for a group effect for greater improvement in verbal fluency in the aerobic walking group. They also found a significant group effect on attention and processing speed in high- versus low-intensity aerobic walking.

The authors stated that theirs was the first trial of the effects of 

 intensity on cognitive function in schizophrenia. The majority (> 90%) of patients completed the trial, with a mean of 3 days of exercise per week, suggesting that this intervention is feasible and acceptable to patients, and that supervision and transportation are associated with retention. Study limitations include the modest sample size (especially the high-intensity group) and relatively short study duration, as well as the inability for blinding to the intervention.

“Mrs M” is a 48-year-old Black woman with a history of chronic schizophrenia. During hospitalization for an episode of illness exacerbation, her antipsychotic medication was changed. Over the next 4 months, she gained approximately 50 lb. Mrs M declined to lower the dose of her antipsychotic or change medications because of her clinical improvement and worry about risk of another illness relapse. However, she was receptive to the recommendation for increased physical activity for weight loss. Mrs M started walking with a neighbor friend for about 30 minutes at a moderate pace at least 3 times per week. Over the next year, she lost 36 pounds. Although there were no clinically appreciable changes in her cognitive function, she reported “feeling better” as a result of her exercise regimen.

A supervised aerobic walking program involving moderate-intensity exercise is feasible and acceptable in patients with schizophrenia. Higher intensity aerobic exercise may have modest pro-cognitive effects in these patients.

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, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.

1. Hoe M, Nakagami E, Green MF, Brekke JS. 

The causal relationships between neurocognition, social cognition and functional outcome over time in schizophrenia: a latent difference score approach.

Pharmacological cognitive enhancement in schizophrenia

The magic of movement; the potential of exercise to improve cognition

4. Firth J, Stubbs B, Rosenbaum S, et al. Aerobic exercise improves cognitive functioning in people with schizophrenia: a systematic review and meta-analysis. 

Effects of aerobic walking on cognitive function in patients with schizophrenia: a randomized controlled trial

Schizophrenia is associated with cognitive impairment, and treatment of cognitive dysfunction in these patients represents an area of unmet need. What is the role of exercise?

Exercise and Cognition in Schizophrenia: Is There a Link?

Leslie Citrome, MD, MPH, talks about asenapine, or SECUDADO, the first-and-only transdermal patch formulation for the treatment of adults with schizophrenia approved by the U.S. Food and Drug Administration.

Read more about the asenapine transdermal system 

. Alternatively, visit the product website 

is Clinical Professor of Psychiatry and Behavioral Sciences at New York Medical College.

The first-and-only transdermal patch for adults with schizophrenia offers a new treatment. 

The Asenapine Transdermal System

In an award-winning study, researchers from The University of Texas Health Science Center at Houston (UTHealth) discovered a gene signaling pathway linked to a higher risk for developing schizophrenia by observing human-induced pluripotent stem cells created from blood samples of a single family. The pathway, phosphoinositide 3-kinase/glycogen synthase kinase 3 (PI3K/GSK3), contains differentially expressed genes, including serum-glucocorticoid kinase 1 (SGK1). This is an inhibitor of GSK3 beta and has been associated with schizophrenia.

“We believe this has direct implications for the treatment of patients,” senior author Consuelo Walss-Bass, PhD, MD, said to the press. “There is a new antipsychotic that just received approval from the Food and Drug Administration that directly targets the pathway we identified as dysregulated in neurons from the patients, and several other antipsychotics also target this pathway. This could help pinpoint who may respond better to treatments.”

Walss-Bass, the first author, and postdoctoral research fellow Laura Stertz, PhD, took blood samples from members of a large Costa Rican family with multiple individuals with schizophrenia. The blood cells were changed into stem cells using human-induced pluripotent stem cell (hiPSC) technology. These cells were then redirected to become brain neurons. This allowed them to be studied in a virtual biopsy and compared to neurons from family members who did not have schizophrenia.

In the biopsies, researchers saw 5 schizophrenia candidate genes previously identified by genome association studies. Alterations caused by gene SGK1, which inhibits GSK3 activity, are linked to whether a person has a higher risk of schizophrenia.

Walss-Bass had this to say on the discovery: “Mental health research has lagged behind because we don't know what is happening biologically. We are diagnosing people based on what they are telling us. Even postmortem, the brain tissue in mental health disorders looks perfectly fine. In Alzheimer disease, you can see a difference compared to controls. But not in psychiatric disorders. Now by studying virtual brain biopsies, we can tell what is happening biologically.”

Walss-Bass also said that identifying patients with specific biological pathway markers could identify them as the best candidates for medications. This pre-emptive, personal pharmacology may be what is needed to best treat psychiatric disorders.

“We were able to find significant, meaningful differences with a small control group,” Walss-Bass said. “Neurons of patients with schizophrenia had alterations in the signaling pathway. This research may help to understand how or why some antipsychotics targeting GSK3 work and also to develop other target-specific medications.”

1. Stertz L, Di Re J, Pei G, Fries G, et al. Convergent genomic and pharmacological evidence of PI3K/GSK3 signaling alterations in neurons from schizophrenia patients. 

2. University of Texas Health Science Center at Houston. Gene pathway linked to schizophrenia identified through stem cell engineering. News release. 

https://www.sciencedaily.com/releases/2020/12/201221134136.htm

Researchers have discovered a gene signaling pathway associated with a higher risk for developing schizophrenia. 

Gene Pathway Linked to Development of Schizophrenia

Synthetic cannabinoids and cathinones are novel psychoactive substances (NPS) that have surreptitiously emerged on the market to mimic the effects of 

 These designer substances are gaining popularity due to their widespread availability and safety misperceptions. Temporal trend epidemiological data analyzed by the Centers for Disease Control indicate that acute poisonings related to synthetic cannabinoids and cathinones are increasing in the 

The rise in synthetic cathinone and cannabinoid use among patients susceptible to adverse neuropsychiatric reactions has been linked to a wide range of unpredictable effects, including 

 Emergency department (ED) psychiatrists are on the frontlines of care, and must provide the initial management and stabilization of the complex and challenging toxic effects of these drugs. Prompt recognition and management is essential to reduce morbidity and mortality.

, these designer synthetic cannabinoid receptor agonists have potent intrinsic activity at the cannabinoid (CB) 1 and 2 

 The compounds were originally developed to study the endocannabinoid system, but they emerged as 

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

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

 As a consequence, there is no specific toxidrome 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. Moreover, patients may additionally present with marijuana intoxication symptoms (ataxia, delayed reaction time, and 

conjunctival injection). Laboratory studies are indicated in cases of severe intoxication with agitation or seizures due to the resulting life-threatening metabolic derangements.

Rates of synthetic cannabinoid use are increasing in the United States, with the lifetime prevalence estimated to be between 0.2% and 4%.

 Moreover, between January 2016 and September 2019, ED visits related to synthetic cannabinoid toxicity significantly increased in the country’s Midwestern and Northeastern regions.

 Overall, synthetic cannabinoids harms are increasing, and psychiatrists need to be cognizant about the clinical presentations and evidence based treatments. 

, these agents are synthetic psychostimulants structurally related to cathinone, a monoamine alkaloid found in the Khat plant. As substituted phenethylamines, synthetic cathinones are structurally and pharmacologically similar to amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). These agents are commonly abused for their euphoric, empathogenic, and stimulating effects. The most commonly abused synthetic cathinones are 4-methylmethcathinone (mephedrone), 3,4-methylenedioxy-N-methylcathinone (methylone), and 4-methylenedioxypyrovalerone (MDPV).

 Synthetic cathinones produce major effects on the Central Nervous System (CNS), and are linked to adverse neuropsychiatric complications (

). Synthetic cathinones 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 (perceptual distortions, depersonalization, synesthesia) can be highly distressing, which often prompts 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.

Self-reported prevalence of synthetic cathinone use is an estimated 0.05%. Current estimates are imprecise, however, as established surveys and standard immunoassay testing are not sensitive for detecting cathinones.

 The most recent data from the Drug Abuse Warning Network report indicates 22,904 ED visits were related to synthetic cathinone toxicity in 2014. The frequency of ED utilization is likely increasing, as synthetic cathinones are steadily becoming more popular despite the potential harms.

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 oftentimes adulterated with other illicit drugs such as MDMA.

 Although there is no specific toxidrome, patients will typically present with signs and symptoms of adrenergic neurohumoral activation.

 The neurotoxic symptoms (including aggression, confusion, and psychosis) may overlap with a primary mental illness, and psychiatrists must rely on the clinical history and physical exam findings to accurately diagnose toxicity. Urine immunoassay testing is the most common method to screen for substance use. In the setting of acute intoxication, however, urine immunoassay testing has a low positive predictive value for synthetic cannabinoids and cathinones.

 While gas chromatography/mass spectrometry (GC/MS) is considered the gold standard for detecting substances, the molecular geometry of synthetic cannabinoids and cathinones is everchanging, making it increasingly difficult to directly identify these compounds.

 Moreover, GC/MS is not readily available in all emergency hospitals, and the results may not return in a timely manner to aid in the diagnosis process. An atypical onset of psychosis and agitation alongside hyper-sympathetic activation and a mixed toxidrome is strongly suggestive of intoxication.

Because of the variability in clinical presentations and lack of diagnostic testing, 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, but rather 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 sympathomimetic neural stimulation (including hypertension, agitation, and seizures).

Agitation is the most common neuropsychiatric complication associated with synthetic cannabinoid and cathinone ingestion. Katz and colleagues reported that 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-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-severe agitation (BARS score > 6), benzodiazepines remain the first line treatment for reducing moderate to severe agitation.

 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 administering antipsychotics in acute poisonings settings must be carefully considered. Specifically, antipsychotics: 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 subset of patients will develop excited delirium following ingestion of psychostimulants. 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: a minimum of 6 out 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 cardio-respiratory 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 standard of care is to administer benzodiazepines and antipsychotics to decrease psychomotor agitation. In the emergency setting, IM ketamine (4-5 mg/kg) is increasingly used for sedation of agitated patients with excited delirium. Initial studies in the pre-hospital 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 (emergency department) is a safe and effective treatment for excited delirium while not significantly affecting the cardiopulmonary system.

 Mankowitz and colleagues reported that more patients required intubation after ketamine administration in the pre-hospital setting (30%) compared to the hospital setting (1.8%).

 Prospective studies conducted in the emergency department have demonstrated that there is no significant difference in incidence of complications between IM ketamine and IM haloperidol.

 The side effects of single doses of IM ketamine for agitation are generally transient and self-limiting: 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 administration of ketamine 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, leading to renal failure, electrolyte abnormalities, and arrhythmias.

Synthetic cannabinoids have been linked to psychotic reactions, such as paranoia, catatonia, dissociation, 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 pro-psychotic effects, potentially triggering a psychotic state in vulnerable groups of 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 in stimulant psychosis, 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 side effect profiles. Among the first-generation antipsychotics, the butyrophenone neuroleptics IM haloperidol and IM droperidol are reasonable pharmacotherapeutic options.

 In comparison to IM haloperidol, IM droperidol has a faster onset of action, rapidly preventing and treating emergent psychotic agitation within 5 to 10 minutes of intramuscular administration.

 Some expert panels have recommended avoiding butyrophenone neuroleptics in cases of substance-induced psychosis due to the pro-convulsant properties, cardiotoxic effects, and extrapyramidal symptoms. Among the second-generation antipsychotics, p.o. olanzapine has a track record of treating NPS-induced psychosis, and pro-drug websites have touted olanzapine as the ideal medication to terminate so-called “bad trips.”

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

 epidemiological studies do not support a correlation between ziprasidone and torsade 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 antipsychotic naïve patients, 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 a underlying primary psychotic illness.

Synthetic cannabinoid and cathinone harms are increasing, and psychiatrists need to be cognizant of the clinical presentations and evidence-based treatments. Synthetic cannabinoids and cathinones have pro-psychotic and agitative effects, and the toxic reactions can mimic a primary mental illness. There is no definitive diagnostic test to differentiate primary versus secondary drug induced mental illness, and ED psychiatrists must rely on the history and physical examination. In a subset of cases, the overstimulation of catecholamines may result in an excited delirium. Benzodiazepines are considered the first line treatment to reduce the sympathomimetic neural stimulation.

is anassistant professor of Medical Education and Psychiatry at California University of Sciences and Medicine, Arrowhead Regional Medical Center in San Bernardino, CA. 

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

1. Dignam G, Bigham C. Novel psychoactive substances: a practical approach to dealing with toxicity from legal highs. 

2. Riederer AM, Campleman SL, Carlson RG, et al. Acute poisonings from synthetic cannabinoids - 50 U.S. toxicology investigators consortium registry sites, 2010-2015. 

3. Cohen K, Weinstein AM. Synthetic and non-synthetic cannabinoid drugs and their adverse effects-a review from public health prospective. 

4. Tai S, Fantegrossi WE. Pharmacological and toxicological effects of synthetic cannabinoids and their metabolites. 

5. Wiley JL, Marusich JA, Huffman JW, et al. Hijacking of basic research: the case of synthetic cannabinoids. 

6. Castaneto MS, Gorelick DA, Desrosiers NA, et al. Synthetic cannabinoids: epidemiology, pharmacodynamics, and clinical implications. 

7. Zuba D, Byrska B. Prevalence and co-existence of active components of ‘legal highs.’ 

9. Loeffler G, Delaney E, Hann M. International trends in spice use: prevalence, motivation for use, relationship to other substances, and perception of use and safety for synthetic cannabinoids. 

10. Roehler DR, Hoots BE, Vivolo-Kantor AM. Regional trends in suspected synthetic cannabinoid exposure from January 2016 to September 2019 in the United States. 

11. Weinstein AM, Rosca P, Fattore L, London ED. Synthetic cathinone and cannabinoid designer drugs pose a major risk for public health. 

12. Baumann MH, Walters HM, Niello M, Sitte HH. Neuropharmacology of synthetic cathinones. 

13. Palamar JJ, Martins SS, Su MK, Ompad DC. Self-reported use of novel psychoactive substances in a US nationally representative survey: prevalence, correlates, and a call for new survey methods to prevent underreporting. 

14. The DAWN Report. “Bath salts” were involved in over 20,000 drug-related emergency department visits in 2011. Substance Abuse and Mental Health Services Administration. 2013. Accessed November 30, 2020. https://www.samhsa.gov/data/sites/default/files/spot117-bath-salts-2013/spot117-bath-salts-2013.pdf

15. Oliver CF, Palamar JJ, Salomone A, et al. Synthetic cathinone adulteration of illegal drugs. 

16. Arntson A, Ofsa B, Lancaster D, et al. Validation of a novel immunoassay for the detection of synthetic cannabinoids and metabolites in urine specimens. 

17. Moeller KE, Kissack JC, Atayee RS, Lee KC. Clinical interpretation of urine drug tests: what clinicians need to know about urine drug screens. 

18. 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. 

19. Katz KD, Leonetti AL, Bailey BC, et al. Case series of synthetic cannabinoid intoxication from one toxicology center. 

20. 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. 

21. Hui D. Benzodiazepines for agitation in patients with delirium: selecting the right patient, right time, and right indication. 

22. 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. 

23. Gonin P, Beysard N, Yersin B, Carron PN. Excited delirium: a systematic review. 

24. Li M, Martinelli AN, Oliver WD, Wilkerson RG. Evaluation of ketamine for excited delirium syndrome in the adult emergency department. 

25. 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. 

26. 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. 

27. 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. 

28. Lebin JA, Akhavan AR, Hippe DS, et al. Psychiatric outcomes of patients with severe agitation following administration of prehospital ketamine. 

29. Annas GJ. The last resort--the use of physical restraints in medical emergencies. 

30. Hurst D, Loeffler G, McLay R. Psychosis associated with synthetic cannabinoid agonists: a case series. 

31. 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. 

32. Murrie B, Lappin J, Large M, Sara G. Transition of substance-induced, brief, and atypical psychoses to schizophrenia: a systematic review and meta-analysis. 

33. 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. 

34. Vallersnes OM, Dines AM, Wood DM, et al. Psychosis associated with acute recreational drug toxicity: a European case series. 

35. Calver L, Drinkwater V, Gupta R, et al. Droperidol v. haloperidol for sedation of aggressive behavior in acute mental health: randomized controlled trial. 

36. Thomas H, Schwartz E, Petrilli R. Droperidol versus haloperidol for chemical restraint of agitated and combative patients. 

37. Valeriani G, Corazza O, Bersani FS, 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. 

 Be on the lookout for these novel psychoactive substances. 

Assessing and Addressing Synthetic Cannabinoids and Cathinones in Neuropsychiatric Toxicological Emergencies 

A Polish study seeking to understand the potential association between lifestyle choices and schizophrenia observed a significant relationship between reported habits and severity of schizophrenia symptoms. According to researchers, patients with schizophrenia who eat poorly, have insufficient physical activity, and use nicotine are at increased risk for lifestyle diseases, such as hypertension, obesity, and type 2 diabetes.

From 2011 to 2016, the study enrolled 106 participants with schizophrenia, 42 male and 64 female, aged 18 to 69 years. Many of these patients were recruited from inpatient and outpatient psychiatric facilities and wards at the Department of Psychiatry of the Pomeranian Medical University in Szczecin (Poland). Patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), and completed a survey that gathered additional information, like their illness duration, selected eating habits, sweet beverage consumption, nicotine use, and physical activity in the last 3 months.

Increased physical activity was correlated with a reduced total PANSS score, improved negative and general symptomatology, and improvement of the lipid profile and blood glucose levels. Participants’ physical activity was gauged using a 3-point scale: 1 for low physical activity (sedentary), 2 for moderate activity (physical for daily routines), and 3 for intense activity (physical activity at least 3 times per week for more than 30 minutes). The study did not seek to cause any lifestyle-changing interventions, and patients did not receive lifestyle education at any time during the study’s duration. However, patients were allowed to view their laboratory test results and were free to consult a general practitioner or psychiatrist.

Significant adverse effects of smoking on metabolic parameters were observed, particularly on the lipid profile values; however, there is also evidence that smokers had significantly lower PANSS scores within the 

. This may be related to the relationship between smoking and the use of antipsychotics.

Researchers also noted an interesting development; while lifestyle education was not offered, many patients changed their behavior after completing the questionnaires. Positive change was noted in the number of cigarettes smoked per day, consumed coffee and sodas, and especially intake of sugar and sweets. Male participants especially were observed to consume significantly higher amounts of sweets and sweet beverages than their female counterparts, but many cut back on sweets and sodas after their follow-up.

There are clear benefits to providing educational interventions on physical activity and proper eating habits to patients with schizophrenia, especially since, “physical activity and exercise are now recognized as fundamental tools for reducing the impact of chronic diseases…”

 Both mental and physical outcomes could be improved for these patients.

Negative Symptoms in Schizophrenia: Etiology, Hypotheses, and Treatment Implications.

1. Kalinowska S, Trześniowska-Drukała B, Kloda K, Safranow K, et al. The association between lifestyle choices and schizophrenia symptoms. 

2. Belvederi Murri M, Ekkekakis P. Can exercise decrease mortality risk in patients with depression? 

Improving physical activity levels and eating habits could help patients with schizophrenia.  

Risk of Lifestyle Diseases for Patients with Schizophrenia

Decades of research have investigated inflammation and mental illness, suggesting that there is a robust and complex link. However, the link lacks diagnostic specificity and varies considerably among individuals, and with each stage of illness. Chronic, low-grade 

appears to precede the initial illness episode, at least in some individuals.

 Drugs that modulate the immune system may also affect an individual’s mood and have possible psychiatric adverse effects (AEs). Perhaps the best example is that interferon-α treatment of hepatitis C precipitates depressive episodes.

 is associated with reduction in inflammatory markers.

Statins are best known as competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Statin treatment results in lower low-density lipoprotein cholesterol levels and in benefits to cardiovascular health. Statins also have anti-inflammatory mechanisms of action, including T-cell downregulation, suppression of cytokines, production of chemokines and C-reactive protein, and downregulation of transcription factors.3 In a post hoc, pooled analysis (N = 969) of data collected at baseline and at a 1-year follow-up from a study of patients with acute coronary syndrome, statin treatment was shown to reduce levels of interleukin (IL)-6 and IL-18. Raised levels of these cytokines appeared to predict depression after acute coronary syndrome.

Many epidemiological studies have shown that 

 is associated with a lower risk for depression (

 A population cohort study (N = 4,607,990) using Swedish national registry data investigated the relationship between statin use and the development of depression. The use of any statin was associated with an 8% decrease in risk for depression (odds ratio [OR], 0.92) compared with individuals who did not use statins.

 Elsewhere, in a cohort of individuals 55 years and older (N = 2804), statin use was associated with decreased depression (OR, 0.71).

 However, no association between statin use and depression was determined in an analysis of data from 19,114 individuals, most of whom were 70 years and older, of whom 5987 used statins.

Evidence from clinical trials suggests that, adjuvant to treatment with antidepressants, some statins are associated with better treatment outcomes. A 

 showed that treatment with lovastatin, atorvastatin, and simvastatin, adjunctive to antidepressant treatment, was superior to treatment with a placebo adjunctive to antidepressant treatment for improving depression (indexed by the Hamilton Depression Rating Scale).

 More recently, the results of a trial of rosuvastatin for young individuals with depression indicated that rosuvastatin failed to beat the placebo on the primary outcome, but it was positive on a number of secondary outcome measures, leaving the benefit uncertain.

A trial comparing simvastatin (n = 33) with placebo (n = 33) in participants with schizophrenia treated with risperidone found significantly higher reduction in the first group in negative symptom scores (P = .003) and total score (P = .001). These results measured the time period from baseline to week 8, using the Positive and Negative Syndrome Scale (PANSS).

 Simvastatin did not significantly differ from placebo for treating schizophrenia in an underpowered study (N = 36).

Two meta-analyses of statin add-on therapy in the antipsychotic treatment of schizophrenia have been conducted. 

 identified 5 randomized controlled trials (N = 236) showing improvement of PANSS total score, but not of PANSS subscale scores.

 The meta-analysis included studies of atorvastatin, lovastatin, pravastatin, and simvastatin. Risperidone was used in 3 studies; antipsychotic use was varied or not reported for 2 studies. 

 identified 6 randomized controlled trials (N = 339) showing benefit for improvement of PANSS positive and negative subscales.

 The meta-analysis by Shen et al included all 5 trials from the Nomura et al meta-analysis plus an additional trial of simvastatin versus placebo.

 have been associated with an increased risk for cardiovascular disease (CVD), independent of psychotropic medication use. This comorbidity is bidirectional, since depression is a common outcome after myocardial infarction and is also associated with higher comorbidity and mortality.

 In this context, treatment with statins may have an important dual purpose, with benefits to both mental and cardiovascular health. Evidence from a nested case-control study has shown that exposure to statins and aspirin is associated with a reduced risk of de novo major depression.

Atorvastatin, lovastatin, and simvastatin are lipophilic, while pravastatin, rosuvastatin, pitavastatin, and fluvastatin are hydrophilic. The lipophilic statins readily cross the blood-brain barrier. Hydrophilic statins or their active metabolites may also be detected in the brain, although less readily. Laboratory studies have suggested that statins may be neuroprotective against a range of neurotoxic insults, but statins themselves may be neurotoxic at higher concentrations than those obtained at therapeutic doses.

The best evidence that statins reduce markers of inflammation is derived from the JUPITER study of rosuvastatin.

 It is unclear whether brain penetrance or reduction in peripheral markers of inflammation is the more important mechanism in terms of potential therapeutic efficacy.

There is a potential for drug-drug interactions between statins and psychotropic agents (

). Psychotropic agents with lower cytochrome P450 (CYP450)activity should be considered ahead of those with known strong CYP450 activity to reduce the risk of pharmacokinetic drug-drug interactions.

 Andrade suggests that risks of pharmacokinetic drug-drug interactions between selective serotonin reuptake inhibitors (SSRIs) and statins are negligible at standard therapeutic doses for escitalopram, citalopram, and paroxetine with rosuvastatin, pitavastatin, and pravastatin; there is possible but low risk of interactions for combinations of fluvoxamine with atorvastatin, simvastatin, or lovastatin.

 A study of blood specimens collected from elderly patients (N = 194) investigated the interactions between statins and antiepileptic drugs, including the mood stabilizers lamotrigine and carbamazepine. Carbamazepine, but not lamotrigine, significantly interfered with 

, with lipids reduced for patients taking either drug but significantly greater reduction in lipids for those taking 

 Risks of adverse events may be greater in elderly cohorts compared to nonelderly individuals.

Antipsychotics may upregulate gene expression of lipid metabolism pathways, resulting in metabolic side effects, weight gain, and dyslipidemia. Individuals receiving antipsychotics may have reduced response to treatment with statins for dyslipidemia, with a common gene variant (SREBF1) for a transcription factor in the lipid metabolism pathway.

 Dyslipidemia in individuals treated with antipsychotics may benefit from personalised treatment plans, in which statins may have an important but variable role.

In the clinical setting, medication changes, dose adjustments, and polypharmacy are common in psychiatric practice and are associated with a greater risk of adverse effects. Adding a statin to an existing regimen entails an additional risk that needs to be considered when the statin is first introduced and whenever there are changes to comedications throughout the course of treatment. Case reports on statins and psychotropic comedications have identified rare adverse events of rash,25 QTc interval prolongation,

Preliminary evidence, mainly from small studies, suggests that adjuvant treatment with a statin may be beneficial for individuals taking psychotropic drugs for depression and schizophrenia. People with depression, bipolar disorder, and schizophrenia are substantially more vulnerable to metabolic syndrome and earlier age of mortality than the general population, predominantly from CVD. Such medical comorbidities warrant aggressive prophylactic therapy with available agents, including statins. Thus, there is sufficient evidence to suggest that combining statin therapy with antidepressant or antipsychotic therapy may be sensible for patients with comorbidities when both pharmacotherapies are indicated. However, adjuvant treatment with a statin purely as an augmentation strategy for psychopharmacotherapy is still experimental. Although there is a good theoretical basis and promising preliminary data, further research is required, especially larger, multisite, placebo-controlled randomized clinical trials.

 is a principal fellow in the Department of Psychiatry, University of Melbourne, a clinical associate professor at the Centre for Youth Mental Health, University of Melbourne, and a clinical associate professor in the School of Medicine, Deakin University, Melbourne, Australia. D

is a psychiatrist in the Hospital Clinic de Barcelona in Spain and a researcher at IMPACT, Univer-sity Hospital Geelong, Australia. 

is the Alfred Deakin Professor of Psychiatry and director of IMPACT, the Institute for Mental and Physical Health and Clinical Translation, Deakin University, Melbourne, Australia.

Inflammation and depression: a causal or coincidental link to the pathophysiology?

2. Qato DM, Ozenberger K, Olfson M. Prevalence of prescription medications with depression as a potential adverse effect among adults in the United States. 

3. Kim SW, Kang HJ, Jhon M, et al. Statins and inflammation: new therapeutic opportunities in psychiatry. 

4. Kim SW, Kang HJ, Bae KY, et al. Interactions between pro-inflammatory cytokines and statins on depression in patients with acute coronary syndrome. 

Prog Neuropsychopharmacol Biol Psychiatry. 

5. Köhler O, Benros ME, Nordentoft M, et al. 

Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials

6. Redlich C, Berk M, Williams LJ, . Statin use and risk of depression: a Swedish national cohort study. 

Preliminary studies suggest that adjuvant treatment with a statin may be beneficial for patients who are also prescribed psychotropic drugs for depression and schizophrenia.

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