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 covered a wide variety of psychiatric issues and industry updates, from important suicide prevention tips to new insights into ketamine response. Here are some highlights from the week.

Study Explores Effects of Experimenter Sex on Ketamine Response

Does a health care provider’s sex impact how well active agents perform? The answer appears to be a “yes,” according to a new study that examined the antidepressant response to ketamine and its bioactive metabolite (

)-hydroxynorketamine when the drug was administered to mice by men compared to women. 

Suicide Prevention Month Tips and Insights

September is National Suicide Prevention Month. In this Mental Health Minute, Susan J. Noonan, MD, MPH, of McLean Hospital and Massachusetts General Hospital shares the risk factors and warning signs of suicide that clinicians must know. 

A traumatic brain injury (TBI) occurs when brain function is altered due to an external blow to the head or body. National surveillance data indicates there are approximately 3 million new cases of TBI each year in the United States, and that the incidence of TBI has been increasing since 1995. Rates of TBI are increasing in all age groups, but particularly for adults over the age of 65, primarily due to falls. According to some estimates, mild traumatic brain injury (mTBI), or concussion, accounts for as many as 75% to 90% of all traumatic brain injuries. 

NDA for Long-Acting Injectable for Schizophrenia and Bipolar I Accepted

The US Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for aripiprazole 2-month, ready-to-use, long-acting injectable, a medication administered for the treatment of schizophrenia in adults and for maintenance monotherapy treatment of bipolar I disorder in adults. It is intended for dosing every 2 months via intramuscular injection in the gluteal muscle. 

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Do you have a comment on any of these or other articles? Have a good idea for an article and want to write? Interested in sharing your perspectives? Write to us at 

From ketamine response to differences between mTBI and concussion, here are highlights from the week in Psychiatric Times.

The Week in Review: September 12-16

“Ms James” is a 23-year-old African-American female with a 5-year history of schizophrenia. She is currently stable on a second-generation antipsychotic medication, with no hospitalizations in the past 4 years. Her BMI is normal. She does not smoke, drink alcohol, or use illicit drugs. She sees her outpatient psychiatrist every 3 months. Two months after her last appointment, she calls the clinic because she is 9 weeks pregnant. She asks whether it is safe for the baby to continue her current second-generation antipsychotic medication. She also informs the nurse that when she briefly stopped this medication in the past, she experienced an increase in paranoia as well as suicidal ideation. As her psychiatrist, how would you advise and manage this patient?

Untreated perinatal psychotic disorders can have a range of serious adverse effects on the physical and mental health of women and their children.

 Untreated or inadequately treated maternal psychosis is also a risk factor for maternal suicide.

 There is evidence for increased use of second-generation antipsychotics (SGAs) during pregnancy.

 The association between maternal SCA exposure and risk of congenital malformations is unclear, with both negative

 studies. No previous studies have investigated this association in Asian patients.

 investigated the association between first-trimester antipsychotic exposure and major congenital malformations in Japan. The authors studied pregnant women who had accessed the Japan Drug Information Institute in Pregnancy between October 2005 and December 2016 and consented to a pregnancy outcome survey (prepaid mailer) 1 month after the expected date of delivery. They included only women with singleton pregnancies; women with multifetal pregnancies were excluded.

Background demographic and clinical characteristics were obtained. Women self-reported medical diagnoses. Timing of SGA exposure was based on the last menstrual period (estimated from gestational age at delivery and the survey date). The SGA group consisted of women with exposure to at least 1 SGA during the first trimester. The comparison group consisted of women with no exposure to any known teratogens. Women with SGA use before pregnancy or during the second or third trimesters were excluded.

The primary study outcomes were live birth rate and the rate of major congenital malformations. Elective abortions were a secondary outcome. Malformations were diagnosed by pediatricians during the 1-month medical examination and recorded in maternal and child health handbooks, which are given to all pregnant women in Japan. Data were analyzed using logistic regression, and adjustment for potential confounders by inverse probability weighting.

During the study period, 7249 women were enrolled, of whom 593 had first-trimester SGA exposure; 520 (885) of these women and 5139 (90%) of control women consented to the pregnancy outcome survey, which was completed by 404 (78%) in the SGA group and 4328 (84%) in the control group. The most common SGAs were aripiprazole (n=147), quetiapine (n=91), olanzapine (n=83), and risperidone (n=71). The SGA group had a higher percentage of primiparas, preconception BMI, maternal diabetes (3% vs 1%), and smoking (24% vs 14%). After becoming aware of pregnancy, more women in the SGA group continued to smoke (10% vs 4%). The prevalence of illicit drug use was <0.25% in both groups. The prevalence of occupational exposures to radiation or organic solvents was <1.3% in both groups.

The live birth rate was 87% in the SGA group and 90% in the control group. Major congenital malformation occurred in 0.9% of live births (3/351) in the SGA group and 1.8% (70/3899) in the control group, which was not statistically significant. The malformations in the SGA group were right hydronephrosis, complex malformation, spina bifida, and hydrocephalus. Six children in the SGA group had minor congenital malformations (hemangioma, patent foramen ovale, inguinal hernia [2], hydrocele, and hypertrophic pyloric stenosis). The elective abortion rate was non-significantly higher in the SGA group (4% vs 2%).

The authors concluded that SGA exposure during the first trimester was not associated with increased risk of major congenital malformations in Japan. Study strengths include that this was the first Japanese observational cohort study of this association, and findings were consistent with studies from several other countries. Limitations included the absence of data on maternal diagnosis or illness severity and the lower rate of survey completion in the SGA group (which could lead to an underestimation of risk), and the higher prevalence of elective abortions in the SGA group (potentially due to malformations).

This study did not find evidence for an association between first-trimester SGA exposure and risk of major congenital malformations. Findings provide some reassurance for pregnant women who require these medications.

is a professor in the Department of Psychiatry and Health Behavior at 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, and the Stanley Medical Research Institute.

1. Jones I, Chandra PS, Dazzan P, Howard LM. 

Bipolar disorder, affective psychosis, and schizophrenia in pregnancy and the post-partum period

2. Orsolini L, Valchera A, Vecchiotti R, et al. 

Suicide during perinatal period: epidemiology, risk factors, and clinical correlates

3. Reutfors J, Cesta CE, Cohen JM, et al. 

Antipsychotic drug use in pregnancy: a multinational study from ten countries

4. Viguera AC, Freeman MP, Góez-Mogollón L, et al. 

Reproductive safety of second-generation antipsychotics: updated data from the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics

 [published correction appears in J Clin Psychiatry. 2021 Oct 5;5(82):]. 

5. Huybrechts KF, Hernández-Díaz S, Patorno E, et al. 

Antipsychotic use in pregnancy and the risk for congenital malformations

6. McKenna K, Koren G, Tetelbaum M, et al. 

Pregnancy outcome of women using atypical antipsychotic drugs: a prospective comparative study

7. Habermann F, Fritzsche J, Fuhlbrück F, et al. 

Atypical antipsychotic drugs and pregnancy outcome: a prospective, cohort study

8. Kulkarni J, Worsley R, Gilbert H, et al. 

A prospective cohort study of antipsychotic medications in pregnancy: the first 147 pregnancies and 100 one year old babies

9. Yakuwa N, Takahashi K, Anzai T, et al. 

Pregnancy outcomes with exposure to second-generation antipsychotics during the first trimester

Will it hurt my baby? Researchers investigated associations between first trimester exposure to second-generation antipsychotics and major congenital malformations.

First Trimester Antipsychotic Exposure and Pregnancy Outcomes

The US Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for aripiprazole 2-month, ready-to-use, long-acting injectable, a medication administered for the treatment of schizophrenia in adults and for maintenance monotherapy treatment of bipolar I disorder in adults. It is intended for dosing every 2 months via intramuscular injection in the gluteal muscle.

If approved, it would be the first 2-month LAI antipsychotic indicated for both the treatment of schizophrenia and the maintenance treatment of bipolar I disorder in the United States.

“This is an important milestone in our efforts to offer adult patients with schizophrenia or bipolar I disorder a new option designed to support treatment goals and offer greater flexibility. The trial results reinforce the long-standing efficacy and safety profile of the once-monthly aripiprazole long-acting injectable,” said Johan Luthman, executive vice president, Lundbeck Research & Development.

The 2-month long-acting injectable of aripiprazole in 960 mg and 720 mg prefilled syringes will deliver sustained plasma concentrations similar to that demonstrated in studies with aripiprazole once-monthly long-acting injectable.

“Stability is critical for patients with schizophrenia and bipolar I – which means delaying time to relapse or recurrence and supporting their role as functioning members of their community,” said Robert McQuade, PhD, executive vice president and chief strategy officer of Otsuka Pharmaceutical Development & Commercialization. “As we continue our efforts to bring aripiprazole 2-month to market, we remain committed to our patients and confident that the favorable safety and tolerability profile will be clearly visible.”

The FDA target date for review completion is April 27, 2023.

Visit psychiatrictimes.com regularly for more updates and breaking news.

1. Otsuka and Lundbeck Announce U.S. FDA acceptance of new drug application for aripiprazole 2-month, ready-to-use, long-acting injectable to treat schizophrenia and bipolar I disorder in adults. News release. Business Wire. September 13, 2022. 

https://www.businesswire.com/news/home/20220913005499/en/Otsuka-and-Lundbeck-Announce-U.S.-FDA-Acceptance-of-New-Drug-Application-for-Aripiprazole-2-month-Ready-to-Use-Long-acting-Injectable-to-Treat-Schizophrenia-and-Bipolar-I-Disorder-in-Adults

The FDA has accepted the NDA for aripiprazole 2-month, ready-to-use, long-acting injectable.

When used as clinically indicated at the appropriate doses, stimulants are safe and effective for the treatment of 

 (ADHD); however, misuse may lead to serious adverse effects, including medication-induced persistent psychotic disorder. A case report published in 

found that the long-acting injectable haloperidol decanoate may be able to improve compliance and prognosis in patients with ADHD.

As described by Desai et al, long-acting injectable haloperidol decanoate—although not FDA approved for the treatment of stimulant-induced psychosis—was successfully used to treat a patient with stimulant-induced psychosis and a history of noncompliance with antipsychotic treatment.

In the case example, Desai et al describe “Mr X,” a 29-year-old Caucasian male who was brought to the emergency department (ED) for altered mental status. Mr X was found to be agitated, incoherent, and responding to internal stimuli when evaluated by emergency medical services. Mr X has a past psychiatric history of ADHD, anxiety disorder, and stimulant-induced psychosis, though there is no known psychiatric history in Mr X’s family. Mr X was diagnosed with ADHD as an adult, and was prescribed Adderall at the age of 19, taking a dosage of up to 90 mg per day. Mr X had been hospitalized before in an inpatient psychiatric unit for a similar symptomatic presentation that was attributed to Adderall use above the approved dosage. Previously, he was prescribed olanzapine and risperidone for 

, but was noncompliant with treatment. Following his last discharge from an inpatient unit, Mr X continued to obtain Adderall.

Following this inpatient admission, Mr X was started on oral risperidone 1 mg BID; however, he continued to refuse medications. Eventually, Mr X agreed to take oral Haldol 5 mg BID that was later up titrated to 7.5 mg BID. Throughout his inpatient stay, he continued to remain insistent on getting Adderall or Vyvanse for his ADHD without specifying dosage. Due to his 2 inpatient psychiatric hospitalizations in the past 6 months, his continuation of Adderall abuse, and noncompliance with prescribed antipsychotic treatment, clinicians offered Mr X long-acting Haldol. He was given 2 injections of Haldol Decanoate 50 mg and 100 mg intramuscularly. Additionally, Mr X was prescribed clonidine 0.1 mg daily for the management of his ADHD. Mr X tolerated the prescribed treatment without any adverse effects. His behaviors were reduced significantly, and he was safely discharged, where he remained compliant with the treatment plan for a follow-up period of 6 months.

“Long-acting Haldol provided a great response; however, further research is required to assess long-acting injectables as a definitive treatment for stimulant-induced psychotic disorders, especially in patients with a history of noncompliance and recurrent hospitalizations,” wrote the authors.

 might increase the risk of developing subsequent psychotic disorders during adulthood.

 Prolonged stimulant misuse might contribute to the development of a subsequent psychotic disorder in genetically susceptible individuals; more research is needed to determine. Overdiagnosis and treatment of ADHD, plus a rise in prescription stimulant misuse, might further complicate this relationship.

Amphetamines can mimic psychosis, especially when taken recreationally above approved doses. Acute amphetamine intoxication can present as a substance-induced psychotic disorder, although some individuals may go on to develop a psychotic disorder with onset during intoxication that continues. This poses an especially unique challenge in young adults, when separating first onset psychosis from a stimulant-induced psychotic disorder and subsequent transition to schizophrenia-like illness, can be difficult but is crucial for determining appropriate care.

Distinguishing First Onset Psychosis From Stimulant-Induced Psychosis

Some studies indicated there may be different symptom presentations in the case of amphetamine-induced persistent psychosis. Yang et al suggested that methamphetamine-induced psychosis presents with less 

 and negative symptoms compared with patients with primary schizophrenic psychosis.

Obvious predictors of amphetamine-induced psychosis include the dosage and duration of amphetamine use, but research has highlighted the additional role of gamma-aminobutyric acid (GABA) dysfunction resulting in a heightened risk of stimulant-induced psychosis. A study by Ahn et al suggested that preexisting GABA deficits increased vulnerability to stimulant-induced psychosis in healthy subjects.

Treatment of stimulant-induced psychosis may be similar to treatment of psychotic disorders and schizophrenia. For example, a recent systematic review by Fluyau et al found that aripiprazole (Abilify), haloperidol (Haldol), quetiapine (Seroquel), olanzapine (Zyprexa), and risperidone (Risperdal) were able to reduce or control stimulant-induced psychosis with similar efficacy.

 Additionally, a systematic review by Coles et al found long-acting injectable antipsychotics to be an effective treatment for dual diagnosis schizophrenia and substance use disorder.

Desai et al noted further research is needed to identify individuals that are at increased risk of developing persistent psychosis from stimulant abuse. They suggested that α2-adrenergic agonists may be a safer alternative for the management of ADHD in such cases.

Adderall-induced persistent psychotic disorder managed with long-acting injectable haloperidol decanoate.

2. Nourredine M, Gering A, Fourneret P, et al. 

Association of attention-deficit/hyperactivity disorder in childhood and adolescence with the risk of subsequent psychotic disorder: a systematic review and meta-analysis.

Methamphetamine-associated psychosis: links to drug use characteristics and similarity to primary psychosis.

Role of GABA deficit in sensitivity to the psychotomimetic effects of amphetamine.

Antipsychotics for amphetamine psychosis. A systematic review.

6. Coles AS, Knezevic D, George TP, et al. 

Long-acting injectable antipsychotic treatment in schizophrenia and co-occurring substance use disorders: a systematic review.

Long-acting injectable haloperidol decanoate may work as a treatment for Adderall-induced persistent psychosis. 

Stimulant-Induced Persistent Psychotic Disorder: New Treatment Potential  

“Mrs Blue” is a 70-year-old Caucasian woman with a 45-year history of schizophrenia. She also has posttraumatic stress disorder (PTSD) stemming from a sexual assault in early adulthood and occasionally smokes marijuana. Her current psychotropic regimen includes aripiprazole (Abilify), valproic acid (Depakote), and citalopram (Celexa), and she is overall stable with no psychiatric hospitalizations in the past 6 years. Prior to the schizophrenia diagnosis, she underwent a hysterectomy at age 20 for ovarian cancer. She has comorbid obesity, hypertension, hyperlipidemia, and osteoporosis. Three years ago, she received a diagnosis of chronic renal failure. Her most recent blood urea nitrogen to creatinine ratio is 51:2.15, with a glomerular filtration rate of 26.

 affects more than 3 million individuals in the United States and is associated with substantial psychiatric, substance-related, and medical 

, patterns of comorbidity in schizophrenia have not been systematically described using real-word data.

 To address this gap, Lu and colleagues leveraged a nationwide health insurance claims data set from Aetna to assess population-level phenotypes associated with schizophrenia.

The investigators conducted data-driven analyses on patient phenotypes before and after the index diagnosis of schizophrenia and compared data on phenotypes with those of matched controls without schizophrenia. The Aetna data set contained 86 million participants from all 50 states, the District of Columbia, 5 populated territories, and Armed Forces Europe, with claims data from January 2008 to December 2019. 

International Classification of Diseases, Ninth Revision

 codes formed the basis of corresponding phenotype codes or phecodes. Schizophrenia was defined as at least 3 occurrences of phecodes 295 and 295.1. 

Inclusion criteria were documented birth year, biological sex, and zip code information. Participants also had to have been on the insurance plan for at least 12 months prior to their first schizophrenia diagnosis. Patients younger than 15 years old were excluded. Patients in the schizophrenia cohort were matched to controls without schizophrenia based on birth year, biological sex, and the first 3 digits of the zip code.

The authors analyzed 1890 phenotypes based on phecodes (requiring at least 3 occurrences) before diagnosis for patients with a first documentation of schizophrenia between ages 15 and 29 years. Data for all participants were analyzed using the Fisher exact test. Data on phenotypes occurring after the onset of schizophrenia were analyzed using Cox proportional hazards models. Patients were removed from these analyses if the phecode was within 1 year of the first schizophrenia diagnosis. The Bonferroni correction was applied to P-values for multiple comparisons.

The authors identified 61,453 patients with schizophrenia (prevalence, 0.7%; 47% were male); average length of patient records was 6 years. The investigators noted 144 phecodes were significantly enriched in patients who later received a schizophrenia diagnosis. Some of the top phecodes were suicidal ideation (odds ratio [OR], 51.2), bipolar (OR, 36.1), antisocial/borderline personality (OR, 18.4), substance addiction and disorders (OR, 17.6), and PTSD (OR, 16.2). Women who later developed schizophrenia were more likely to have type 2 diabetes, obstructive sleep apnea, and eating disorders; men were more likely to have acute renal failure, developmental delay, and rhabdomyolysis (

The authors also noted that 402 phecodes were significantly enriched after the diagnosis of schizophrenia. Some of the top phecodes were coma/stupor/brain damage (HR, 87.3), altered mental status (HR, 86.2), alcoholism (HR, 47.3), and septicemia (HR, 30.4). Women were more likely to develop encephalopathy, epilepsy, and adverse drug events or allergies; men were more likely to develop impulse control disorder, esophageal bleeding, and acute osteomyelitis.

Thus, the authors concluded there was a broad range of comorbidities enhanced in schizophrenia both before and after diagnosis, including PTSD, other anxiety disorders, and alcohol and other substance use disorders. In addition, patient sex significantly influenced associated comorbidities.

Study strengths included the large sample size and comprehensive data, consideration of comorbidities before and after the diagnosis of schizophrenia, and statistical correction for multiple comparisons. Study limitations included the potential lack of generalizability to other schizophrenia populations (ie, the investigation leveraged an employer-sponsored insurance claims data set), the relatively short follow-up time, and the inherent nature of phecodes that represent coarse categories of clinical phenotypes.

This study demonstrates the utility of large-scale, real-world data analyses to elucidate patterns of disease comorbidity, which can provide clinically useful information to treating clinicians.

How often do you see comorbidities in patients with schizophrenia? Which comorbidities are the most troublesome to treatment? Email us at 

is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. He is on the Editorial Board and serves as the Schizophrenia & Psychosis section editor for

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

1. Patel KR, Cherian J, Gohil K, Atkinson D. 

Schizophrenia: overview and treatment options

Large-scale real-world data analysis identifies comorbidity patterns in schizophrenia

A recent study demonstrates how large-scale, real-world data analyses can elucidate patterns of disease comorbidity.

Comorbidity Complexities: Patterns and Implications

“Mr Charles” is a 34-year-old Caucasian male with a 16-year history of schizophrenia. He has been on clozapine since age 21, at a current dose of 400 mg at bedtime. He previously took up to 500 mg clozapine, but the dose was reduced due to excessive sedation. He also currently takes risperidone 3 mg daily and lamotrigine 200 mg twice daily. He previously had significant persecutory delusions and associated auditory hallucinations, which largely resolved with clozapine. He also has chronic, enduring negative symptoms. Both Mr Charles and his parents report very few outside interests and no friends outside of family members. His affect is chronically restricted. He has stated that he has no motivation and has a diminished sense of purpose. He does not have any social drive. He currently attends adequately to activities of daily living (ADLs), but impaired hygiene was a problem in the past. He has not had any significant clinical improvement with trials of adjunctive lumateperone, topiramate, minocycline, doxycycline, celecoxib, or oxytocin. His parents inquire about a trial of adjunctive N-acetylcysteine. As his psychiatrist, how would you advise this patient and his family?

There are currently no approved pharmacologic agents for the treatment of negative symptoms of schizophrenia, which contribute to impaired functioning and quality of life.

 Clozapine is the gold-standard antipsychotic for treatment-resistant psychosis, but about 40% of patients are clozapine nonresponders.

 There is limited evidence for augmenting agents that improve residual negative symptoms in clozapine nonresponders.

N-acetylcysteine (NAC) is a glutathione (GSH) precursor that modulates glutamate and dopamine and reduces oxidative stress and inflammation.

 There is evidence for decreased GSH levels in schizophrenia in CSF and MRI studies.

 One previous 24-week study of NAC in schizophrenia

 found a significant effect, particularly for negative symptoms. In that study, about half of participants treated with NAC were taking clozapine. There is also evidence from a meta-analysis for a large effect of NAC on negative symptoms in schizophrenia.

Neill and colleagues performed a 52-week randomized, placebo-controlled trial of NAC in patients stabilized on clozapine but with residual symptoms in 4 Australian cities.

 Participants were allocated to 2 g/day NAC or placebo (2 capsules twice daily), and assessed at 0, 8, 24, and 52 weeks. Inclusion criteria were DSM-5 schizophrenia or schizoaffective disorder; age 18 to 65; on a stable dose of clozapine for at least 6 months with a blood level of > 350 µg/L; and residual symptoms (a score of > 4 on 2 or more PANSS negative scale items or PANSS total score ≥ 60). 

Exclusion criteria were current treatment with NAC; allergy to NAC; currently taking nitroglycerin, aralen, or selenium; diabetes mellitus; history of autoimmune disorder, gastrointestinal ulcer, or kidney stones; and pregnancy or not using adequate contraception in females.

The primary outcome measure was change in the PANSS negative subscale. Secondary outcomes included PANSS positive and general symptoms, quality of life (Manchester short assessment), and mood (Calgary depression scale for schizophrenia and PANSS depression subscale). Cognition was assessed using the MATRICS consensus cognitive battery. Data were analyzed using mixed-model repeated-measures analysis, controlling for PANSS positive and depression subscale scores.

The authors randomized 85 participants (42 to NAC and 43 to placebo). There were no significant differences between the groups on baseline clinical and demographic variables. The mean subject age was 40, and 72% of subjects were male. The completion rate was 85% at 8 weeks, 71% at 24 weeks, and 48% at 52 weeks, and similar between groups. Clinic site was included as a covariate in the analyses, due to different attrition rates and number of prescribed medications between sites. 

Although there was a significant time effect on improvement in negative symptoms, there was no significant group x time interaction (p=0.62). NAC did not significantly improve cognition (global or domain scores) or quality of life at any time point. There was some evidence for improvements in depression with NAC, although the association was no longer significant after removing patients with changes in clozapine dose. There was no significant increase in side effects over the trial with NAC.

The authors performed the first randomized controlled trial (RCT) of NAC for patients with clozapine-resistant schizophrenia. Although there was no difference in side effect burden, they did not find any efficacy of this adjunctive agent over 52 weeks. There was exploratory evidence for improvement in depression with NAC, although this finding warrants investigation in a group enriched for depressive symptoms. Study limitations included lower than expected recruitment and potential underdosing of NAC (a previous trial investigated 3.6 g/day).

This study did not support the efficacy of NAC for negative symptoms in clozapine-resistant patients with schizophrenia.

1. Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. 

Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis

Clozapine response rates among people with treatment-resistant schizophrenia: data from a systematic review and meta-analysis

3. Siskind DJ, Lee M, Ravindran A, et al. 

Augmentation strategies for clozapine refractory schizophrenia: a systematic review and meta-analysis

4. Wagner E, Kane JM, Correll CU, et al. 

Clozapine combination and augmentation strategies in patients with schizophrenia—recommendations from an international expert survey among the Treatment Response and Resistance in Psychosis (TRRIP) working group

The promise of N-acetylcysteine in neuropsychiatry

N-acetyl cysteine as a glutathione precursor for schizophrenia—a double-blind, randomized, placebo-controlled trial

7. Do KQ, Trabesinger AH, Kirsten-Krüger M, et al. 

Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo

8. Yolland CO, Hanratty D, Neill E, et al. 

Meta-analysis of randomised controlled trials with 

-acetylcysteine in the treatment of schizophrenia

9. Neill E, Rossell SL, Yolland C, et al. 

N-Acetylcysteine (NAC) in schizophrenia resistant to clozapine: a double-blind, randomized, placebo-controlled trial targeting negative symptoms

 [published online ahead of print, 2022 Jul 20]. 

Getting the “NAC” of treating negative symptoms: Researchers performed a randomized controlled trial of N-acetylcysteine in clozapine-resistant schizophrenia.

A Randomized Controlled Trial of N-Acetylcysteine in Clozapine-Resistant Schizophrenia

The US Food and Drug Administration (FDA) sent a Complete Response Letter (CRL) regarding the supplemental new drug application (sNDA) for pimavanserin (Nuplazid) for the treatment of hallucinations and delusions associated with Alzheimer disease psychosis (ADP), according to Acadia Pharmaceuticals.

The CRL indicated that the FDA has completed review of the application and could not approve the sNDA in its present form. The FDA recommended that Acadia conduct an additional trial in ADP.

“We are disappointed with this outcome. The treatment of Alzheimer disease psychosis continues to be an area of high unmet need, for which there is no approved therapy,” said Steve Davis, chief executive officer. “We want to express our gratitude to all of the patients, their families and investigators who have participated in our clinical trials.”

In Study 019, the FDA agreed the results demonstrated a statistically significant treatment effect on its primary endpoint, but the agency concluded there are limitations in the interpretability of said results. The FDA also stated that the positive treatment effect of pimavanserin on dementia-related psychosis in Study 045 (HARMONY) appeared to be driven by the robustly positive results in the Parkinson disease dementia subgroup, a condition they stated is subsumed within the currently approved Nuplazid Parkinson disease psychosis (PDP) indication.

This recent sNDA was Acadia's second attempt to secure approval for expanded use of the drug. In early 2021, the FDA rejected Acadia’s clinical trial data, which they stated were not sufficient to support approval of pimavanserin in patients with dementia-related psychosis.

1. Acadia Pharmaceuticals receives complete response letter from U.S. FDA for supplemental new drug application for pimavanserin for the treatment of hallucinations and delusions associated with Alzheimer’s disease psychosis. Business Wire. August 4, 2022. Accessed August 8, 2022. 

https://www.businesswire.com/news/home/20220804006095/en/Acadia-Pharmaceuticals-Receives-Complete-Response-Letter-from-U.S.-FDA-for-Supplemental-New-Drug-Application-for-Pimavanserin-for-the-Treatment-of-Hallucinations-and-Delusions-Associated-with-Alzheimer’s-Disease-Psychosis

2. U.S. FDA declines to approve expanded use of Acadia's antipsychotic drug. Reuters. August 5, 2022. Accessed August 8, 2022. 

https://www.reuters.com/business/future-of-health/us-fda-declines-approve-expanded-use-acadias-antipsychotic-drug-2022-08-05/

Alzheimer disease psychosis treatment pimavanserin receives Complete Response Letter from the FDA. 

Caution Ahead: FDA Asks for More Info on Expanded Use of Antipsychotic Drug

Positive topline results for the phase 3 EMERGENT-2 trial evaluating the efficacy, safety, and tolerability the investigational agent xanomeline-trospium (KarXT) for adults with schizophrenia was announced by Karuna Therapeutics.

The trial met its primary endpoint: KarXT demonstrated a statistically significant and clinically meaningful 9.6-point reduction in the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo (-21.2 KarXT versus -11.6 placebo, p<0.0001) at week 5 (Cohen’s d effect size of 0.61). Starting at week 2, KarXT also demonstrated an early and sustained statistically significant reduction of symptoms, as assessed by PANSS total score. KarXT maintained this reduction through all timepoints in the trial.

“Despite the number of available treatment options, there continues to be a tremendous unmet need in the treatment of schizophrenia, placing an immense burden on both patients and their caregivers,” said Rishi Kakar, MD, chief scientific officer, Segal Trials and lead investigator of the phase 3 EMERGENT-2 trial. “These data build on the growing body of clinical evidence supporting the potential of KarXT as a new and differentiated approach for schizophrenia, demonstrating notable improvements across both positive and negative symptoms, while not being associated with common problematic side-effects of current therapies, such as weight gain, sedation, and movement disorders. This unique profile of KarXT has the potential to provide a new meaningful treatment option for our patients and their families beyond the current standard of care.”

KarXT also met key secondary endpoints, demonstrating a statistically significant reduction in both positive symptoms (eg, hallucinations or delusions) and negative symptoms (eg, difficulty enjoying life or withdrawal from others) of schizophrenia as measured by the PANSS positive (-6.8 KarXT versus -3.9 placebo, p<0.0001), PANSS negative (-3.4 KarXT versus -1.6 placebo, p=0.0055), and PANSS negative Marder factor subscales (-4.2 KarXT vs. -2.0 placebo, p=0.0022).

KarXT was generally well tolerated. Overall discontinuation rates were similar between KarXT and placebo groups (25% versus 21%). The overall treatment-emergent adverse events rate for KarXT and placebo was 75% and 58%, respectively. The most common treatment-emergent adverse events (>5%) in the KarXT arm were all mild to moderate in severity and included constipation, dyspepsia, nausea, vomiting, headache, increases in blood pressure, dizziness, gastroesophageal reflux disease (acid reflux), abdominal discomfort, and diarrhea.

“We are thrilled that these topline results from the Phase 3 EMERGENT-2 trial confirm what was seen in our Phase 2 EMERGENT-1 trial and underscore the potential for KarXT, with its novel and unique mechanism of action, to redefine what successful treatment looks like for the 21 million people living with schizophrenia worldwide, and potentially usher in the first new class of medicine for these patients in more than 50 years,” said Steve Paul, MD, chief executive officer, president and chairman of Karuna Therapeutics. “These results represent our second positive registrational trial. We look forward to continuing to gather long-term safety data to support our submission of a New Drug Application with the US Food and Drug Administration [FDA] for KarXT as a treatment for schizophrenia, which we expect to occur in mid-2023.”

To see more on KarXT, watch the video “

Promising Publication: The Novel Schizophrenia Treatment Gaining Traction

,” in which Stephen Brannan, MD, chief medical officer of Karuna Therapeutics, shared more information on the phase II clinical data.

1. Karuna Therapeutics announces positive results from phase 3 EMERGENT-2 Trial of KarXT in schizophrenia. Business Wire. August 8, 2022. 

https://www.businesswire.com/news/home/20220808005222/en/Karuna-Therapeutics-Announces-Positive-Results-from-Phase-3-EMERGENT-2-Trial-of-KarXT-in-Schizophrenia

This novel schizophrenia treatment showed positive results in a phase 3 trial evaluating efficacy, safety, and tolerability. 

“A New and Differentiated Approach for Schizophrenia”: Positive Results for Phase 3 Trial 

, we worked with experts from multiple psychiatric areas to bring you thoughtful articles about a wide variety of psychiatric issues, from the new 988 suicide hotline to the role of antipsychotic selection in reducing nonadherence in schizophrenia. Here are some highlights from the issue.

The National Suicide Prevention Lifeline is getting an upgrade. On July 16, 2022, the Lifeline will change from its previous number (800-273-8255) to just 3 digits: 988. Although the old number will remain available for calls, individuals may call, text, or chat 988, where they will be connected with trained counselors.

Additionally, if functioning as intended, operators will be able to counsel callers 24 hours a day and dispatch specially trained responders, hopefully reducing armed law enforcement interventions and emergency department (ED) visits. 

It's Time to Think of Women: Mental Health Services for First-Episode Psychosis

As the World Health Organization reminds us, gender is a critical determinant of health, including mental health. Psychosis affects 3 in 100 individuals worldwide and typically develops around age 21 years. It includes diagnoses such as those of the schizophrenia spectrum and affective disorders. Early intervention services hold the promise of changing the trajectory of psychosis by providing specialized, coordinated care to individuals experiencing their first episode of psychosis (FEP). Evidence shows that FEP services can improve short-term and long-term outcomes for the individual (eg, employment) and for their community (eg, reduced disruptive public behavior, legal charges). What remains unknown, and maybe overlooked, is that women experiencing FEP might encounter gender-based disparities in accessing and receiving specialized care. 

Antipsychotic Selection is Important for Reduced Nonadherence in Schizophrenia

“Mr Spear” is a white man, age 43 years, with a 20-year history of schizophrenia who presents for an initial outpatient appointment with a primary complaint of insomnia. Upon further questioning, he explains that he is afraid to sleep due to paranoia because there are individuals outside his home at night who want to kill him. He will not take any medication that makes him drowsy. His mental status is otherwise unremarkable. He denies any suicidal or homicidal ideations and does not appear to attend to internal stimuli. He reports several previous psychiatric hospitalizations, but none in the past 3 years. He works full-time in construction and denies any work-related problems. After a discussion of risks and benefits, he agrees to a trial of daily low-dose aripiprazole (morning) and to return to the clinic in 4 weeks. However, Mr Spear does not show up for his follow-up appointment, he does not return a phone call to reschedule, and he never returns to the clinic. 

Caregiving: Walking the Personal and Professional Tightrope

August 16, 2019, in New Haven, Connecticut, was a beautiful summer evening. A delicious dinner at the Study at Yale hotel, where we were staying for the night, wrapped up a packed day of activities. These included a presentation and conversations about evidence-based addictions treatment modalities. The day could not have been better. I remember thinking that this was addiction treatment done right. A colleague invited a group of us to walk over to the Arethusa Farm Dairy store for their famous “designer” ice cream. I asked for a minute to go to my room and slip on some comfortable shoes for the 5-minute walk. I never returned. Instead, I called my colleague to tell him and everyone else to go ahead—I had to handle an urgent matter. I had at least 10 missed calls and several text messages from 2 neighbors. 

The experts weighed in on a wide variety of psychiatric issues for the July 2022 issue of Psychiatric Times.

From the Pages of Psychiatric Times: July 2022

A 27-year-old man presents to an outpatient psychiatrist for intake 5 days after discharge from an inpatient psychiatric hospitalization. He had no prior psychiatric history until 10 days before the appointment, when he was brought to the emergency department (ED) by police after his landlord called 911. The landlord told police that the patient was acting unusually, making verbal threats to other tenants, and expressing paranoid and persecutory beliefs. He required ketamine 200 mg IM before he was cooperative enough to accept IV fluid hydration. Medical work-up was within normal limits, and urine toxicology testing was positive for methamphetamines.

During the ED evaluation, he became increasingly depressed, reporting suicidal ideation and continued auditory hallucinations. He was admitted to an inpatient psychiatric unit, where he was prescribed risperidone 1 mg orally twice per day. Over the course of his hospitalization, he reported remission of suicidal ideation as well as improvement in hallucinations and his level of paranoia. He was discharged on hospital day 5. At the initial outpatient assessment, he reported adherence with risperidone since discharge and denied any psychotic symptoms. However, he was experiencing sedation during the day. Although he endorsed cravings for methamphetamine, he said he was committed to not resuming substance use. Citing the adverse effects he was experiencing, he wanted to know if he could safely discontinue the antipsychotic medication.

 in the United States is a growing problem, with approximately 1.6 million adults using it yearly.

 It can be taken orally, nasally, or intravenously to produce euphoria and mood elevation. Acute intoxication can lead to increased mental acuity and reduction in appetite.

 It can also inhibit fatigue, which is why it is used concomitantly with sedating substances of abuse such as alcohol or opioids. Withdrawal is associated with somnolence, reduced cognitive ability, and dysphoric or irritable mood, which can contribute to the increased risk of suicide.

There is a robust association between methamphetamine use and the development of psychotic symptoms, such as paranoid delusions, ideas of reference, and auditory hallucinations. Clinical observations suggest that there are 2 distinct types of methamphetamine-associated psychosis (MAP): Some patients have quick resolution of psychotic symptoms with cessation of substance use, but for other patients, psychotic symptoms are slow to remit. In 1 cross-sectional study, more than half (52%) of patients with MAP saw a remission of their psychotic symptoms within a week of abstinence from methamphetamines. Psychotic symptoms remained in 26% of patients after 1 month and in 16% of patients after 3 months.

 For those patients who present with persistent psychotic symptoms after methamphetamine use has stopped, it remains unclear if they are already genetically vulnerable and methamphetamine use triggers the development of a psychotic disorder. Clinical management of a patient with onset of psychotic symptoms in the context of methamphetamine use may present a challenge for psychiatric providers in an ambulatory, longitudinal treatment setting.

Our current understanding of the biology of MAP suggests 2 possible scenarios for a clinician to consider. The first is that methamphetamine use causes acute changes that result in psychosis that will remit as methamphetamine use remits. The second is that methamphetamine use can cause permanent psychosis, either through direct changes to previously normal brain function or through unmasking a genetic vulnerability to psychosis.

The effects of methamphetamine use on the central nervous system are primarily mediated through dopaminergic transmission—the same system thought to play a major role in schizophrenia and other related disorders. The rewarding effects of substances are also mediated through dopaminergic pathways in the mesolimbic system. Methamphetamine inhibits dopamine (DA) reuptake through inhibition of the DA transporter and the vesicular monoamine transporter. This leads to elevated concentrations of DA, potentially to neurotoxic levels. Higher dopaminergic signaling in the mesolimbic, nigrostriatal, and mesocortical pathways causes elevated glutamate levels that damage GABAergic interneurons. This leads to glutamate dysregulation and impairment of N-methyl-D-aspartate receptors, resulting in damage to the cortex and the onset of psychotic symptoms.

Neuroimaging studies demonstrate structural changes in the brains of patients who develop psychosis with the use of methamphetamine compared with those who do not develop psychosis.

 Changes in these brain regions have also been seen in patients with primary psychotic disorders.

Genetic studies also suggest an overlap in genes associated with the development of primary and methamphetamine-associated psychosis.

 Using a stress-vulnerability model of psychosis in which methamphetamine is an additional “hit” or stressor precipitating the onset of psychotic symptoms, the amount, frequency, and duration of drug use needed to cause MAP could vary greatly based on the individual’s genetic vulnerability.

Acute onset of psychotic symptoms in a previously healthy individual requires a comprehensive evaluation. In addition to brain imaging, laboratory work including basic metabolic panel, HIV, rapid plasma reagin, and thyroid stimulating hormone can help rule out possible medical causes. IV fluids may be necessary to replace fluid loss and to address hyperthermia caused by methamphetamine intoxication.

Withdrawal from alcohol or benzodiazepines can present with psychosis, and because methamphetamine is often used in conjunction with other substances, this should be included on the differential diagnosis. Benzodiazepines are the preferred treatment in this situation, and they are used as first-line agents in the treatment of patients with agitated psychosis. Ketamine is widely used for sedation in emergency department settings and can be administered intravenously or intramuscularly.

 Both first- and second-generation antipsychotic medications can be used in acute management of agitated psychosis, often in conjunction with anticholinergic medications to prevent possible extrapyramidal symptoms.

Exploring the association between methamphetamine use and the development of psychotic symptoms, such as paranoid delusions, ideas of reference, and auditory hallucinations.

Schizophrenia/Psychosis