The schizophrenia syndrome, circa 2024: What we know and how that informs its nature.

With new data about different aspects of schizophrenia being continually generated, it becomes necessary to periodically revisit exactly what we know. Along with a need to review what we currently know about schizophrenia, there is an equal imperative to evaluate the construct itself. With these objectives, we undertook an iterative, multi-phase process involving fifty international experts in the field, with each step building on learnings from the prior one. This review assembles currently established findings about schizophrenia (construct, etiology, pathophysiology, clinical expression, treatment) and posits what they reveal about its nature. Schizophrenia is a heritable, complex, multi-dimensional syndrome with varying degrees of psychotic, negative, cognitive, mood, and motor manifestations. The illness exhibits a remitting and relapsing course, with varying degrees of recovery among affected individuals with most experiencing significant social and functional impairment. Genetic risk factors likely include thousands of common genetic variants that each have a small impact on an individual's risk and a plethora of rare gene variants that have a larger individual impact on risk. Their biological effects are concentrated in the brain and many of the same variants also increase the risk of other psychiatric disorders such as bipolar disorder, autism, and other neurodevelopmental conditions. Environmental risk factors include but are not limited to urban residence in childhood, migration, older paternal age at birth, cannabis use, childhood trauma, antenatal maternal infection, and perinatal hypoxia. Structural, functional, and neurochemical brain alterations implicate multiple regions and functional circuits. Dopamine D-2 receptor antagonists and partial agonists improve psychotic symptoms and reduce risk of relapse. Certain psychological and psychosocial interventions are beneficial. Early intervention can reduce treatment delay and improve outcomes. Schizophrenia is increasingly considered to be a heterogeneous syndrome and not a singular disease entity. There is no necessary or sufficient etiology, pathology, set of clinical features, or treatment that fully circumscribes this syndrome. A single, common pathophysiological pathway appears unlikely. The boundaries of schizophrenia remain fuzzy, suggesting the absence of a categorical fit and need to reconceptualize it as a broader, multi-dimensional and/or spectrum construct.

Pimavanserin treatment increases plasma brain-derived neurotrophic factor levels in rats.

Background: Pimavanserin, a serotonin 5HT-2A receptor inverse agonist is the first-line, FDA-approved treatment of hallucinations and delusions associated with Parkinson's Disease psychosis (PDP), which occurs in up to 50% of PD patients. The neurobiological mechanism underlying the therapeutic effectiveness of Pimavanserin in PDP remains unknown. Several earlier studies have shown that treatment with 5HT-2A antagonists and other drugs acting on the serotonergic system such as SSRIs increase Brain derived neurotrophic factor (BDNF) levels in rodents. BDNF is synthesized as the precursor proBDNF, that undergoes cleavage intra or extracellularly to produce a mature BDNF (mBDNF) protein. mBDNF is believed to play a key role in neuroplasticity and neurogenesis. The present study tested the hypothesis that treatment with Pimavanserin is associated with higher and sustained elevations of mBDNF. Methods: Adult Sprague-Dawley male rats were treated with Pimavanserin, Fluoxetine or vehicle for 4 weeks (chronic) or 2 h (acute). BDNF levels were determined by enzyme-linked Immunosorbent assay (ELISA). Results: We found significant increases in plasma mBDNF levels in rats following chronic Pimavanserin treatment, but not in Fluoxetine-treated rats. No significant changes in mBDNF levels were found in the prefrontal cortex or hippocampus following Pimavanserin or Fluoxetine treatment. Conclusion: These findings suggest that increase in mBDNF levels could be a contributing mechanism for the neuroprotective potential of Pimavanserin.

High-dose armodafinil in treatment-refractory bipolar depression.

BACKGROUND: Bipolar depression is a serious neuropsychiatric disorder associated with a high risk of morbidity and suicidality. Standard antidepressants approved for treating major depressive disorder fail to exert efficacy in bipolar depression. Although 5 agents have been developed for the treatment of bipolar depression, treatment resistance is still observed in some patients, and requires off-label pharmacotherapy. Modafinil and armodafinil have been reported to improve treatment-resistant bipolar depression, but with inconsistent results. METHODS: We present a case of a 65-year-old woman with severe bipolar depression who failed to respond to electroconvulsive therapy and IV ketamine but later responded to high-dose armodafanil. RESULTS: The patient responded to high-dose armodafinil (gradually titrated to 1,000 mg/d) and achieved remission with good tolerability for 5 years. Recently, she contracted COVID-19 and developed muscular weakness. After a lengthy workup, we became concerned for myopathy as an adverse effect from armodafinil. The patient's dose of armodafinil was significantly reduced and she subsequently became very depressed and functionally disabled before improving again when armodafinil 1,000 mg/d was reinstated. CONCLUSIONS: We propose that some of the negative results seen in research of armodafinil for bipolar depression may be due to the use of low doses (100 to 200 mg/d), and higher doses may be needed for adequate response in treatment-resistant bipolar depression.

The role of the insula in cognitive impairment of schizophrenia.

Cognitive impairment is one of the core clinical symptom domains of schizophrenia. Research shows that cognitive deficits in this neuropsychiatric syndrome is associated with neurodevelopmental pathology affecting multiple brain regions such as the dorsolateral prefrontal cortex, the hippocampus and the parietal lobe. The insula is a relatively small structure that is highly connected with several brain regions as well as multiple brain networks. A large number of studies have reported the involvement of the insula in many of the psychotic and nonpsychotic manifestations of schizophrenia. Here we review the role of the insula as a hub across key neurocircuits which have been implicated in the various cognitive pathologies in schizophrenia. Structural and functional abnormalities in the right and left insulae may serve as a biomarker for susceptibility to schizophrenia.

The Association of the Gut Microbiota with Clinical Features in Schizophrenia.

The connection between gut microbiota and schizophrenia has become a fertile area of research. The relationship is bidirectional and quite complex, but is likely to lead to practical clinical applications. For example, commensal microbiota have been shown to produce inflammatory metabolites that can cross the blood-brain barrier-a possible neurobiological precursor of psychosis. Antipsychotics that treat these individuals have been shown to alter gut microbiota. On the other hand, life style in schizophrenia, such as diet and decreased exercise, can be disruptive to the normal microbiome diversity. In the present paper, we conduct a review of PubMed literature focusing on the relationship of gut microbiota with clinical symptoms of schizophrenia, which, to our knowledge, has not yet been reviewed. Numerous clinical characteristics were identified correlating to gut microbial changes, such as violence, negative symptoms, treatment resistance, and global functioning. The most consistently demonstrated correlations to gut microbial changes across studies were for the overall symptom severity and negative symptom severity. Although numerous studies found changes in these domains, there is much variability between the bacteria that change in abundance between studies, likely due to the regional and methodological differences between studies. The current literature shows promising correlations between gut microbiota profiles and several clinical features of schizophrenia, but initial studies require replication.

Pimavanserin for negative symptoms of schizophrenia: results from the ADVANCE phase 2 randomised, placebo-controlled trial in North America and Europe.

BACKGROUND: Negative symptoms of schizophrenia are associated with adverse clinical outcomes, but there are few effective treatments. We aimed to assess the effects of pimavanserin, a selective 5-HT2A inverse agonist and antagonist, on negative symptoms of schizophrenia. METHODS: The ADVANCE study was a phase 2, 26-week, randomised, double-blind, placebo-controlled study of pimavanserin in stable outpatients with schizophrenia aged 18-55 years with predominant negative symptoms. Patients were randomly assigned (1:1) across 83 sites (18 in North America and 65 in Europe) to receive pimavanserin or placebo daily, added to an ongoing antipsychotic medication, per a computer-generated schedule (stratification by geographical region). Eligible patients had a score of at least 20 on the sum of seven Positive and Negative Syndrome Scale (PANSS) Marder negative factor items (and scores of ≥4 on at least three or ≥5 on at least two of negative symptom items). The starting dosage of 20 mg of pimavanserin or placebo could be adjusted to 34 mg or 10 mg within the first 8 weeks of the study, after which dosage remained stable until the end of the study. Both pimavanserin and placebo were administered orally once daily as two individual tablets (pimavanserin tablets were either 10 mg or 17 mg). The primary endpoint was change in total score using the 16-item Negative Symptom Assessment (NSA-16) from baseline to week 26. Primary outcomes were analysed in patients who received at least one dose of the study drug and had NSA-16 assessments at baseline and at least once post-baseline (full analysis set). Safety outcomes were analysed in patients who had received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02970305, and is complete. FINDINGS: Between Nov 4, 2016, and April 16, 2019, we randomly assigned 403 patients to pimavanserin (n=201; 131 [65%] male; 187 [93%] White) or placebo (n=202; 137 [68%] male, 186 (92%) White), of whom 400 were included in the efficacy analysis (199 in the pimavanserin group, 201 in the placebo group). Mean age was 37·7 years (SD 9·4) in the pimavanserin group and 36·7 (9·2) years in the placebo group. The change in total NSA-16 score from baseline to week 26 was significantly improved with pimavanserin (least squares mean -10·4 [SE 0·67]) versus placebo (least squares mean -8·5 [0·67]; p=0·043; effect size: 0·211). The number of patients with treatment-emergent adverse events (TEAEs) was similar between groups: 80 (40%) patients experienced TEAEs in the pimavanserin group and 71 (35%) in the placebo group. Most TEAEs were headache (6% [n=13] vs 5% [n=10]) and somnolence (5% [n=11] vs 5% [n=10]). One patient from the placebo group reported severe headache (0·5%), rhinorrhoea (0·5%), cough (0·5%), and influenza (0·5%). In the pimavanserin group, one patient reported severe toothache (0·5%), and two patients had worsening of schizophrenia (1%). Mean change in QTcF interval was higher with pimavanerin (4·5 ms [SD 18·0]) than with placebo (0·0 ms [16·0]). INTERPRETATION: Stable patients with predominant negative symptoms of schizophrenia showed a reduction in negative symptoms after treatment with pimavanserin. However, given the small effect size, further investigation with optimised dosing is warranted to determine the clinical significance of this effect. FUNDING: Acadia Pharmaceuticals.

Aripiprazole lauroxil 2-month formulation with 1-day initiation in patients hospitalized for an acute exacerbation of schizophrenia: exploratory efficacy and patient-reported outcomes in the randomized controlled ALPINE study.

BACKGROUND: A randomized, controlled, phase 3b study (ALPINE) evaluated efficacy and safety of a 2-month formulation of aripiprazole lauroxil (AL) using a 1-day initiation regimen in patients hospitalized for an acute exacerbation of schizophrenia. Paliperidone palmitate (PP) was used as an active control. Exploratory endpoint assessments included severity of illness, positive and negative symptoms, quality of life, caregiver burden, and satisfaction with medication. METHODS: Adults were randomly assigned to AL 1064 mg q8wk or PP 156 mg q4wk as inpatients, discharged after 2 weeks, and followed through week 25. Exploratory efficacy measures included the 3 original PANSS subscales, Clinical Global Impression-Severity (CGI-S) subscale, and caregiver Burden Assessment Scale. Exploratory patient-reported outcomes (PROs) included the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) and the Medication Satisfaction Questionnaire. Within-group changes from baseline through week 25 were analyzed for AL and PP separately. PROs were summarized based on observed data. RESULTS: Of 200 patients randomized (AL, n = 99; PP, n = 101), 99 completed the study (AL, n = 56; PP, n = 43). For AL, PANSS subscale and CGI-S scores improved from baseline through week 25 (mean [SE] change from baseline at week 25: Positive, -7.5 [0.70]; Negative, -3.9 [0.46]; General, -11.8 [0.83]; CGI-S, -1.3 [0.12]). Caregiver burden also improved (mean [SD] changes from baseline at week 9: -8.4 [10.15]; week 25: -8.9 [12.36]). Most AL patients were somewhat/very satisfied with treatment at each timepoint (70.8%-74.7%); mean Q-LES-Q-SF total scores were stable in the outpatient period. For PP, results were similar: PANSS Positive, -7.3 (0.67); Negative, -3.6 (0.69); General, -10.9 (1.22); CGI-S, -1.4 (0.16); caregiver burden, week 9: -8.8 (11.89) and week 25: -9.2 (14.55); satisfaction with treatment, 64.7%-69.3%; and stable Q-LES-Q-SF scores. CONCLUSIONS: ALPINE patients initiating the 2-month AL formulation using the 1-day initiation regimen as inpatients and continuing outpatient care experienced schizophrenia symptom improvement, sustained patient satisfaction with medication, stable quality of life, and reduced caregiver burden. A similar benefit pattern was observed for PP. These results support the feasibility of starting either long-acting injectable in the hospital and transitioning to outpatient treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03345979 [trial registration date: 15/11/2017].

Measurement-based care training curriculum in psychiatry residency programs: I: Description of the curriculum and demonstration of implementation.

BACKGROUND: Recent literature shows that most practicing psychiatrists do not receive training in measurement-based care (MBC). Among the primary barriers to MBC implementation are the lack of formal training and curriculums. We present the first comprehensive MBC curriculum for use in adult psychiatric practice, and describe how the curriculum is adapted and implemented in psychiatry residency training programs. METHODS: The Standard for Clinicians' Interview in Psychiatry (SCIP) was developed as a measurement-based care tool for clinicians' use. The SCIP is the only instrument that includes 18 reliable and validated clinician-rated scales covering most adult psychiatric disorders. The SCIP has simple, unified rules of measurement that apply to the 18 scales. The MBC curriculum includes 2 instruction manuals, 4 didactic lectures, and 12 videotaped interviews. We describe the annual learning and implementation of MBC curriculum in residency programs. RESULTS: The curriculum implementation at West Virginia University and Delaware Psychiatric Center began in 2019 and is ongoing. We present 3 case demonstrations of the implementation of MBC in clinical settings. CONCLUSIONS: Comprehensive implementation of MBC curriculum in residency programs has the potential to facilitate research and create a "culture" of MBC in future generations of psychiatrists.

The effect of antipsychotic medications on white matter integrity in first-episode drug-naïve patients with psychosis: A review of DTI studies.

BACKGROUND: Psychotic episodes have been associated with damage to both grey matter (GM) and white matter (WM). Although a recent meta-analysis suggest that in long term treatment, first generation antipsychotics (FGA) are associated with progressive reduction in GM, second generation antipsychotics (SGA) seem to have benefits to WM microstructure. METHODS: A search was conducted to identify controlled trials published from January 2000 to January 2021, which assessed WM integrity as measured by DTI in drug-naïve patients with FEP before and after antipsychotic administration. RESULTS: 3 studies met the criteria for inclusion. All studies demonstrated lower FA in psychotic patients vs HC. A 6-week study reported that antipsychotic medication results in a further decrease in FA within the bilateral ACG and right ACR, regions important in emotional processing. An 8-week study found that antipsychotic treatment increase FA in the SLF, resulting in improved symptoms and increased processing speed. A 3rd study found an increase in FA in several regions along with a negative correlation between FA and PANSS at remission. CONCLUSIONS: Drug-naïve FEP patients have WM dysfunction at baseline and antipsychotic medications appear to alter or improve WM especially at remission. More controlled trials are warranted to validate these conclusions.