An Integrated Process for Co-Developing and Implementing Written and Computable Clinical Practice Guidelines.

The goal of this article is to describe an integrated parallel process for the co-development of written and computable clinical practice guidelines (CPGs) to accelerate adoption and increase the impact of guideline recommendations in clinical practice. From February 2018 through December 2021, interdisciplinary work groups were formed after an initial Kaizen event and using expert consensus and available literature, produced a 12-phase integrated process (IP). The IP includes activities, resources, and iterative feedback loops for developing, implementing, disseminating, communicating, and evaluating CPGs. The IP incorporates guideline standards and informatics practices and clarifies how informaticians, implementers, health communicators, evaluators, and clinicians can help guideline developers throughout the development and implementation cycle to effectively co-develop written and computable guidelines. More efficient processes are essential to create actionable CPGs, disseminate and communicate recommendations to clinical end users, and evaluate CPG performance. Pilot testing is underway to determine how this IP expedites the implementation of CPGs into clinical practice and improves guideline uptake and health outcomes.

The prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression.

This article is a clinical guide which discusses the "state-of-the-art" usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion-this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy-while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward "bridging" methods that may be used to transition simply and safely from other antidepressants to MAOIs.

Performance in Practice: Practice Assessment Tool for the Care of Patients With Schizophrenia.

Schizophrenia is associated with significant health, social, occupational, and economic burdens, including increased mortality. Despite extensive and robust research on the treatment of individuals with schizophrenia, many individuals with the illness do not currently receive evidence-based pharmacological and nonpharmacological treatments. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia, Third Edition, aims to enhance knowledge and increase the appropriate use of interventions for schizophrenia, thereby improving the quality of care and treatment outcomes. To this end, this evidence-based Performance in Practice tool can facilitate the implementation of a systematic approach to practice improvement for the care of individuals with schizophrenia. This practice assessment activity can also be used in partial fulfillment of Continuing Medical Education and Maintenance of Certification, part IV, requirements, which can also satisfy requirements for the Centers for Medicare & Medicaid Services Merit-based Incentive Payment System program.

The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia.

(Reprinted with permission from The American Journal of Psychiatry 2020; 177:868-872).

Lead-Time Bias Confounds Association Between Duration of Untreated Psychosis and Illness Course in Schizophrenia.

OBJECTIVE: At first hospitalization, a long duration of untreated psychosis (DUP) predicts illness severity and worse treatment outcomes. The mechanism of this association, however, remains unclear. It has been hypothesized that lengthy untreated psychosis is toxic or that it reflects a more severe form of schizophrenia. Alternatively, the association may be an artifact of lead-time bias. These hypotheses are tested in a longitudinal study of schizophrenia with 2,137 observations spanning from childhood to 20 years after first admission. METHODS: Data were from the Suffolk County Mental Health Project. The cohort included 287 individuals with schizophrenia or schizoaffective disorder. DUP was defined as days from first psychotic symptom to first psychiatric hospitalization. Psychosocial function was assessed using the Premorbid Adjustment Scale and the Global Assessment of Functioning Scale. Psychosocial function trajectories were estimated using multilevel spline regression models adjusted for gender, occupational status, race, and antipsychotic medication. RESULTS: Both long- and short-DUP patients experienced similar declines in psychosocial function, but declines occurred at different times relative to first admission. Long-DUP patients experienced most of these declines prior to first admission, while short-DUP patients experienced declines after first admission. When psychosocial function was analyzed relative to psychosis onset, DUP did not predict illness course. CONCLUSIONS: The association between DUP and psychosocial function may be an artifact of early detection, creating the illusion that early intervention is associated with improved outcomes. In other words, DUP may be better understood as an indicator of illness stage than a predictor of course.

Physical Functional Limitations in a First-Admission Cohort at Midlife: Findings From the Suffolk County Mental Health Project.

BACKGROUND: Psychosis is a risk factor for aging-related conditions and early mortality. Little is known about the age-specific risk of objectively measured physical functional limitations among individuals with serious mental illness. METHODS: The Suffolk County Mental Health Project is a prospective study of individuals hospitalized for the first time for psychosis. To assess physical functioning at midlife and to identify emerging risk factors for older-age changes, 101 participants with schizophrenia (mean age = 47.2, SD = 8.0 years; 41.6% female) and 112 participants with other psychoses (mean age = 48.2, SD = 9.5 years; 45.5% female) were assessed for chair-rise and balance limitations 20 years after diagnosis. A never-psychotic comparison group of 237 age/sex/geographically matched community controls was similarly assessed (mean age = 50.3, SD = 8.8 years; 44.7% female). Logistic regression was used to examine group differences in prevalence of poor performance and demographic, medical, and treatment correlates. RESULTS: Chair-rise limitations (45.5% [35.8-55.3]) and balance limitations (17.2% [9.8-24.5]) were common in individuals with schizophrenia. Prevalence of chair-rise limitations was higher in schizophrenia (46.3%) than in other psychotic disorders (31.9%) and never-psychotic group (22.1%), whereas risk of balance limitations was higher in schizophrenia (17.2%) compared with never-psychotic controls (8.1%). Schizophrenia was a significant risk factor for chair-rise (adjusted odds ratio = 3.01 [1.79-5.08], p < .001) and balance limitations (adjusted odds ratio = 2.63, [1.25-5.51], p = .010). Multivariable analysis of symptom severity found avolition was associated with chair-rise limitations, but not balance, independent of diagnosis. CONCLUSION: Physical limitations are crucial because they identify existing problems with mobility and portend an increased risk of disability and death. Because participants with schizophrenia were at increased risk of physical limitations, assessments of chair-rise and balance limitations may be critical to monitoring individuals with psychosis.

Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry.

Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke's R2 = 0.032; liability R2 = 0.017; P < 10-52), Latino (Nagelkerke's R2 = 0.089; liability R2 = 0.021; P < 10-58), and European individuals (Nagelkerke's R2 = 0.089; liability R2 = 0.037; P < 10-113), further highlighting the advantages of incorporating data from diverse human populations.

Long-term Changes in Cognitive Functioning in Individuals With Psychotic Disorders: Findings From the Suffolk County Mental Health Project.

Importance: It remains uncertain whether people with psychotic disorders experience progressive cognitive decline or normal cognitive aging after first hospitalization. This information is essential for prognostication in clinical settings, deployment of cognitive remediation, and public health policy. Objective: To examine long-term cognitive changes in individuals with psychotic disorders and to compare age-related differences in cognitive performance between people with psychotic disorders and matched control individuals (ie, individuals who had never had psychotic disorders). Design, Setting, and Participants: The Suffolk County Mental Health Project is an inception cohort study of first-admission patients with psychosis. Cognitive functioning was assessed 2 and 20 years later. Patients were recruited from the 12 inpatient facilities of Suffolk County, New York. At year 20, the control group was recruited by random digit dialing and matched to the clinical cohort on zip code and demographics. Data were collected between September 1991 and July 2015. Analysis began January 2016. Main Outcomes and Measures: Change in cognitive functioning in 6 domains: verbal knowledge (Wechsler Adult Intelligence Scale-Revised vocabulary test), verbal declarative memory (Verbal Paired Associates test I and II), visual declarative memory (Visual Reproduction test I and II), attention and processing speed (Symbol Digit Modalities Test-written and oral; Trail Making Test [TMT]-A), abstraction-executive function (Trenerry Stroop Color Word Test; TMT-B), and verbal fluency (Controlled Oral Word Association Test). Results: A total of 705 participants were included in the analyses (mean [SD] age at year 20, 49.4 [10.1] years): 445 individuals (63.1%) had psychotic disorders (211 with schizophrenia spectrum [138 (65%) male]; 164 with affective psychoses [76 (46%) male]; 70 with other psychoses [43 (61%) male]); and 260 individuals (36.9%) in the control group (50.5 [9.0] years; 134 [51.5%] male). Cognition in individuals with a psychotic disorder declined on all but 2 tests (average decline: d = 0.31; range, 0.17-0.54; all P < .001). Cognitive declines were associated with worsening vocational functioning (Visual Reproduction test II: r = 0.20; Symbol Digit Modalities Test-written: r = 0.25; Stroop: r = 0.24; P < .009) and worsening negative symptoms (avolition: Symbol Digit Modalities Test-written: r = -0.24; TMT-A: r = -0.21; Stroop: r = -0.21; all P < .009; inexpressivity: Stroop: r = -0.22; P < .009). Compared with control individuals, people with psychotic disrders showed age-dependent deficits in verbal knowledge, fluency, and abstraction-executive function (vocabulary: ß = -0.32; Controlled Oral Word Association Test: ß = -0.32; TMT-B: ß = 0.23; all P < .05), with the largest gap among participants 50 years or older. Conclusions and Relevance: In individuals with psychotic disorders, most cognitive functions declined over 2 decades after first hospitalization. Observed declines were clinically significant. Some declines were larger than expected due to normal aging, suggesting that cognitive aging in some domains may be accelerated in this population. If confirmed, these findings would highlight cognition as an important target for research and treatment during later phases of psychotic illness.

Schizophrenia polygenic risk score and 20-year course of illness in psychotic disorders.

Understanding whether and how the schizophrenia polygenic risk score (SZ PRS) predicts course of illness could improve diagnosis and prognostication in psychotic disorders. We tested whether the SZ PRS predicts symptoms, cognition, illness severity, and diagnostic changes over the 20 years following first admission. The Suffolk County Mental Health Project is an inception cohort study of first-admission patients with psychosis. Patients were assessed six times over 20 years, and 249 provided DNA. Geographically- and demographically-matched never psychotic adults were recruited at year 20, and 205 provided DNA. Symptoms were rated using the Schedule for the Assessment of Positive Symptoms and Schedule for the Assessment of Negative Symptoms. Cognition was evaluated with a comprehensive neuropsychological battery. Illness severity and diagnosis were determined by consensus of study psychiatrists. SZ PRS was significantly higher in first-admission than never psychotic groups. Within the psychosis cohort, the SZ PRS predicted more severe negative symptoms (ß = 0.21), greater illness severity (ß = 0.28), and worse cognition (ß = -0.35), across the follow-up. The SZ PRS was the strongest predictor of diagnostic shifts from affective to non-affective psychosis over the 20 years (AUC = 0.62). The SZ PRS predicts persistent differences in cognition and negative symptoms. The SZ PRS also predicts who among those who appear to have a mood disorder with psychosis at first admission will ultimately be diagnosed with a schizophrenia spectrum disorder. These findings show potential for the SZ PRS to become a tool for diagnosis and treatment planning.

Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases.

BACKGROUND: Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood. METHODS: Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis. RESULTS: CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10-5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden. CONCLUSIONS: CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.

Apolipoprotein E-ε4 allele predicts escalation of psychotic symptoms in late adulthood.

BACKGROUND: Research on a putative link between apolipoprotein-ε4 allele (APOE-ε4) and schizophrenia has been inconclusive. However, prior studies have not investigated the association between APOE-ε4 and symptom trajectories, nor has the existing literature taken into account the potentially moderating effect of age in genetic association studies. METHODS: The association between APOE-ε4 and four symptom dimensions was investigated in a longitudinal study of 116 individuals with schizophrenia initially assessed during their first admission for psychosis and evaluated five times over the following 20years. A meta-analysis identified 29 case-control studies of APOE-ε4 allele frequency in schizophrenia, which were analyzed using random-effects meta-regression to test the potentially moderating effect of age. RESULTS: Longitudinal models identified a specific association between APOE-ε4 and symptom trajectories, showing that APOE-ε4 portends worsening severity of hallucinations and delusions in late adulthood among people with schizophrenia, at a rate of a 0.46 standard deviation increase per decade. Meta-analysis showed a significant effect of age: the association between APOE-ε4 and schizophrenia was not detectable in younger people but became pronounced with age, such that APOE-ε4 increased the odds of diagnosis by 10% per decade. CONCLUSIONS: Taken together, the meta-analysis and longitudinal analysis implicate APOE-ε4 as an age-related risk factor for worsening hallucinations and delusions, and suggest APOE-ε4 may play an age-mediated pathophysiological role in schizophrenia. The presence of an APOE-ε4 allele may also identify a subgroup of patients who require intensive monitoring and additional targeted interventions, especially in mid-to late-life.