Geolocation as a Digital Phenotyping Measure of Negative Symptoms and Functional Outcome

ObjectiveNegative symptoms and functional outcome have traditionally been assessed using clinical rating scales, which rely on retrospective self-reports and have several inherent limitations that impact validity. These issues may be addressed with more objective digital phenotyping measures. In the current study, we evaluated the psychometric properties of a novel “passive” digital phenotyping method: geolocation. MethodParticipants included outpatients with schizophrenia or schizoaffective disorder (SZ: n = 44), outpatients with bipolar disorder (BD: n =19), and demographically matched healthy controls (CN: n = 42) who completed 6 days of “active” digital phenotyping assessments (eg, surveys) while geolocation was recorded. ResultsResults indicated that SZ patients show less activity than CN and BD, particularly, in their travel from home. Geolocation variables demonstrated convergent validity by small to medium correlations with negative symptoms and functional outcome measured via clinical rating scales, as well as active digital phenotyping behavioral indices of avolition, asociality, and anhedonia. Discriminant validity was supported by low correlations with positive symptoms, depression, and anxiety. Reliability was supported by good internal consistency and moderate stability across days. ConclusionsThese findings provide preliminary support for the reliability and validity of geolocation as an objective measure of negative symptoms and functional outcome. Geolocation offers enhanced precision and the ability to take a “big data” approach that facilitates sophisticated computational models. Near-continuous recordings and large numbers of samples may make geolocation a novel outcome measure for clinical trials due to enhanced power to detect treatment effects.     

Cognitive Subtyping in Schizophrenia: A Latent Profile Analysis

Cognitive dysfunction is a core feature of schizophrenia. The subtyping of cognitive performance in schizophrenia may aid the refinement of disease heterogeneity. The literature on cognitive subtyping in schizophrenia, however, is limited by variable methodologies and neuropsychological tasks, lack of validation, and paucity of studies examining longitudinal stability of profiles. It is also unclear if cognitive profiles represent a single linear severity continuum or unique cognitive subtypes. Cognitive performance measured with the Brief Assessment of Cognition in Schizophrenia was analyzed in schizophrenia patients (n = 767). Healthy controls (n = 1012) were included as reference group. Latent profile analysis was performed in a schizophrenia discovery cohort (n = 659) and replicated in an independent cohort (n = 108). Longitudinal stability of cognitive profiles was evaluated with latent transition analysis in a 10-week follow-up cohort. Confirmatory factor analysis (CFA) was carried out to investigate if cognitive profiles represent a unidimensional structure. A 4-profile solution was obtained from the discovery cohort and replicated in an independent cohort. It comprised of a “less-impaired” cognitive subtype, 2 subtypes with “intermediate cognitive impairment” differentiated by executive function performance, and a “globally impaired” cognitive subtype. This solution showed relative stability across time. CFA revealed that cognitive profiles are better explained by distinct meaningful profiles than a severity linear continuum. Associations between profiles and negative symptoms were observed. The subtyping of schizophrenia patients based on cognitive performance and its associations with symptomatology may aid phenotype refinement, mapping of specific biological mechanisms, and tailored clinical treatments.     

Comorbid Depressive and Anxiety Disorders in 509 Individuals With an At-Risk Mental State: Impact on Psychopathology and Transition to Psychosis

Background: The current diagnostic system for subjects at enhanced clinical risk of psychosis allows concurrent comorbid diagnoses of anxiety and depressive disorders. Their impact on the presenting high-risk psychopathology, functioning, and transition outcomes has not been widely researched. Methods: In a large sample of subjects with an At-Risk Mental State (ARMS, n = 509), we estimated the prevalence of DSM/SCID anxiety or depressive disorders and their impact on psychopathology, functioning, and psychosis transition. A meta-analytical review of the literature complemented the analysis. Results: About 73% of ARMS subjects had a comorbid axis I diagnosis in addition to the “at-risk” signs and symptoms. About 40% of ARMS subjects had a comorbid diagnosis of depressive disorder while anxiety disorders were less frequent (8%). The meta-analysis conducted in 1683 high-risk subjects confirmed that baseline prevalence of comorbid depressive and anxiety disorders is respectively 41% and 15%. At a psychopathological level, comorbid diagnoses of anxiety or depression were associated with higher suicidality or self-harm behaviors, disorganized/odd/stigmatizing behavior, and avolition/apathy. Comorbid anxiety and depressive diagnoses were also associated with impaired global functioning but had no effect on risk of transition to frank psychosis. Meta-regression analyses confirmed no effect of baseline anxiety and/or depressive comorbid diagnoses on transition to psychosis. Conclusions: The ARMS patients are characterized by high prevalence of anxiety and depressive disorders in addition to their attenuated psychotic symptoms. These symptoms may reflect core emotional dysregulation processes and delusional mood in prodromal psychosis. Anxiety and depressive symptoms are likely to impact the ongoing psychopathology, the global functioning, and the overall longitudinal outcome of these patients.Key words: psychosis, schizophrenia, ultra high risk, ARMS, prodromal, attenuated psychosis, psychosis risk, depression, anxiety     

Stigma Resistance in Patients With Schizophrenia

Background: An individual''s capacity to counteract the stigma of mental illness, stigma resistance (SR), is considered as playing a crucial role in fighting stigma. However, little is known about SR and its correlates in patients with schizophrenia or schizoaffective disorder. Aim: Exploring SR in patients with schizophrenia or schizoaffective disorder. Method: One hundred fifty-seven participants completed the “Internalized Stigma of Mental Illness” (ISMI) Scale including its subscale on SR. Measures of perceived devaluation and discrimination, depression, self-esteem, empowerment, quality of life, and demographic and clinical variables were obtained. Results: Two-thirds of all patients showed high SR. SR correlated positively with self-esteem, empowerment, and quality of life and negatively with stigma measures and depression. A social network with a sufficient number of friends, being single or married, in contrast to being separated, as well as receiving outpatient treatment, was associated with higher SR. Conclusions: SR is a new and promising concept. The development of stigma-resisting beliefs might help individuals in their hope of finding a fulfilling life and in their recovery from mental illness.     

Risk of Mental Illness in Offspring of Parents With Schizophrenia,Bipolar Disorder,and Major Depressive Disorder: A Meta-Analysis of Family High-Risk Studies

Objective: Offspring of parents with severe mental illness (SMI; schizophrenia, bipolar disorder, major depressive disorder) are at an increased risk of developing mental illness. We aimed to quantify the risk of mental disorders in offspring and determine whether increased risk extends beyond the disorder present in the parent. Method: Meta-analyses of absolute and relative rates of mental disorders in offspring of parents with schizophrenia, bipolar disorder, or depression in family high-risk studies published by December 2012. Results: We included 33 studies with 3863 offspring of parents with SMI and 3158 control offspring. Offspring of parents with SMI had a 32% probability of developing SMI (95% CI: 24%–42%) by adulthood (age >20). This risk was more than twice that of control offspring (risk ratio [RR] 2.52; 95% CI 2.08–3.06, P < .001). High-risk offspring had a significantly increased rate of the disorder present in the parent (RR = 3.59; 95% CI: 2.57–5.02, P < .001) and of other types of SMI (RR = 1.92; 95% CI: 1.48–2.49, P < .001). The risk of mood disorders was significantly increased among offspring of parents with schizophrenia (RR = 1.62; 95% CI: 1.02–2.58; P = .042). The risk of schizophrenia was significantly increased in offspring of parents with bipolar disorder (RR = 6.42; 95% CI: 2.20–18.78, P < .001) but not among offspring of parents with depression (RR = 1.71; 95% CI: 0.19–15.16, P = .631). Conclusions: Offspring of parents with SMI are at increased risk for a range of psychiatric disorders and one third of them may develop a SMI by early adulthood.Key words: schizophrenia, bipolar disorder, depression, offspring, meta-analysis     

Identification of Central Symptoms in Depression of Older Adults With the Geriatric Depression Scale Using Network Analysis and Item Response Theory

ObjectiveThis study aimed to identify the central symptoms of late-life depression using network analysis and the item response theory. MethodsA total of 3,472 older adults were enrolled and the Geriatric Depression Scale-15 (GDS-15) was used to evaluate the depressive symptoms. To identify the central symptoms and the network structures among the individual symptoms, the analyses of symptom network structures and item response theory were performed. ResultsAmong items on the GDS-15, “Happy,” “Hopeless,” “Empty,” “Bored,” “Worthless,” and “Good spirits” showed significantly higher strength centrality than the other symptoms. Among all the edges, the edge between “Empty” and “Bored” was the strongest; however, these two symptoms were not connected strongly to other symptoms. In the analysis of item response theory, “Empty,” “Bored,” “Hopeless,” “Worthless,” “Happy,” “Helpless,” and “Satisfied” presented a very high value on the discrimination parameter. ConclusionOur study identified the central symptoms and the network structures among symptoms listed on the GDS-15. Most of central symptoms identified by network analysis and item response theory coincided. Our results suggest that these central symptoms need to be prioritized as highly comorbid symptoms and can contribute to the development of a brief screening tool for the elderly.     

A Meta-analysis of Cognitive Remediation for Schizophrenia: Efficacy and the Role of Participant and Treatment Factors

The number of randomized, controlled studies of cognitive remediation (CR) for schizophrenia, a therapeutic approach designed to improve cognitive skills and function, has grown substantially over the past 20 years. Active elements of CR treatment, however, remain unknown. The current meta-analysis investigated treatment, study, and participant factors in the size of observed treatment effects. Electronic databases were searched up to May 2020 using variants of the key words “cognitive remediation,” “clinical trials,” and “schizophrenia.” This search produced 73 unique, randomized, controlled trials. Data were independently extracted by 3 reviewers with excellent reliability. Random-effects models were used to assess primary cognitive and secondary symptom and functional outcomes. Moderator analyses investigated the role of a variety of treatment, study, and participant factors. The meta-analysis (4594 participants) revealed that CR produced significant small-to-moderate size improvements in all domains of cognition studied (Hedge’s gs = .19–.33). and a significant small improvement in function (Hedge’s g = .21). CR programs that included a discussion (“bridging”) group to help apply acquired cognitive skills to everyday life produced larger effects on global cognition and verbal memory. CR programs with strategy-coaching produced larger effects on episodic memory. Sample age, gender, positive, negative, and overall symptoms, and medication dose did not serve as barriers to treatment gains. CR produces small-to-moderate improvements in cognition and function in schizophrenia. Programs of CR that utilize bridging groups and strategy-coaching are more cognitively potent. Future research should focus on ways to modify CR to bolster generalization of cognitive improvements to function.     

The Relationship of Attitudinal Beliefs to Negative Symptoms,Neurocognition, and Daily Functioning in Recent-Onset Schizophrenia

Background: In the early course of schizophrenia, premorbid functioning, negative symptoms, and neurocognition have been robustly associated with several domains of daily functioning. Research with chronic schizophrenia patients suggests that attitudinal beliefs may influence daily functioning. However, these relationships have not been examined in recent-onset schizophrenia patients. Methods: The sample consisted of recent-onset schizophrenia outpatients (n = 71) who were on average 21.7 (SD = 3.3) years old, had 12.5 (SD = 1.8) years of education, and 5.9 (SD = 6.3) months since psychosis onset. Patients were assessed for premorbid adjustment, positive and negative symptoms, neurocognition, attitudinal beliefs, and daily functioning. Normal controls (n = 20) were screened for psychopathology and demographically matched to the patients. Results: Comparisons indicated that recent-onset patients had higher levels of dysfunctional attitudes and lower self-efficacy compared to healthy controls (t = 3.35, P < .01; t = −4.1, P < .01, respectively). Dysfunctional attitudes (r = −.34) and self-efficacy (r = .36) were significantly correlated with daily functioning. Negative symptoms were found to mediate the relationship between self-efficacy and daily functioning (Sobel test, P < .01), as well as between dysfunctional attitudes and daily functioning (Sobel test, P < .05). Neurocognition was a significant mediator of the relationship between self-efficacy and daily functioning (Sobel test, P < .05). Discussion: Early course schizophrenia patients have significantly more dysfunctional attitudes and lower self-efficacy than healthy subjects. Both self-efficacy and dysfunctional attitudes partially contribute to negative symptoms, which in turn influence daily functioning. In addition, self-efficacy partially contributes to neurocognition, which in turn influences daily functioning.Key words: recent-onset schizophrenia, dysfunctional attitudes, self-efficacy, negative symptoms, neurocognition, daily functioning, mediation models, premorbid history     

Accelerated Brain Aging in Schizophrenia and Beyond: A Neuroanatomical Marker of Psychiatric Disorders

Structural brain abnormalities are central to schizophrenia (SZ), but it remains unknown whether they are linked to dysmaturational processes crossing diagnostic boundaries, aggravating across disease stages, and driving the neurodiagnostic signature of the illness. Therefore, we investigated whether patients with SZ (N = 141), major depression (MD; N = 104), borderline personality disorder (BPD; N = 57), and individuals in at-risk mental states for psychosis (ARMS; N = 89) deviated from the trajectory of normal brain maturation. This deviation was measured as difference between chronological and the neuroanatomical age (brain age gap estimation [BrainAGE]). Neuroanatomical age was determined by a machine learning system trained to individually estimate age from the structural magnetic resonance imagings of 800 healthy controls. Group-level analyses showed that BrainAGE was highest in SZ (+5.5 y) group, followed by MD (+4.0), BPD (+3.1), and the ARMS (+1.7) groups. Earlier disease onset in MD and BPD groups correlated with more pronounced BrainAGE, reaching effect sizes of the SZ group. Second, BrainAGE increased across at-risk, recent onset, and recurrent states of SZ. Finally, BrainAGE predicted both patient status as well as negative and disorganized symptoms. These findings suggest that an individually quantifiable “accelerated aging” effect may particularly impact on the neuroanatomical signature of SZ but may extend also to other mental disorders.Key words: neuroanatomical dysmaturation, biomarker, machine learning, accelerated aging, schizophrenia, depression, borderline personality disorder     

Heterogeneity of Outcomes and Network Connectivity in Early-Stage Psychosis: A Longitudinal Study

Imaging studies in psychotic disorders typically examine cross-sectional relationships between magnetic resonance imaging (MRI) signals and diagnosis or symptoms. We sought to examine changes in network connectivity identified using resting-state functional MRI (fMRI) corresponding to divergent functional recovery trajectories and relapse in early-stage psychosis (ESP). Prior studies have linked schizophrenia to hyperconnectivity in the default mode network (DMN). Given the correlations between the DMN and behavioral impairments in psychosis, we hypothesized that dynamic changes in DMN connectivity reflect the heterogeneity of outcomes in ESP. Longitudinal data were collected from 66 ESP patients and 20 healthy controls. Longitudinal cluster analysis identified subgroups of patients with similar trajectories in terms of symptom severity and functional outcomes. DMN connectivity was measured in a subset of patients (n = 36) longitudinally over 2 scans separated by a mean of 12 months. We then compared connectivity between patients and controls, and among the different outcome trajectory subgroups. Among ESP participants, 4 subgroups were empirically identified corresponding to: “Poor,” “Middle,” “Catch-up,” and “Good” trajectory outcomes in the complete dataset (n = 36), and an independent replication (n = 30). DMN connectivity changes differed significantly between functional subgroups (F_3,32 = 6.06, P-FDR corrected = .01); DMN connectivity increased over time in the “Poor” outcome cluster (β = +0.145) but decreased over time in the “Catch-up” cluster (β = −0.212). DMN connectivity is dynamic and correlates with a change in functional status over time in ESP. This approach identifies a brain-based marker that reflects important neurobiological processes required to sustain functional recovery.     

The 5-Year Course of Obsessive-Compulsive Symptoms and Obsessive-Compulsive Disorder in First-Episode Schizophrenia and Related Disorders

Objective: To determine the course of obsessive-compulsive symptoms (OCS) and obsessive-compulsive disorder (OCD) in first-episode schizophrenia and related disorders and their relationship with clinical characteristics. Methods: Consecutively, admitted patients with a first-episode of schizophrenia, schizophreniform disorder, or schizoaffective disorder were screened for OCS, and these were measured with the Yale-Brown Obsessive-Compulsive Scale. Positive and Negative Syndrome Scale and Montgomery Åsberg Depression Rating Scale were used to assess severity of other symptoms. The course of 3- and 5-year symptoms, psychotic relapse, substance use, remission, full recovery, suicide, and social functioning were assessed. Results: One hundred and eighty-six consecutively admitted and consenting patients were included. Five years after admission, OCS could be assessed in 172 patients. Ninety-one patients (48.9%) reported no OCS symptoms on any of the assessments. OCS restricted to the first assessments occured in 15.1%, 13.4% had persistent OCS, 7.0% had no OCS at first assessment but developed OCS subsequently, and 15.6% had intermittent OCS. The proportion of patients with comorbid OCD varied between 7.3% and 11.8% during follow-up. OCD was associated with more severe depressive symptoms and poorer premorbid functioning and social functioning at follow-up. Conclusions: The 5-year course of OCS/OCD in patients with first-episode schizophrenia or related disorders is variable. OCS/OCD comorbidity was not associated with a more severe course of psychotic symptoms and relapse. Comorbid OCD was associated with more severe depressive symptoms, social dysfunction and worse premorbid functioning. Specific treatment options for schizophrenia patients with comorbid OCD are needed.     

Schizophrenia Candidate Gene ERBB4: Covert Routes of Vulnerability to Psychosis Detected at the Population Level

Prior genetic and functional evidence established ERBB4 as a probable schizophrenia susceptibility gene that may confer risk via modulating brain information processing dependent on the integrity of frontotemporal brain circuitry. Utilizing retrospective data drawn from the cross-sectional population-based Athens Study of Psychosis Proneness and Incidence of Schizophrenia (ASPIS) (n = 1127), we attempted to independently replicate and further extend previous findings by examining the effects of ERBB4 gene variants on 3 broad population–based psychosis-related phenotypes: verbal working memory (VWM), trait schizotypy, and stress-induced subclinical psychotic experiences (PE). Three common ERBB4 single nucleotide polymorphisms that were previously associated with schizophrenia and impaired frontotemporal-related information processing (rs7598440, rs839523, and rs707284), their haplotypes, and corresponding diplotypes were tested. VWM performance was significantly associated with rs839523 and rs707284 markers even after correction for multiple testing, thus validating reported findings that have implicated ERBB4 gene variation on working memory. No associations were detected between these ERBB4 variants and trait schizotypy. However, we were able to detect a significant effect of rs7598440 marker on PE expressed under stressful environmental conditions. Combined haplotype analysis of the above 3 markers, identified a “yin-yang” pattern of association, confirmed at the diplotype level. While GGG haplotype homozygotes were associated with “protective” effects on VWM performance and PE, AAA “risk” haplotype carriers were associated with worse VWM performance and simultaneously exhibited significantly elevated PE. This dual, possibly pleiotropic, impact on frontotemporal circuitry and increased sensitivity to psychosocial stress may represent subtle manifestations of ERBB4-related vulnerability to psychosis, expressed at the population level.     

Depressive factors and their relationships with other symptom domains in schizophrenia, schizoaffective disorder, and psychotic depression

Relationships among different symptom domains were investigated in patients with acute exacerbation of schizophrenia with depressive symptoms, psychotic depression, or schizoaffective disorder, depressive subtype. Scores for depression and depressive factors were correlated with positive, negative, and extrapyramidal symptoms within diagnostic categories. No between-group differences in the relationship of different symptom domains could be found, and no substantial relationship between depression and positive symptoms could be revealed in any diagnostic subgroup. Only the retardation factor of depression showed a significant overlap with negative symptoms; depressive core symptoms did not. Core symptoms of depression were independent from other symptoms in all investigated diagnostic groups. Depression seems to represent a heterogeneous symptom domain with unique relationships of components to positive and negative symptoms across nosological borders. A more differentiated assessment, analysis, and treatment of depressive symptoms is therefore recommended for patients with combined depressive and psychotic symptoms.     

Distinguishing Between Schizophrenia and Other Psychotic Disorders

The Diagnostic and Statistical Manual of Mental Disorders (DSM) has provided diagnostic reliability across observers while neglecting biological validity. The current theme issue explores the boundaries between schizophrenia and bipolar disorder, using neuro-cognition, systems neuroscience, and genetics as points of departure to begin consideration of a biologically based reclassification of these illnesses.Key words: schizophrenia, bipolar, validity, classification

“Ce n’est qu’un début, continuons le débat.” (“This is just the beginning, let’s continue the debate.”)French students (May 1968)

In the ongoing debate over where to draw the boundary (if any) between schizophrenia and bipolar disorder, the arguments are familiar, the battle lines clearly drawn, but the scientific observations continue to be updated in important ways that make a reassessment timely. The current issue of the Bulletin features comprehensive overviews from the vantage points of genetics and systems neuroscience that continue to reshape the nature of the debate.Arguments over the discrete vs continuous nature of schizophrenia and bipolar disorder are important because they promise to translate into improved, more patient-specific prognoses and therapies.Disease classifications proceed from some logical beginning: In the absence of both informative biological data and clinical physical signs, clinical phenomenology, family history, and disease course constitute the mandatory starting points on the road to meaningful diagnostic categories. Hence, Kraepelin began in 1893 by defining these 2 entities based on longitudinal course and outcome. He had already begun to backtrack from this dichotomy by 1920 in the final edition of his Lehrbuch.¹ Before that, the follow-up studies from his pupil Zendig² demonstrated favorable outcome in a third of Kraepelin’s own large schizophrenia case series. The boundaries between clinical entities defined by phenomenology appear to be distributed on a continuum and to lack sharp demarcations. Thus, one-third of patients with schizophrenia simultaneously meet criteria for major depression,³ one-third of patients with bipolar illness manifest psychotic symptoms, which in some cases persist between overt episodes of mood disturbance.⁴ Recently, Keshavan⁵ showed no point of symptomatic rarity between schizophrenia, psychotic bipolar disorder, and schizoaffective disorder in the large Bipolar Schizophrenia Network on Intermediate Phenotypes sample. Similarly, the Suffolk County mental health project showed a lack of boundary, defined in terms of functioning, between schizoaffective disorder and schizophrenia,⁶ although there are occasional reports of biological distinctions between them, for example.⁷ Response to medications has not been especially helpful as a guide. The early Northwick Park studies offered some suggestion that patients with psychosis responded to antipsychotics, patients with mood disorders responded to lithium, and patients with features of both syndromes responded to both medicines.⁸ However, antipsychotic medications are now prescribed routinely for schizophrenia, bipolar disorder, and antidepressant treatment–resistant major depression, presumably, in part because they are effective in these conditions. Real-world experience with these patients shows that many are being prescribed polypharmaceutical cocktails of antipsychotic, antidepressant, and mood stabilizer medications. As is frequently pointed out, the one exception to this cross-diagnostic promiscuity seems to be lithium, to which about one-third of nonpsychotic bipolar patients and a much smaller proportion of classic schizophrenia patients respond with symptom remission.⁹ Although both schizophrenia and bipolar disorder are clearly heritable, as Cardno and Owen¹⁰ illustrate in this issue, segregation within families is less clear-cut than believed previously, and these conditions do not decisively “breed true,”¹¹ although psychotic bipolar illness may aggregate familially.⁴ Genome wide–association studies tend to uncover candidate single-nucleotide polymorphisms that confer risk for both disorders, and genes such as DISC-1 are also associated with increased risk for schizophrenia, bipolar illness, major depression, and other conditions.As pointed out by Frangou¹² in this issue, emergent properties such as cognition are an excellent starting point for examining differences between syndromes because they are reliably assessed across centers with standardized tests. Because they demonstrate both heritability and frequent abnormality in unaffected first-degree relatives, they constitute phenotypes, conceptually.¹¹ In this issue, Reilly and Sweeney¹³ point out, “Considerable evidence supports the notion that broadly impaired cognitive functioning is central to the pathophysiology of psychosis, and … [its] magnitude, rather than [its] presence differentiates syndromes within the psychosis spectrum.” They further suggest, “The detection of specific effects … is challenging yet critical if the field is to further advance development of pharmacological treatments targeting cognitive deficits … .” In our search for specificity, we ask if there is any point in the illness course where differences emerge? Frangou¹² notes that important differences are detectable in that premorbid cognitive and social abnormalities appear to be less marked in bipolar illness, although these differences diminish after illness onset. Similarly, copy number variants occurring in central nervous system–relevant genes are significantly commoner in schizophrenia than bipolar disorder, although, as mentioned earlier, genetic differences are not schizophrenia-specific, being found in association with other serious neurodevelopmental disorders, including epilepsy, learning disabilities, and autism spectrum disorders.Where do we go from here? This debate will continue until distinct etiopathologies for schizophrenia and bipolar disorder emerge—parallel events that ultimately ended this type of debate in clinical medicine. Ultimately, though, we are likely to define the new “illnesses” based on regularly co-occurring biological (including genetic) characteristics. One possibility in the short term is that we remain diagnostically uncommitted and code psychosis and mood disorder separately, as suggested by Kotov.¹⁴ Some researchers have argued strongly against this stance.¹⁵ Different associations with indices of neurodevelopmental impairment may be one point of departure as suggested in this issue by Cardno and Owen¹⁰ and Frangou.¹² Frangou suggests that “abnormalities in multiple large-scale neural networks and alterations in local micro-scale circuitry within associative and sensory cortices” caused by environmental insults and genetic variation, “disrupt processes responsible for orderly neuronal configuration” (eg, synaptic integrity, neurotransmission). Identifying such abnormalities then proceeds logically toward a redefinition of major mental illnesses based on systems neuroscience and the defining of “more homogeneous groups of patients.”¹² This strategy may reveal similarities across all putatively developmentally based psychiatric illnesses, including autism and learning disabilities, extending beyond schizophrenia and bipolar disorder. Cardno and Owen¹⁰ suggest we move away from lifetime diagnostic categories toward a system that relies more on “categorical or dimensional syndromes, networks of correlated symptoms, and/or endophenotypes … according to particular research or clinical requirements.”Regarding the genetic underpinnings of these disorders, we ask, “Precisely what is being inherited?” One possibility is that a small number of genes are being passed on that are responsible for multiple clinical manifestations, from mood instability to psychoticism (ie, an instance of pleiotropy). Another possibility is that risk is being inherited for more than one behavioral trait, which happens to commonly co-occur, for a variety of reasons including assortative mating. For example, “psychoticism,” whose pure form is expressed as Kraepelinian schizophrenia, and “mood instability,” whose pure form is expressed as nonpsychotic bipolar illness, may both be passed on, with the possibility of them being mixed together in various combinations to produce, eg, schizoaffective or psychotic bipolar disorder.What might the new disease landscape look like, whether based on neuronal circuit-based endophenotypes or commonalities in risk genes and their associated molecular biological processes? One possibility is that several clinical groupings will emerge that are phenomenologically heterogeneous, containing examples of what we now define clinically as schizophrenia and bipolar disorder, but consistent in their underlying biological markers. This would be analogous to the fate of “dropsy” in medicine. A less satisfactory outcome would be that more knowledge of etiopathology would result in the fissuring of familiar clinical syndromes into unique biological clusters, representing agglomerations defined by differing pathologic processes leading to disruption in final common biological pathways, more along the lines of the manner in which Alzheimer’s disease is now considered. The ultimate hope is to aggregate disorders according to biological mechanisms that underlie clinical phenomena and that point us toward evidence-based treatment targets and interventions. This is consistent with the National Institute of Mental Health’s Research Domain Criteria¹⁶ and the earlier cognitive neuropsychiatric approach.^17–19 This debate began with Kraepelin, is moving forward, but continues.     

Depression and cognitive deficits in geriatric schizophrenia

Objective

Past reports have found patients with comorbid depression and schizophrenia spectrum disorders exhibit greater deficits in memory and attention compared to schizophrenia spectrum disorder patients without depressive symptoms. However, in contrast to younger schizophrenia patients, the few past studies using cognitive screens to examine the relationship between depression and cognition in inpatient geriatric schizophrenia have found that depressive symptomatology was associated with relatively enhanced cognitive performance. In the current study we examined the relationship between depressive symptoms and cognitive deficits in geriatric schizophrenia spectrum disorder patients (n = 71; mean age = 63.7) on an acute psychiatric inpatient service.

Method

Patients completed a battery of cognitive tests assessing memory, attention and global cognition. Symptom severity was assessed via the PANSS and Calgary Depression Scale for Schizophrenia.

Results

Results revealed that geriatric patients' depression severity predicted enhancement of their attentional and verbal memory performance. Patients' global cognitive functioning and adaptive functioning were not associated with their depression severity.

Conclusion

Contrary to patterns typically seen in younger patients and non-patient groups, increasing depression severity is associated with enhancement of memory and attention in geriatric schizophrenia spectrum disorder patients. Also, diverging from younger samples, depression severity was unassociated with patients adaptive and global cognitive functioning.     

Meta-analysis of Positive and Negative Symptoms Reveals Schizophrenia Modifier Genes

Background: Evidence suggests that genetic factors may influence both schizophrenia (Scz) and its clinical presentation. In recent years, genome-wide association studies (GWAS) have demonstrated considerable success in identifying risk loci. Detection of “modifier loci” has the potential to further elucidate underlying disease processes. Methods: We performed GWAS of empirically derived positive and negative symptom scales in Irish cases from multiply affected pedigrees and a larger, independent case–control sample, subsequently combining these into a large Irish meta-analysis. In addition to single-SNP associations, we considered gene-based and pathway analyses to better capture convergent genetic effects, and to facilitate biological interpretation of these findings. Replication and testing of aggregate genetic effects was conducted using an independent European-American sample. Results: Though no single marker met the genome-wide significance threshold, genes and ontologies/pathways were significantly associated with negative and positive symptoms; notably, NKAIN2 and NRG1, respectively. We observed limited overlap in ontologies/pathways associated with different symptom profiles, with immune-related categories over-represented for negative symptoms, and addiction-related categories for positive symptoms. Replication analyses suggested that genes associated with clinical presentation are generalizable to non-Irish samples. Conclusions: These findings strongly support the hypothesis that modifier loci contribute to the etiology of distinct Scz symptom profiles. The finding that previously implicated “risk loci” actually influence particular symptom dimensions has the potential to better delineate the roles of these genes in Scz etiology. Furthermore, the over-representation of distinct gene ontologies/pathways across symptom profiles suggests that the clinical heterogeneity of Scz is due in part to complex and diverse genetic factors.Key words: schizophrenia, meta-analysis, clinical heterogeneity, modifier genes, negative symptoms, positive symptoms     

Multicenter Study of Brain Volume Abnormalities in Children and Adolescent-Onset Psychosis

The goal of the study is to determine the extent of structural brain abnormalities in a multicenter sample of children and adolescents with a recent-onset first episode of psychosis (FEP), compared with a sample of healthy controls. Total brain and lobar volumes and those of gray matter (GM), white matter, and cerebrospinal fluid (CSF) were measured in 92 patients with a FEP and in 94 controls, matched for age, gender, and years of education. Male patients (n = 64) showed several significant differences when compared with controls (n = 61). GM volume in male patients was reduced in the whole brain and in frontal and parietal lobes compared with controls. Total CSF volume and frontal, temporal, and right parietal CSF volumes were also increased in male patients. Within patients, those with a further diagnosis of “schizophrenia” or “other psychosis” showed a pattern similar to the group of all patients relative to controls. However, bipolar patients showed fewer differences relative to controls. In female patients, only the schizophrenia group showed differences relative to controls, in frontal CSF. GM deficit in male patients with a first episode correlated with negative symptoms. Our study suggests that at least part of the GM deficit in children and adolescent-onset schizophrenia and in other psychosis occurs before onset of the first positive symptoms and that, contrary to what has been shown in children-onset schizophrenia, frontal GM deficits are probably present from the first appearance of positive symptoms in children and adolescents.     

Treating comorbid anxiety and depression: Psychosocial and pharmacological approaches

Comorbid anxiety with depression predicts poor outcomes with a higher percentage of treatment resistance than either disorder occurring alone. Overlap of anxiety and depression complicates diagnosis and renders treatment challenging. A vital step in treatment of such comorbidity is careful and comprehensive diagnostic assessment. We attempt to explain various psychosocial and pharmacological approaches for treatment of comorbid anxiety and depression. For the psychosocial component, we focus only on generalized anxiety disorder based on the following theoretical models: (1) “the avoidance model”; (2) “the intolerance of uncertainty model”; (3) “the meta-cognitive model”; (4) “the emotion dysregulation model”; and (5) “the acceptance based model”. For depression, the following theoretical models are explicated: (1) “the cognitive model”; (2) “the behavioral activation model”; and (3) “the interpersonal model”. Integration of these approaches is suggested. The treatment of comorbid anxiety and depression necessitates specific psychopharmacological adjustments as compared to treating either condition alone. Serotonin reuptake inhibitors are considered first-line treatment in uncomplicated depression comorbid with a spectrum of anxiety disorders. Short-acting benzodiazepines (BZDs) are an important “bridging strategy” to address an acute anxiety component. In patients with comorbid substance abuse, avoidance of BZDs is recommended and we advise using an atypical antipsychotic in lieu of BZDs. For mixed anxiety and depression comorbid with bipolar disorder, we recommend augmentation of an antidepressant with either lamotrigine or an atypical agent. Combination and augmentation therapies in the treatment of comorbid conditions vis-à-vis monotherapy may be necessary for positive outcomes. Combination therapy with tricyclic antidepressants, gabapentin and selective serotonin/norepinephrine reuptake inhibitors (e.g., duloxetine) are specifically useful for comorbid chronic pain syndromes. Aripiprazole, quetiapine, risperidone and other novel atypical agents may be effective as augmentations. For treatment-resistant patients, we recommend a “stacking approach” not dissimilar from treatment of hypertension In conclusion, we delineate a comprehensive approach comprising integration of various psychosocial approaches and incremental pharmacological interventions entailing bridging strategies, augmentation therapies and ultimately stacking approaches towards effectively treating comorbid anxiety and depression.     

Antipsychotics Use Is Associated With Greater Adherence to Cardiometabolic Medications in Patients With Schizophrenia: Results From a Nationwide,Within-subject Design Study

BackgroundPeople with schizophrenia/schizoaffective disorder (schizophrenia) die early, largely due to cardiovascular-related mortality. Antipsychotics are associated with lower mortality. We aimed to explore whether antipsychotic use can reduce discontinuation of medications for cardiovascular risk factors and diseases (“cardiometacolic drugs”), using a within-study design controlling for subject-related factors.MethodsPersons diagnosed with schizophrenia between 1972 and 2014, aged <65 years at cohort entry were identified in Finnish national databases. Four subcohorts were formed based on cardiometabolic drug use during the follow-up period, 1996–2017, namely statin (n = 14,047), antidiabetic (n = 13,070), antihypertensive (n = 17,227), and beta-blocker (n = 21,464) users. To control for subject-related factors, including likelihood of adherence as a trait characteristic, we conducted a within-subject study comparing the risk of discontinuation of each cardiometabolic drug during periods on vs off antipsychotics within each subject. We also accounted for number of psychiatric and nonpsychiatric visits in sensitivity analyses.ResultsIn 52,607 subjects with schizophrenia, any antipsychotic use vs nonuse was associated with decreased discontinuation risk of antidiabetics (adjusted hazard ratio [aHR] = 0.56, 95% confidence interval [CI] = 0.47–0.66), statins (aHR = 0.61, 95%CI = 0.53–0.70), antihypertensives (aHR = 0.63, 95%CI = 0.56–0.71), and beta-blockers (aHR = 0.79, 95%CI = 0.73–0.87). Antipsychotics ranking best for discontinuation of all cardiometabolic drug categories were clozapine (aHR range = 0.34–0.55), followed by olanzapine (aHR = 0.43–0.71). For statins, aHRs ranged from aHR = 0.30 (95%CI = 0.09–0.98) (flupentixol-long-acting injectable (LAI) to aHR = 0.71 (95%CI = 0.52–0.97) (risperidone-LAI), for anti-diabetic medications from aHR = 0.37 (95%CI = 0.28–0.50) (clozapine) to aHR = 0.70 (95%CI = 0.53–0.92) (quetiapine), for antihypertensives from aHR = 0.14 (95%CI = 0.04–0.46) (paliperidone-LAI) to aHR = 0.69 (95%CI = 0.54–0.88) (perphenazine), for beta-blockers from aHR = 0.55 (95%CI = 0.48–0.63) (clozapine) to aHR = 0.76 (95%CI = 0.59–0.99) (perphenazine-LAI). The decreased risk of discontinuation associated with antipsychotic use somewhat varied between age strata. Sensitivity analyses confirmed main findings.DiscussionIn this national database within-subject design study, current antipsychotic use was associated with substantially decreased risk of discontinuation of statins, anti-diabetics, antihypertensives, and beta-blockers, which might explain reduced cardiovascular mortality observed with antipsychotics in people with schizophrenia.