Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2022 Jun 30.
Published in final edited form as: Psychiatry Res Neuroimaging. 2021 Apr 7;312:111287. doi: 10.1016/j.pscychresns.2021.111287

An Exploratory Magnetic Resonance Imaging Study of Suicidal Ideation in Individuals at Clinical High-Risk for Psychosis

Ragy R Girgis 1,*,#, Rakshathi Basavaraju 1,#, Jeanelle France 1, Melanie M Wall 1, Gary Brucato 1, Jeffrey A Lieberman 1, Frank A Provenzano 1
PMCID: PMC8137659  NIHMSID: NIHMS1692833  PMID: 33848727

Abstract

Suicide is a major cause of death in psychosis and associated with significant morbidity. Suicidal ideation (SI) is very common in those at clinical high-risk for psychosis (CHR) and predicts later suicide. Despite substantial work on the pathobiology of suicide in schizophrenia, little is known of its neurobiological underpinnings in the CHR or putatively prodromal state. Therefore, in this pilot study, we examined the neurobiology of SI in CHR individuals using structural MRI. Subjects were aged 14–30 and met criteria for the Attenuated Positive Symptom Psychosis-Risk Syndrome (APSS) delineated in the Structured Interview for Psychosis-Risk Syndromes (SIPS). Suicidality was assessed using the Columbia Suicide Severity Rating Scale (C-SSRS). Volumetric MRI scans were obtained on a 3T Phillips scanner. MRI data were available for 69 individuals (19 CHR without SI, 31 CHR with SI and 19 healthy control subjects). CHR individuals with SI had thicker middle temporal and right insular cortices than CHR individuals without SI and healthy control subjects. The location of these findings is consistent with neurobiological findings regarding suicide in syndromal psychosis. These findings underscore the potential for the use of brain imaging biomarkers of suicide risk in CHR individuals.

Keywords: clinical high-risk for psychosis, psychosis, suicide, suicidal ideation, MRI, magnetic resonance imaging, attenuated positive symptoms

1. Introduction

Individuals with schizophrenia die almost 15 years earlier than individuals without schizophrenia (Hjorthoj et al., 2017). Much of this excess risk is related to suicidality (Bushe et al., 2010). Upwards of half of individuals with psychotic disorders experience suicidal ideation (SI) during their lifetimes (Fenton et al., 1997; Skodlar et al., 2008) and approximately 30% attempt suicide at some point in their lives (Barrett et al., 2011). The lifetime risk of dying by suicide in schizophrenia and related disorders has been reported to be between 5–10% (Carlborg et al., 2008; Kasckow et al., 2011; Palmer et al., 2005; Siris, 2001). Therefore, suicidality constitutes a significant problem among individuals with psychotic disorders.

Suicide and suicidal ideation are especially problematic in the early stages of psychosis when patients are at an even greater risk of dying by suicide (Dutta et al., 2010; Mortensen and Juel, 1993; Nordentoft et al., 2004; Palmer et al., 2005). Neurobiological work on suicide in psychosis is limited but has revealed abnormalities in white matter (Lee et al., 2016; Long et al., 2018; Rusch et al., 2008) and brain function (Minzenberg et al., 2015; Potvin et al., 2018). Some of the most consistent work has demonstrated cortical thinning or lower gray matter volumes in several regions including in temporal and insular cortices (Besteher et al., 2016; Giakoumatos et al., 2013) as well as other abnormalities (Aguilar et al., 2008; Spoletini et al., 2011). The importance of these brain regions to suicide is highlighted by a recent, comprehensive review by Schmaal and colleagues (Schmaal et al., 2020). In this review, Schmaal and colleagues provide a model of suicidal thoughts and behaviors in which an extended ventral and posterior network, including temporal and insular cortices, may be responsible for negative and blunted emotional and mood states, while a more dorsal network would be more responsible for suicidal behavior due to its role in cognitive control and flexibility (Schmaal et al., 2020).

There is substantially less work on suicidality in the pre-syndromal or clinical high-risk (CHR) period. However, the available evidence suggests that SI and suicide attempts are very common – upwards of 50% or more in some studies (Andriopoulos et al., 2011; DeVylder et al., 2012; Gill et al., 2015; Hutton et al., 2011). These data are consistent with evidence that the mere presence of positive symptoms, either frank or attenuated, is strongly associated with suicidality (Kelleher et al., 2013; Kelleher et al., 2012; Yates et al., 2019).

Despite these important findings which suggest that identifying suicidality, and biomarkers of suicidality, in the early stages of psychosis could potentially identify those who will go on to attempt suicide, there remain no studies of the neurobiology of suicide in the CHR phase of the illness.

Aleman and Denys have written that despite the prevalence of suicidality, its societal impact, and its financial burden, as well as that suicidality is preventable and treatable, not enough progress has been made towards understanding and treating suicidal behavior (Aleman and Denys, 2014). They suggest that psychiatry has neglected research on suicidality for reasons such as cultural taboo, its complicated and multi-factorial nature, and potentially diverse etiologies between fatal and non-fatal suicide attempts. To address these issues, they advise a number of solutions, including funding further research on the psychological and neurobiological roots of suicide.

Therefore, the goals of this exploratory, pilot study were to examine the neurobiology of SI, the precursor to suicidal behavior, among CHR individuals. We focused on cortical thickness given that the most robust and replicated findings on the neurobiology of suicide in psychosis suggest abnormalities in cortical thickness and gray matter volumes in schizophrenia (Girgis, 2020). In particular, while we examined the full cortical mantle, our primary areas of interest were insula and temporal cortex given that these were the primary areas found to be abnormal in two prior studies of cortical thickness and gray matter volume in individuals with schizophrenia and related psychotic disorders who had previously attempted suicide (Besteher et al., 2016; Giakoumatos et al., 2013). We hypothesized that temporal and insular cortices among CHR individuals with SI would be thinner than in CHR individuals without SI and healthy control subjects.

2. Methods

2.1. Participants

Subjects were recruited at the Center of Prevention and Evaluation (COPE), an outpatient research program for the evaluation and treatment of attenuated positive symptoms of psychosis at the New York State Psychiatric Institute (NYSPI)/Columbia University Irving Medical Center (CUIMC) in New York City. The NYSPI Institutional Review Board approved the research. All adults provided written informed consent, while minors provided written assent, with written informed consent obtained from a parent.

Potential participants were referred to COPE by a network of academic centers, private practitioners, clinics, and hospitals, or were self-referred after reviewing the center’s web site, for evaluation of possible emergent psychotic symptoms. All participants were between the ages of 14 and 30 and met criteria for the Attenuated Positive Symptom Psychosis-Risk Syndrome (APSS), Progression Subtype, delineated in the Structured Interview for Psychosis-Risk Syndromes (SIPS; McGlashan et al., 2001; McGlashan et al., 2014; Miller et al., 2003; Miller et al., 2002; Rosen et al., 2002). The SIPS, with which all participants were examined, involves a semi-structured interview that probes for past and current signs and symptoms of attenuated versus threshold psychotic illness. It defines criteria for psychosis-risk states, as well as threshold psychosis. The measure contains 19 subscales, divided into Positive, Negative, Disorganization, and General Symptom components. The total score for the four General symptoms on the SIPS is recorded as “GTOT.” The critical items for determining attenuated versus full-blown psychosis, are the five positive symptoms: P.1.: Unusual Thought Content/Delusional Ideas, P.2.: Suspiciousness/Persecutory Ideas, P.3.: Grandiose Ideas, P.4.: Perceptual Abnormalities/Hallucinations, and P.5.: Disorganized Communication. These are scored 0–6 according to specific anchors provided for each symptom that distinguish among degrees of frequency, conviction and behavioral impact: 0, absent; 1, questionably present; 2, mild; 3, moderate; 4, moderately severe; 5, severe, but not psychotic; and 6, psychotic, delusional conviction, at least intermittently. Negative, disorganization and general signs and symptoms are rated from 0 (absent) to 6 (extreme).

The SIPS APSS criteria require at least one positive symptom occurring at least once weekly in the past month and scored between 3 and 5. Symptoms must not be better explained by another psychiatric or medical condition. The syndrome is ruled out by past or present syndromal psychosis (i.e., at least one positive symptom scored 6, occurring for at least one hour daily for four days weekly throughout one month, or causing severe disorganization, or endangering self or others). As noted, all patients in this cohort met criteria for the Progression subtype of the SIPS APSS syndrome, which additionally requires that at least one positive symptom is new or has worsened by one or more points in the past year. Consensus of individuals SIPS scores and diagnostic categories were established by certified administrators.

All data presented here were collected at baseline. In addition to a general clinical interview, each participant was also evaluated with either the Diagnostic Interview for Genetic Studies (Nurnberger Jr et al., 1994) or Structured Clinical Interview for DSM-IV Axis-I Disorders, Patient Edition (SCID-I/P; (First et al., 2002)). Subjects were followed for up to two years to determine transition to syndromal psychosis.

Exclusion criteria included lack of proficiency in English; a current or lifetime DSM psychotic disorder, including affective psychoses; a DSM disorder better accounting for the clinical presentation; I.Q.<70; medical conditions affecting the central nervous system; marked risk of harm to self or others; unwillingness to participate in research; geographic distance; or a DSM diagnosis of current substance or alcohol abuse or dependence. Use of antipsychotic medication was not exclusionary, provided that there was clear evidence that positive symptoms of an attenuated, but never fully psychotic level syndrome were present at medication onset. We also recruited healthy control subjects who did not meet criteria for any psychosis risk-syndrome on the SIPS, did not meet criteria for any Axis I disorder on the SCID or Diagnostic Interview for Genetic Studies, were non-substance using, and had never taken psychiatric medications. The study sample is described in Table 1.

Table 1:

Sociodemographic and clinical variables

CHR w/Suicidal Ideation (SI +) (N=31) CHR w/o Suicidal Ideation (SI −) (N=19) Healthy Controls (HC) (N=19) F(df)/t/X2 p
Gender 23M, 8F 12M,7F 14M,5F 0.78776 0.6744
Age* 20.45 (3.61) 21.68 (4.18) 23.32 (3.5) 3.455(2,66)# 0.0374
Race 16C, 5AA, 3As, 0AI, 7M 7C, 5AA, 1As, 0AI, 6M 8C, 4AA, 5As, 1AI, 1M 0.2055
Ethnicity 8H, 23NH 6H,13NH 4H,15NH 0.8326
PTOT* 15.42 (3.7) 14.58(3.99) 0.743 0.4625
NTOT* 19.68 (5.15) 16.95 (6.35) 1.581 0.1237
DTOT* 11.16 (2.41) 10.16 (3.24) 1.168 0.2521
GTOT* 13.48 (4.18) 10.53 (3.39) 2.737 0.0089
GAF* 44.94 (6.14) 49.21 (5.74) −2.488 0.0171
Medications 13None, 2AP, 8AD, 4Both, 2Others, 2UA 9None, 3AP, 4AD, 0Both, 2Others, 1UA 0.467
MDD 14Present, 16Absent,1UA 3Present, 10Absent, 6UA 1.24 0.266
GAD/SP/Anxiety Disorder NOS 5Present, 25Absent, 1UA 3Present, 10Absent, 6UA 0.681
OCD 4Present, 26Absent, 1UA 4Present, 9Absent, 6UA 0.217
Open in a new tab
*

Mean(SD),

#

SI + significantly younger than HC

M=male, F=female, C=Caucasian, AA=African American, As=Asian/Pacific Islander, M=Mixed, AI=American Indian/Alaskan, H=Hispanic, NH=Non-Hispanic, AP=Antipsychotic, AD=Antidepressant, Both=AP+AD, MDD=Major Depressive Disorder, GAD=Generalized Anxiety Disorder, SP=Social Phobia, NOS=Not Otherwise Specified, OCD=Obsessive Compulsive Disorder, UA=Unavailable

PTOT= Positive symptoms total on Structured Interview for Psychosis-Risk Syndromes (SIPS) NTOT=Negative symptoms total on SIPS, DTOT=Disorganization symptoms total on SIPS, GTOT=General symptoms total on SIPS, GAF=Global Assessment of Functioning score

The Columbia-Suicide Severity Rating Scale (C-SSRS) (Posner et al., 2011) contains two constructs relevant to SI: 1) presence (1=Wish to be Dead, 2=Non-Specific Active Suicidal Thoughts, 3= Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act, 4= Active Suicidal Ideation with Some Intent to Act, without Specific Plan, and 5= Active Suicidal Ideation with Specific Plan and Intent); 2) intensity (sum across five items each rated 0–5 or 1–5 for the most severe ideation: Frequency, Duration, Controllability, Deterrents, and Reasons for Ideation). We examined data from the C-SSRS in two ways. First, we categorized CHR individuals into those with and without any SI. We also used the sum score for intensity as a continuous variable for correlational analyses. The frequency of suicidal behavior was so infrequent in this cohort (N=2, 4%) that we limited our analyses to SI.

2.2. Imaging

T1-weighted turbo field echo images were obtained for all subjects with the following parameters: TR=6.7 s, TE=3.1s, FoV=240×240×192mm3, voxel size=0.9×0.9×0.9mm3. Cortical thickness estimations were automatically generated from these T1-weighted MRIs using the open source brain image analysis suite Freesurfer 6.0. A quality check was performed on the T1-weighted images and those of poor quality and gross topological defects were eliminated. Image processing was performed on Freesurfer using sub-mm 3T T1-weighted MRI scans without T2 scans, through a standard T1 only framework. All images underwent pre-processing initially which consisted of skull stripping and intensity normalization, followed by a standard surface-based cortical reconstruction (Dale et al., 1999; Fischl and Dale, 2000; Fischl et al., 1999) yielding white matter, gray matter and CSF boundaries. The volumes defined by these boundaries were used to generate the final cortical and pial surfaces. The cortical surface was defined by following intensity gradients between the previously generated white and gray matter volumes. Cortical thickness measurements of 31 regions of interest (ROI) on each side were identified using the Desikan-Killiany-Tourville (DKT) brain atlas (Desikan et al., 2006; Klein and Tourville, 2012).

2.3. Statistical Analyses

Demographic and clinical variables were compared across the three groups by independent t-test, Analysis of Variance (ANOVA) and Chi-square/Fisher’s Exact test accordingly. Two separate sets of analysis were conducted, one comparing the two groups of CHR with and without suicidal ideation and a second one comparing three groups which included a healthy control group in addition to the above two. Distribution of data was tested for normality. Cortical thickness of each of the 62 ROIs derived was compared between the groups using Analysis of Covariance (ANCOVA), adjusted for the covariates of age and gender. Intracranial volume was not controlled for in the analysis because cortical thickness scales with head size to a much lesser degree than volume measures, as surface area does not influence cortical thickness. In the three-group analysis, a post-hoc comparison was performed using Tukey HSD test. p values less than or equal to 0.05 were considered statistically significant. Given the novel exploratory objective of the study, p-values indicating group differences in cortical thickness are not corrected for multiple brain areas (Rothman, 1990). Confidence intervals of the standard regression coefficients and effect sizes (eta-squared) are reported for all brain areas examined in addition to the p-values. All statistical analyses were performed on the software, R version 3.6.1.

3. Results

3.1. Demographic and clinical variables at baseline

The CHR group with suicidal ideation was significantly younger than the healthy controls (p=0.037). Those with suicidal ideation had a higher severity of general symptoms (GTOT) i.e. sleep, mood, motoric disturbances and impaired tolerance to stress compared to those without suicidal ideation (p=0.009). This is expected given that suicidality would be captured in this section of the SIPS. Also as expected, their functioning (GAF) was significantly lower compared to those without suicidal ideation (p=0.017; Table 1), given that suicidality would also be reflected in the GAF scores. Given the direct relationship between suicidality (our primary independent variable) and GTOT and GAF, and because the presence of SI is an important determinant of GTOT and GAF scores, we did not control for differences in these two variables in subsequent analyses as doing so would have had the effect of controlling for our independent variable of interest. There was no difference between the groups with regards to medications or psychiatric co-morbidity.

Importantly, ten subjects in the CHR with SI group and 6 in the CHR without SI group developed syndromal psychosis (32% overall conversion rate; p=0.96 between the two groups).

3.2. Comparison of cortical thickness between CHR individuals with and without suicidal ideation

ANCOVA examining the difference in cortical thickness of the brain ROIs between CHR individuals with and without suicidal ideation indicated that the right middle temporal cortex (p=0.017), left middle temporal cortex (p=0.022) and the right insula (p=0.034) were thicker in those with suicidal ideation than without (Table 2). Effect sizes were all in the 0.079–0.092 (medium) range. These data are illustrated in a boxplot diagram (Figure 1). In figure 2, we include a three-dimensional brain showing cortical areas that are significantly thicker in CHR individuals with SI compared to those without SI.

Table 2:

Comparison of cortical thickness between CHR individuals with and without suicidal ideation

Structure Right Left
*SI + *SI − F(df) β (95% CI) p ES SI + SI − F(df) β (95% CI) p ES
Caudal Anterior cingulate 2.57 (0.19) 2.64 (0.21) 2.09 (1,46) −0.08 (−0.2:0.03) 0.155 0.042 2.64 (0.2) 2.74 (0.18) 3.95 (1,46) −0.11 (−0.23:0) 0.053 0.078
Caudal Middle frontal 2.49 (0.1) 2.5 (0.14) 0.2 (1,46) −0.02 (−0.08:0.05) 0.661 0.004 2.47 (0.11) 2.43 (0.13) 0.42 (1,46) 0.02 (−0.05:0.09) 0.518 0.008
Cuneus 2.03 (0.1) 2 (0.11) 0.36 (1,46) 0.02 (−0.04:0.08) 0.55 0.007 2.07 (0.11) 2.06 (0.11) 0.07 (1,46) 0.01 (−0.06:0.07) 0.79 0.001
Entorhinal 3.29 (0.36) 3.3 (0.25) 0 (1,46) 0 (−0.2:0.2) 0.991 0 3.29 (0.3) 3.18 (0.17) 2.04 (1,46) 0.11 (−0.05:0.27) 0.16 0.041
Fusiform 2.78 (0.12) 2.71 (0.12) 3.01 (1,46) 0.06 (−0.01:0.13) 0.089 0.057 2.78 (0.1) 2.73 (0.15) 0.59 (1,46) 0.03 (−0.04:0.09) 0.447 0.01
Inferior parietal 2.44 (0.12) 2.39 (0.14) 0.71 (1,46) 0.03 (−0.04:0.1) 0.402 0.013 2.5 (0.11) 2.45 (0.12) 1.22 (1,46) 0.04 (−0.03:0.1) 0.275 0.022
Inferior temporal 2.89 (0.15) 2.86 (0.14) 0.1 (1,46) 0.01 (−0.07:0.09) 0.757 0.002 2.91 (0.13) 2.85 (0.17) 1.03 (1,46) 0.04 (−0.04:0.12) 0.315 0.018
Isthmus cingulate 2.46 (0.21) 2.43 (0.21) 0.06 (1,46) 0.01 (−0.1:0.13) 0.803 0.001 2.52 (0.21) 2.51 (0.18) 0 (1,46) 0 (−0.12:0.12) 0.951 0
Lateral occipital 2.25 (0.12) 2.17 (0.11) 3.16 (1,46) 0.06 (−0.01:0.13) 0.082 0.058 2.28 (0.11) 2.21 (0.09) 3.7 (1,46) 0.06 (0:0.12) 0.061 0.066
Lateral orbitofrontal 2.8 (0.14) 2.74 (0.15) 0.98 (1,46) 0.04 (−0.04:0.11) 0.328 0.016 2.86 (0.15) 2.77 (0.17) 2.61 (1,46) 0.07 (−0.02:0.15) 0.113 0.038
Lingual 2.24 (0.12) 2.25 (0.12) 0.45 (1,46) −0.02 (−0.09:0.05) 0.504 0.009 2.25 (0.1) 2.21 (0.13) 0.43 (1,46) 0.02 (−0.04:0.09) 0.517 0.008
Medial orbitofrontal 2.66 (0.17) 2.65 (0.1) 0.08 (1,46) 0.01 (−0.07:0.1) 0.777 0.002 2.59 (0.18) 2.56 (0.15) 0.07 (1,46) 0.01 (−0.08:0.1) 0.8 0.001
Middle temporal 2.99 (0.12) 2.89 (0.12) 6.15 (1,46) 0.08 (0.01:0.14) 0.017 0.079 2.88 (0.12) 2.78 (0.12) 5.63 (1,46) 0.08 (0.01:0.15) 0.022 0.092
Parahippocampal 2.85 (0.21) 2.91 (0.21) 0.89 (1,46) −0.06 (−0.18:0.07) 0.35 0.018 2.84 (0.29) 2.97 (0.23) 2.4 (1,46) −0.13 (−0.29:0.04) 0.128 0.048
Paracentral 2.41 (0.11) 2.43 (0.14) 0.55 (1,46) −0.03 (−0.1:0.05) 0.462 0.012 2.47 (0.09) 2.49 (0.15) 0.5 (1,46) −0.02 (−0.09:0.04) 0.484 0.01
Parsopercularis 2.77 (0.17) 2.75 (0.13) 0.01 (1,46) 0 (−0.08:0.09) 0.91 0 2.73 (0.17) 2.67 (0.12) 0.79 (1,46) 0.04 (−0.05:0.12) 0.379 0.014
Parsorbitalis 2.91 (0.17) 2.87 (0.17) 0.22 (1,46) 0.02 (−0.07:0.12) 0.643 0.004 2.94 (0.22) 2.83 (0.16) 2.14 (1,46) 0.08 (−0.03:0.2) 0.15 0.038
Parstriangularis 2.66 (0.12) 2.61 (0.14) 0.41 (1,46) 0.02 (−0.04:0.09) 0.527 0.006 2.57 (0.16) 2.5 (0.12) 1.23 (1,46) 0.04 (−0.04:0.12) 0.274 0.021
Pericalcarine 1.85 (0.13) 1.8 (0.1) 1.01 (1,46) 0.04 (−0.04:0.11) 0.321 0.02 1.8 (0.13) 1.77 (0.14) 0.37 (1,46) 0.02 (−0.06:0.11) 0.548 0.008
Postcentral 2.11 (0.1) 2.08 (0.12) 0.56 (1,46) 0.02 (−0.04:0.08) 0.46 0.01 2.12 (0.09) 2.1 (0.1) 0.31 (1,46) 0.02 (−0.04:0.07) 0.58 0.006
Posterior cingulate 2.46 (0.14) 2.5 (0.14) 1.73 (1,46) −0.05 (−0.13:0.03) 0.195 0.032 2.53 (0.15) 2.51 (0.15) 0 (1,46) 0 (−0.08:0.08) 0.968 0
Precentral 2.61 (0.11) 2.59 (0.1) 0.24 (1,46) 0.02 (−0.05:0.08) 0.63 0.005 2.59 (0.1) 2.59 (0.09) 0.02 (1,46) 0 (−0.06:0.05) 0.892 0
Precuneus 2.4 (0.09) 2.37 (0.13) 0.3 (1,46) 0.02 (−0.04:0.08) 0.585 0.006 2.46 (0.11) 2.46 (0.13) 0.34 (1,46) −0.02 (−0.08:0.05) 0.564 0.006
Rostral Anterior cingulate 3.03 (0.18) 2.98 (0.18) 0.7 (1,46) 0.05 (−0.06:0.16) 0.408 0.015 2.93 (0.17) 2.89 (0.22) 0.19 (1,46) 0.02 (−0.09:0.13) 0.666 0.004
Rostral middlefrontal 2.48 (0.13) 2.46 (0.14) 0.12 (1,46) 0.01 (−0.06:0.09) 0.729 0.002 2.42 (0.12) 2.36 (0.13) 1.33 (1,46) 0.04 (−0.03:0.11) 0.255 0.023
Superior frontal 2.69 (0.12) 2.66 (0.15) 0.11 (1,46) 0.01 (−0.06:0.09) 0.747 0.002 2.65 (0.13) 2.6 (0.12) 0.99 (1,46) 0.03 (−0.04:0.1) 0.324 0.018
Superior parietal 2.17 (0.1) 2.11 (0.13) 2.11 (1,46) 0.05 (−0.02:0.12) 0.153 0.041 2.22 (0.11) 2.2 (0.13) 0.41 (1,46) 0.02 (−0.05:0.09) 0.525 0.008
Superior temporal 3.04 (0.13) 3.02 (0.16) 0.06 (1,46) 0.01 (−0.07:0.09) 0.811 0.001 2.92 (0.14) 2.91 (0.15) 0 (1,46) 0 (−0.08:0.08) 0.988 0
Supramarginal 2.53 (0.11) 2.51 (0.15) 0.09 (1,46) 0.01 (−0.06:0.08) 0.769 0.002 2.54 (0.11) 2.52 (0.14) 0.05 (1,46) 0.01 (−0.06:0.08) 0.816 0.001
Transverse temporal 2.7 (0.19) 2.61 (0.24) 1.82 (1,46) 0.08 (−0.04:0.21) 0.183 0.035 2.7 (0.18) 2.67 (0.21) 0.03 (1,46) 0.01 (−0.1:0.12) 0.861 0.001
Insula 3.25 (0.16) 3.15 (0.12) 4.78 (1,46) 0.09 (0.01:0.18) 0.034 0.084 3.26 (0.15) 3.22 (0.11) 0.28 (1,46) 0.02 (−0.05:0.09) 0.602 0.004
Open in a new tab

SI + = Suicidal ideation present, SI − = Suicidal Ideation absent. df = degrees of freedom, F = F statistic of group (SI + versus SI −) in the Analysis of Covariance with age and gender as covariates, β=Standardized co-efficient of group (SI+ v/s SI−) in the ANCOVA models, CI=Confidence Interval, p=significant at =/< 0.05, ES = Effect Size expressed as eta squared.

*

Cortical thickness values given as mean(sd) in millimeters

Figure 1. Comparison of cortical thickness between CHR individuals with and without SI.

Figure 1.

Open in a new tab

Boxplots of cortical thickness of the brain areas significantly different (p<0.05) between CHR individuals with and without SI. mm=millimeter

Figure 2. Cortical thickness and suicidal ideation in CHR individuals.

Figure 2.

Open in a new tab

Right lateral (2A) and Inferior (2B) surfaces of a 3D brain showing cortical areas that are significantly thicker in CHR individuals with SI compared to those without SI (p<0.05).

3.3. Comparison of cortical thickness between CHR individuals with suicidal ideation, CHR without suicidal ideation and healthy controls.

When the healthy control group was included in the comparison, the CHR group with suicidal ideation showed a significantly thicker left middle temporal cortex compared to CHR group without suicidal ideation (p=0.044; Table 3). The differences in right middle temporal cortex (p=0.053) and the insula (p=0.081) fell short of the threshold for statistical significance. Effect sizes for these three areas were medium and similar to those observed in the previous analysis (0.063–0.073). These data are illustrated in a boxplot diagram (Figure 3). No other differences were observed among the 3 groups.

Table 3:

Comparison of cortical thickness between CHR individuals with suicidal ideation, without suicidal ideation and healthy controls

Structure Right Left
F(df) β (95% CI) p ES F(df) β (95% CI) p ES
Caudal Anterior cingulate 1.64 (1,64) −0.09 (−0.2:0.02) 0.203 0.044 2.37 (1,64) −0.12 (−0.23:0) 0.102 0.066
Caudal Middle frontal 0.22 (1,64) −0.01 (−0.08:0.05) 0.803 0.006 0.41 (1,64) 0.02 (−0.04:0.09) 0.664 0.011
Cuneus 0.22 (1,64) 0.02 (−0.04:0.08) 0.8 0.006 0.05 (1,64) 0.01 (−0.05:0.07) 0.949 0.002
Entorhinal 0.48 (1,64) 0 (−0.2:0.2) 0.619 0.015 0.78 (1,64) 0.1 (−0.06:0.27) 0.465 0.023
Fusiform 1.56 (1,64) 0.06 (−0.01:0.14) 0.218 0.043 0.43 (1,64) 0.03 (−0.04:0.1) 0.651 0.011
Inferior parietal 0.61 (1,64) 0.03 (−0.03:0.1) 0.546 0.015 0.8 (1,64) 0.04 (−0.02:0.1) 0.454 0.021
Inferior temporal 0.64 (1,64) 0.02 (−0.06:0.09) 0.528 0.015 2.36 (1,64) 0.05 (−0.03:0.13) 0.102 0.06
Isthmus cingulate 0.03 (1,64) 0.01 (−0.1:0.13) 0.972 0.001 0.17 (1,64) 0 (−0.12:0.12) 0.842 0.005
Lateral occipital 1.78 (1,64) 0.06 (−0.01:0.14) 0.177 0.048 2.24 (1,64) 0.06 (0:0.12) 0.115 0.061
Lateral orbitofrontal 0.71 (1,64) 0.04 (−0.03:0.11) 0.494 0.016 1.28 (1,64) 0.07 (−0.02:0.15) 0.285 0.028
Lingual 0.18 (1,64) −0.02 (−0.09:0.05) 0.837 0.005 0.22 (1,64) 0.02 (−0.05:0.09) 0.801 0.006
Medial orbitofrontal 0.04 (1,64) 0.01 (−0.08:0.1) 0.961 0.001 0.21 (1,64) 0.01 (−0.08:0.11) 0.814 0.005
Middle temporal 3.08 (1,64) 0.08 (0.02:0.14) 0.053 0.063 3.28 (1,64) 0.08 (0.02:0.14) 0.044* 0.073
Parahippocampal 2.54 (1,64) −0.06 (−0.19:0.06) 0.087 0.071 2.26 (1,64) −0.12 (−0.27:0.03) 0.113 0.065
Paracentral 0.48 (1,64) −0.03 (−0.1:0.04) 0.622 0.014 0.6 (1,64) −0.02 (−0.09:0.05) 0.55 0.017
Parsopercularis 0.25 (1,64) 0.01 (−0.08:0.09) 0.782 0.006 1.93 (1,64) 0.04 (−0.05:0.12) 0.154 0.045
Parsorbitalis 0.17 (1,64) 0.03 (−0.06:0.11) 0.842 0.004 1.44 (1,64) 0.08 (−0.03:0.19) 0.244 0.035
Parstriangularis 0.34 (1,64) 0.02 (−0.04:0.09) 0.713 0.008 2.62 (1,64) 0.05 (−0.03:0.13) 0.081 0.06
Pericalcarine 1.26 (1,64) 0.04 (−0.03:0.11) 0.291 0.036 0.53 (1,64) 0.02 (−0.06:0.1) 0.592 0.016
Postcentral 0.83 (1,64) 0.02 (−0.03:0.08) 0.44 0.022 0.19 (1,64) 0.02 (−0.04:0.07) 0.83 0.005
Posterior cingulate 1.11 (1,64) −0.05 (−0.13:0.02) 0.335 0.027 0.01 (1,64) 0 (−0.08:0.08) 0.993 0
Precentral 0.13 (1,64) 0.02 (−0.05:0.08) 0.882 0.004 0.24 (1,64) 0 (−0.06:0.05) 0.785 0.007
Precuneus 0.17 (1,64) 0.02 (−0.04:0.07) 0.841 0.004 0.18 (1,64) −0.02 (−0.08:0.04) 0.838 0.005
Rostral Anterior cingulate 0.73 (1,64) 0.05 (−0.06:0.15) 0.488 0.021 0.18 (1,64) 0.03 (−0.08:0.13) 0.84 0.005
Rostral middlefrontal 0.27 (1,64) 0.01 (−0.06:0.09) 0.764 0.007 2.25 (1,64) 0.04 (−0.03:0.11) 0.114 0.053
Superior frontal 0.41 (1,64) 0.01 (−0.06:0.09) 0.668 0.01 0.72 (1,64) 0.04 (−0.04:0.11) 0.488 0.018
Superior parietal 1.43 (1,64) 0.05 (−0.01:0.11) 0.247 0.038 0.39 (1,64) 0.02 (−0.04:0.09) 0.678 0.012
Superior temporal 0.07 (1,64) 0.01 (−0.06:0.08) 0.935 0.002 0.24 (1,64) 0 (−0.07:0.08) 0.79 0.007
Supramarginal 0.12 (1,64) 0.01 (−0.05:0.08) 0.883 0.003 0.2 (1,64) 0.01 (−0.06:0.07) 0.817 0.005
Transverse temporal 1.52 (1,64) 0.08 (−0.04:0.21) 0.226 0.041 0.97 (1,64) 0.01 (−0.11:0.13) 0.384 0.026
Insula 2.62 (1,64) 0.09 (0.01:0.18) 0.081 0.068 0.92 (1,64) 0.02 (−0.05:0.1) 0.404 0.021
Open in a new tab
*

Post-hoc (Tukey’s HSD)=CHR with suicidal ideation > CHR without suicidal ideation.

df = degrees of freedom, F = F statistic of group (SI + / SI −/healthy control) in the Analysis of Covariance with age and gender as covariates, β=Standardized co-efficient of group in the ANCOVA models, CI=Confidence Interval, p=significant at =/< 0.05, ES = Effect Size expressed as eta squared.

Figure 3. Comparison of cortical thickness between the CHR groups with and without suicidal ideation and healthy controls.

Figure 3.

Open in a new tab

Boxplots of cortical thickness of the brain area significantly different (p<0.05) between the groups. mm=millimeter

3.4. Relationships between cortical thickness and severity of suicidal ideation in CHR individuals with suicidal ideation.

We used the intensity construct of the C-SSRS to examine relationships between cortical thickness and severity of suicidal ideation in CHR individuals with suicidal ideation. There were no relationships between cortical thickness and intensity of SI in any brain region.

4. Discussion

In the current exploratory, pilot MRI study, we observed increased cortical thickness in insular and middle temporal regions in CHR individuals with SI compared to those without SI and, to a lesser degree, healthy control subjects. In addition, we observed no relationships between the intensity of SI and cortical thickness in any cortical regions.

These findings are consistent with the findings of Giakoumatos and colleagues and Besteher and colleagues who found abnormalities in cortical thickness in the same brain regions in syndromal subjects who had attempted suicide (Besteher et al., 2016; Giakoumatos et al., 2013). However, these findings are contrary to our hypothesis, and inconsistent with previous findings, in that we observed increased cortical thickness while Giakoumatos and collegaues and Besteher and colleagues observed cortical thinning.

These interesting findings might be better understood in the context of the extant literature on the neurobiology of suicide in other psychiatric disorders. Regarding location, the insula in particular has been implicated in suicidality, associated with both mood and personality disorders (van Heeringen and Mann, 2014). As a member of brain circuitry involved in mood regulation and decision making, its dysfunction may predispose to maladaptive responses to stress and adverse psychosocial events (van Heeringen and Mann, 2014). In a review by Schmaal and colleagues, temporal and insular cortices were suggested to be part of a network that may be responsible for negative and blunted emotional and mood states, while a more dorsal network would be more responsible for suicidal behavior due to its role in cognitive control and flexibility (Schmaal et al., 2020).

Regarding our finding of increased cortical thickness as opposed to cortical thinning, a recent, article of note reported that neocortical thinning is a nonspecific, transdiagnostic feature of general psychopathology (Romer et al., 2020). This is also evident in schizophrenia. Several reviews report that temporal and insular volumes tend to be lower in general in individuals with schizophrenia (Keshavan et al., 2020; Kuo and Pogue-Geile, 2019; Shenton et al., 2001). This makes our finding of increased cortical thickness of CHR individuals with SI even more interesting. There could be several reasons for this finding. Our patients, by definition, are putatively pre-syndromal for psychosis. Therefore, our patients are substantially younger than patients in other cohorts. In addition, our findings are much less likely to be affected by length of illness, chronic medication treatment, or the potentially neurodegenerative effects of relapses (Lieberman, 1999). It is also possible that there is some type of biological interaction between the pathobiology of pre-syndromal psychosis and suicidal ideation that leads to greater cortical volumes, rather than lower cortical volumes, and affects the formative process inherent in the vulnerability to psychotic disorders.

There are other potential differences between our cohort and those of Giakoumatos and colleagues, and Besteher and colleagues. Our study focused on individuals with SI, while the studies led by Giakoumatos and Besteher focused on individuals who had attempted suicide. It is possible that the neurobiology of SI is distinct from that associated with suicide attempts or completed suicide. In addition, Giakoumatos and colleagues included individuals with bipolar I disorder, and Besteher and colleagues only examined individuals with schizophrenia. Our sample, by contrast, included subjects who were putatively pre-syndromal for any psychotic disorder.

However, a discussion of the findings of the current exploratory, pilot study in the context of the extant literature on the neurobiology of suicide in psychosis, and especially in early psychotic illness, remains very limited due to the paucity of reports in this area. Future studies on the neurobiology of suicide in schizophrenia should focus on replicating previous findings in larger samples and reconciling different pathophysiological theories. In addition, greater emphasis should be placed on examining the transdiagnostic stress-diathesis model of suicidal behavior (van Heeringen and Mann, 2014); for example, by examining relationships between early life adversity, altered decision-making, hopelessness, social media criticism, and genetics and neurobiological phenomena and findings.

Limitations of the current study include the sample size. Although our sample size was relatively modest to large for a brain imaging study of CHR individuals meeting criteria for the APSS Progression subtype, larger sample sizes would be critical to confirm or reject hypotheses and findings. In addition, although we controlled for demographic factors that were distinct between healthy controls and patients, an ideal sample would have included a fully matched control group. Third, we used a primarily categorical measure of SI. In future studies, the use of an instrument that measures more aspects of suicidality may allow a more revealing analysis of relationships between suicidality and MRI-based measures. Finally, although there is a close relationship between SI and suicide attempts in schizophrenia and CHR individuals (Andriopoulos et al., 2011; De Hert et al., 2001; Hor and Taylor, 2010; Shah and Ganesvaran, 1999), it is possible that the neurobiology of suicide attempts and completed suicide in schizophrenia is unique from the neurobiology of SI.

Despite these limitations, these pilot data add to the growing evidence of an important relationship between suicidal ideation and suicide in psychosis (De Hert et al., 2001; Hor and Taylor, 2010; Shah and Ganesvaran, 1999), underscoring how important it is to understand SI in individuals experiencing psychotic illness.

Highlights.

  • Suicide is a major cause of death in psychosis

  • The neurobiology of suicide in psychosis is understudied, especially in early psychosis

  • We used magnetic resonance imaging to examine the neurobiology of suicidal ideation in individuals at clinical high-risk for psychosis (CHR)

  • CHR individuals with SI had thicker middle temporal and right insular cortices than CHR individuals without SI and healthy control subjects

  • These pilot findings underscore the potential for the use of brain imaging biomarkers of suicide risk in CHR individuals.

Acknowledgements

We acknowledge the individuals who participated in this study.

Funding & Disclosure/Conflicts of Interest

This work was supported by the National Institutes of Health R01MH093398-01.

R. Girgis acknowledges receiving research support from Otsuka, Allergan/Forest, BioAvantex, and Genentech and advances/royalties for books published by Wipf and Stock and Routledge/Taylor and Francis. G. Brucato acknowledges receiving advances/royalties for books published by Prometheus Books and Routledge/Taylor and Francis. F. Provenzano is an equity holder in and advisor for IMIJ technologies. All other authors deny any relevant COIs.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  1. Aguilar EJ, Garcia-Marti G, Marti-Bonmati L, Lull JJ, Moratal D, Escarti MJ, Robles M, Gonzalez JC, Guillamon MI, Sanjuan J, 2008. Left orbitofrontal and superior temporal gyrus structural changes associated to suicidal behavior in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 32, 1673–1676. [DOI] [PubMed] [Google Scholar]
  2. Aleman A, Denys D, 2014. Mental health: A road map for suicide research and prevention. Nature 509, 421–423. [DOI] [PubMed] [Google Scholar]
  3. Andriopoulos I, Ellul J, Skokou M, Beratis S, 2011. Suicidality in the “prodromal” phase of schizophrenia. Compr Psychiatry 52, 479–485. [DOI] [PubMed] [Google Scholar]
  4. Barrett EA, Sundet K, Simonsen C, Agartz I, Lorentzen S, Mehlum L, Mork E, Andreassen OA, Melle I, 2011. Neurocognitive functioning and suicidality in schizophrenia spectrum disorders. Compr Psychiatry 52, 156–163. [DOI] [PubMed] [Google Scholar]
  5. Besteher B, Wagner G, Koch K, Schachtzabel C, Reichenbach JR, Schlosser R, Sauer H, Schultz CC, 2016. Pronounced prefronto-temporal cortical thinning in schizophrenia: Neuroanatomical correlate of suicidal behavior? Schizophr Res 176, 151–157. [DOI] [PubMed] [Google Scholar]
  6. Bushe CJ, Taylor M, Haukka J, 2010. Mortality in schizophrenia: a measurable clinical endpoint. J Psychopharmacol 24, 17–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Carlborg A, Jokinen J, Jonsson EG, Nordstrom AL, Nordstrom P, 2008. Long-term suicide risk in schizophrenia spectrum psychoses: survival analysis by gender. Arch Suicide Res 12, 347–351. [DOI] [PubMed] [Google Scholar]
  8. Dale AM, Fischl B, Sereno MI, 1999. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage 9, 179–194. [DOI] [PubMed] [Google Scholar]
  9. De Hert M, McKenzie K, Peuskens J, 2001. Risk factors for suicide in young people suffering from schizophrenia: a long-term follow-up study. Schizophr Res 47, 127–134. [DOI] [PubMed] [Google Scholar]
  10. Desikan RS, Segonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, Buckner RL, Dale AM, Maguire RP, Hyman BT, Albert MS, Killiany RJ, 2006. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 31, 968–980. [DOI] [PubMed] [Google Scholar]
  11. DeVylder JE, Oh AJ, Ben-David S, Azimov N, Harkavy-Friedman JM, Corcoran CM, 2012. Obsessive compulsive symptoms in individuals at clinical risk for psychosis: association with depressive symptoms and suicidal ideation. Schizophr Res 140, 110–113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dutta R, Murray RM, Hotopf M, Allardyce J, Jones PB, Boydell J, 2010. Reassessing the long-term risk of suicide after a first episode of psychosis. Arch Gen Psychiatry 67, 1230–1237. [DOI] [PubMed] [Google Scholar]
  13. Fenton WS, McGlashan TH, Victor BJ, Blyler CR, 1997. Symptoms, subtype, and suicidality in patients with schizophrenia spectrum disorders. Am J Psychiatry 154, 199–204. [DOI] [PubMed] [Google Scholar]
  14. First MB, Spitzer RL, Gibbon M, Williams JBW, 2002. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition. (SCID-I/P), in: Biometrics Research, N.Y.S.P.I. (Ed.), New York. [Google Scholar]
  15. Fischl B, Dale AM, 2000. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci U S A 97, 11050–11055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fischl B, Sereno MI, Dale AM, 1999. Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system. Neuroimage 9, 195–207. [DOI] [PubMed] [Google Scholar]
  17. Giakoumatos CI, Tandon N, Shah J, Mathew IT, Brady RO, Clementz BA, Pearlson GD, Thaker GK, Tamminga CA, Sweeney JA, Keshavan MS, 2013. Are structural brain abnormalities associated with suicidal behavior in patients with psychotic disorders? J Psychiatr Res 47, 1389–1395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gill KE, Quintero JM, Poe SL, Moreira AD, Brucato G, Corcoran CM, Girgis RR, 2015. Assessing suicidal ideation in individuals at clinical high risk for psychosis. Schizophr Res 165, 152–156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Girgis RR, 2020. The neurobiology of suicide in psychosis: A systematic review. J Psychopharmacol, 269881120936919. [DOI] [PubMed] [Google Scholar]
  20. Hjorthoj C, Sturup AE, McGrath JJ, Nordentoft M, 2017. Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis. The lancet. Psychiatry 4, 295–301. [DOI] [PubMed] [Google Scholar]
  21. Hor K, Taylor M, 2010. Suicide and schizophrenia: a systematic review of rates and risk factors. J Psychopharmacol 24, 81–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hutton P, Bowe S, Parker S, Ford S, 2011. Prevalence of suicide risk factors in people at ultra-high risk of developing psychosis: a service audit. Early Interv Psychiatry 5, 375–380. [DOI] [PubMed] [Google Scholar]
  23. Kasckow J, Felmet K, Zisook S, 2011. Managing suicide risk in patients with schizophrenia. CNS Drugs 25, 129–143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kelleher I, Corcoran P, Keeley H, Wigman JT, Devlin N, Ramsay H, Wasserman C, Carli V, Sarchiapone M, Hoven C, Wasserman D, Cannon M, 2013. Psychotic symptoms and population risk for suicide attempt: a prospective cohort study. JAMA Psychiatry 70, 940–948. [DOI] [PubMed] [Google Scholar]
  25. Kelleher I, Lynch F, Harley M, Molloy C, Roddy S, Fitzpatrick C, Cannon M, 2012. Psychotic symptoms in adolescence index risk for suicidal behavior: findings from 2 population-based case-control clinical interview studies. Arch Gen Psychiatry 69, 1277–1283. [DOI] [PubMed] [Google Scholar]
  26. Keshavan MS, Collin G, Guimond S, Kelly S, Prasad KM, Lizano P, 2020. Neuroimaging in Schizophrenia. Neuroimaging Clin N Am 30, 73–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Klein A, Tourville J, 2012. 101 labeled brain images and a consistent human cortical labeling protocol. Frontiers in neuroscience 6, 171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kuo SS, Pogue-Geile MF, 2019. Variation in fourteen brain structure volumes in schizophrenia: A comprehensive meta-analysis of 246 studies. Neurosci Biobehav Rev 98, 85–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lee SJ, Kim B, Oh D, Kim MK, Kim KH, Bang SY, Choi TK, Lee SH, 2016. White matter alterations associated with suicide in patients with schizophrenia or schizophreniform disorder. Psychiatry Res Neuroimaging 248, 23–29. [DOI] [PubMed] [Google Scholar]
  30. Lieberman JA, 1999. Is schizophrenia a neurodegenerative disorder? A clinical and neurobiological perspective. Biol Psychiatry 46, 729–739. [DOI] [PubMed] [Google Scholar]
  31. Long Y, Ouyang X, Liu Z, Chen X, Hu X, Lee E, Chen EYH, Pu W, Shan B, Rohrbaugh RM, 2018. Associations Among Suicidal Ideation, White Matter Integrity and Cognitive Deficit in First-Episode Schizophrenia. Frontiers in psychiatry 9, 391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. McGlashan TH, Miller TJ, Woods SW, Hoffman RE, Davidson LA, 2001. Scale for the assessment of prodromal symptoms and states. , in: Miller T, Mednick SA, McGlashan TH, Liberger J, Johannessen JO (Ed.), Early Intervention in Psychotic Disorders. . Kluwer Academic Publishers, Dordrecht, The Netherlands, pp. 135–149. [Google Scholar]
  33. McGlashan TH, Walsh BC, Woods SW, 2014. Structured interview for psychosis-risk syndromes, English language (version 5.6) PRIME Research Clinic, Yale School of Medicine, New Haven, CT. [Google Scholar]
  34. Miller TJ, McGlashan TH, Rosen JL, Cadenhead K, Cannon T, Ventura J, McFarlane W, Perkins DO, Pearlson GD, Woods SW, 2003. Prodromal assessment with the Sstructured Interview for Prodromal Syndromes: Predictive validity, interrater reliability, and training to reliability. Schizophrenia Bulletin 29, 703–715. [DOI] [PubMed] [Google Scholar]
  35. Miller TJ, McGlashan TH, Rosen JL, Somjee L, Markovich PJ, Stein K, Woods SW, 2002. Prospective diagnosis of the prodrome for schizophrenia: Preliminary evidence of interrater reliability and predictive validity using operational criteria and a structured interview. Am J Psychiat 159, 863–865. [DOI] [PubMed] [Google Scholar]
  36. Minzenberg MJ, Lesh T, Niendam T, Yoon JH, Cheng Y, Rhoades RN, Carter CS, 2015. Frontal Motor Cortex Activity During Reactive Control Is Associated With Past Suicidal Behavior in Recent-Onset Schizophrenia. Crisis 36, 363–370. [DOI] [PubMed] [Google Scholar]
  37. Mortensen PB, Juel K, 1993. Mortality and causes of death in first admitted schizophrenic patients. Br J Psychiatry 163, 183–189. [DOI] [PubMed] [Google Scholar]
  38. Nordentoft M, Laursen TM, Agerbo E, Qin P, Hoyer EH, Mortensen PB, 2004. Change in suicide rates for patients with schizophrenia in Denmark, 1981–97: nested case-control study. BMJ 329, 261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Nurnberger JI Jr, Blejar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J, Severe JB, Malaspina D, Reich T, 1994. Diagnostic interview for genetic studies. Rationale, unique features, and training. Archives of General Psychiatry 51, 849–859. [DOI] [PubMed] [Google Scholar]
  40. Palmer BA, Pankratz VS, Bostwick JM, 2005. The lifetime risk of suicide in schizophrenia: a reexamination. Arch Gen Psychiatry 62, 247–253. [DOI] [PubMed] [Google Scholar]
  41. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, Greenhill L, Shen S, Mann JJ, 2011. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry 168, 1266–1277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Potvin S, Tikasz A, Richard-Devantoy S, Lungu O, Dumais A, 2018. History of Suicide Attempt Is Associated with Reduced Medial Prefrontal Cortex Activity during Emotional Decision-Making among Men with Schizophrenia: An Exploratory fMRI Study. Schizophr Res Treatment 2018, 9898654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Romer AL, Elliott ML, Knodt AR, Sison ML, Ireland D, Houts R, Ramrakha S, Poulton R, Keenan R, Melzer TR, Moffitt TE, Caspi A, Hariri AR, 2020. Pervasively Thinner Neocortex as a Transdiagnostic Feature of General Psychopathology. Am J Psychiatry, appiajp202019090934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Rosen JL, Woods SW, Miller TJ, McGlashan TH, 2002. Prospective observations of emerging psychosis. Journal of Nervous and Mental Disease 190, 133–141. [DOI] [PubMed] [Google Scholar]
  45. Rothman KJ, 1990. No adjustments are needed for multiple comparisons. Epidemiology 1, 43–46. [PubMed] [Google Scholar]
  46. Rusch N, Spoletini I, Wilke M, Martinotti G, Bria P, Trequattrini A, Bonaviri G, Caltagirone C, Spalletta G, 2008. Inferior frontal white matter volume and suicidality in schizophrenia. Psychiatry Res 164, 206–214. [DOI] [PubMed] [Google Scholar]
  47. Schmaal L, van Harmelen AL, Chatzi V, Lippard ETC, Toenders YJ, Averill LA, Mazure CM, Blumberg HP, 2020. Imaging suicidal thoughts and behaviors: a comprehensive review of 2 decades of neuroimaging studies. Mol Psychiatry 25, 408–427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Shah A, Ganesvaran T, 1999. Suicide among psychiatric in-patients with schizophrenia in an Australian mental hospital. Med Sci Law 39, 251–259. [DOI] [PubMed] [Google Scholar]
  49. Shenton ME, Dickey CC, Frumin M, McCarley RW, 2001. A review of MRI findings in schizophrenia. Schizophr Res 49, 1–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Siris SG, 2001. Suicide and schizophrenia. J Psychopharmacol 15, 127–135. [DOI] [PubMed] [Google Scholar]
  51. Skodlar B, Tomori M, Parnas J, 2008. Subjective experience and suicidal ideation in schizophrenia. Compr Psychiatry 49, 482–488. [DOI] [PubMed] [Google Scholar]
  52. Spoletini I, Piras F, Fagioli S, Rubino IA, Martinotti G, Siracusano A, Caltagirone C, Spalletta G, 2011. Suicidal attempts and increased right amygdala volume in schizophrenia. Schizophr Res 125, 30–40. [DOI] [PubMed] [Google Scholar]
  53. van Heeringen K, Mann JJ, 2014. The neurobiology of suicide. The lancet. Psychiatry 1, 63–72. [DOI] [PubMed] [Google Scholar]
  54. Yates K, Lang U, Cederlof M, Boland F, Taylor P, Cannon M, McNicholas F, DeVylder J, Kelleher I, 2019. Association of Psychotic Experiences With Subsequent Risk of Suicidal Ideation, Suicide Attempts, and Suicide Deaths: A Systematic Review and Meta-analysis of Longitudinal Population Studies. JAMA Psychiatry 76, 180–189. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES