Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed health problems, prior pharmacological treatments, and polygenic scores (PGS) has potential to inform risk stratification. We examined self-reported SB and ideation using the Columbia Suicide Severity Rating Scale (C-SSRS) among 3,942 SCZ and 5,414 BPI patients receiving care within the Veterans Health Administration (VHA). These cross-sectional data were integrated with electronic health records (EHRs), and compared across lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. PGS were constructed using available genomic data for related traits. Genome-wide association studies were performed to identify and prioritize specific loci. Only 20% of the veterans who reported SB had a corroborating ICD-9/10 EHR code. Among those without prior SB, more than 20% reported new-onset SB at follow-up. SB were associated with a range of additional clinical diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking initiation, suicide attempt, and major depressive disorder were associated with SB. The GWAS for SB yielded no significant loci. Among individuals with a diagnosed mental illness, self-reported SB were strongly associated with clinical variables across several EHR domains. Analyses point to sequelae of substance-related and psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in health records, underscoring the value of regular screening with direct, in-person assessments, especially among high-risk individuals.

Neurophysiological and clinical effects of the NMDA receptor antagonist lanicemine (BHV-5500) in PTSD: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with hyperarousal and stress reactivity, features consistent with behavioral sensitization. In this Phase 1b, parallel-arm, randomized, double-blind, placebo-controlled trial, we tested whether the selective low-trapping N-methyl-D-aspartate receptor (NMDAR) antagonist [Lanicemine (BHV-5500)] blocks expression of behavioral sensitization. METHODS: Twenty-four participants with elevated anxiety potentiated startle (APS) and moderate-to-severe PTSD symptoms received three infusions of lanicemine 1.0 mg/ml (100 mg) or matching placebo (0.9% saline) (1:1 ratio), over a 5-day period. The primary outcome was change in APS from baseline to end of third infusion. We also examined changes in EEG gamma-band oscillatory activity as measures of NMDAR target engagement and explored Clinician-Administered PTSD Scale (CAPS-5) hyperarousal scores. RESULTS: Lanicemine was safe and well-tolerated with no serious adverse events. Using Bayesian statistical inference, the posterior probability that lanicemine outperformed placebo on APS T-score after three infusions was 38%. However, after the first infusion, there was a 90% chance that lanicemine outperformed placebo in attenuating APS T-score by a standardized effect size more than 0.4. CONCLUSION: We demonstrated successful occupancy of lanicemine on NMDAR using gamma-band EEG and effects on hyperarousal symptoms (Cohen's d = 0.75). While lanicemine strongly attenuated APS following a single infusion, differential changes from placebo after three infusions was likely obscured by habituation effects. To our knowledge, this is the first use of APS in the context of an experimental medicine trial of a NMDAR antagonist in PTSD. These findings support selective NMDAR antagonism as a viable pharmacological strategy for salient aspects of PTSD.

Nicotine Inhalation and Suicide: Clinical Correlates and Behavioral Mechanisms.

BACKGROUND AND OBJECTIVES: Extensive evidence links smoking and suicide independently of psychiatric diagnoses, but there are questions about the pathophysiology and specificity of this relationship. We examined characteristics of this linkage to identify potential transdiagnostic mechanisms in suicide and its prevention. METHODS: We reviewed literature that associated suicide with smoking and e-cigarettes, including the temporal sequence of smoking and suicide risk and their shared behavioral risk factors of sensitization and impulsivity. RESULTS: Smoking is associated with increased suicide across psychiatric diagnoses and in the general population, proportionately to the number of cigarettes smoked per day. Rapid nicotine uptake into the brain through inhalation of conventional cigarettes, electronic cigarettes (e-cigarette), or even second-hand smoke can facilitate long-term sensitization and short-term impulsivity. Both impair action regulation and predispose to negative affect, continued smoking, and suicidal behavior. Intermittent hypoxia, induced by cigarettes or e-cigarettes, synergistically promotes impulsivity and sensitization, exacerbating suicidality. Two other shared behavioral risks also develop negative urgency (combined impulsivity and negative affect) and cross-sensitization to stressors or to other addictive stimuli. Finally, early smoking onset, promoted by e-cigarettes in never-smokers, increases subsequent suicide risk. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Prevention or cessation of nicotine inhalation can strategically prevent suicidality and other potentially lethal behavior regardless of psychiatric diagnoses. Medications for reducing smoking and suicidality, especially in younger smokers, should consider the neurobehavioral mechanisms for acute impulsivity and longer-term sensitization, potentially modulated more effectively through glutamate antagonism rather than nicotine substitution. (Am J Addict 2021;30:316-329).

Mixed features: evolution of the concept, past and current definitions, and future prospects.

Mixed states address the relationships between episodes and the course of an illness, presenting significant clinical challenges. Recurrent affective disorders were described thousands of years ago as dimensional disturbances of the basic elements of behavior, combining the characteristics of what we would now consider manic and depressive episodes. It was recognized from the beginning that combinations of depressive and manic features are associated with a severe illness course, including increased suicide risk. Early descriptions of affective disorders formulated them as systemic illnesses, a concept supported by more recent data. Descriptions of affective disorders and their course, including mixed states, became more systematic during the 19th century. Structured criteria achieved importance with evidence that, in addition to early onset, frequent recurrence, and comorbid problems, mixed states had worse treatment outcomes than other episodes. In contrast to 2000 years of literature on recurrent affective episodes and mixed states, the unipolar-bipolar disorder distinction was formalized in the mid-20th century. Mixed-state criteria, initially developed for bipolar disorder, ranged from fully combined depression and mania to the DSM-5 criteria, no longer limited to bipolar disorder, of a primary depressive or manic episode with at least three symptoms of the other episode type. The challenges involved in understanding and identifying mixed states center largely on what drives them, including (1) their formulation as either categorical or dimensional constructs, (2) the specificity of their relationships to depressive or manic episodes, and (3) specificity for bipolar versus major depressive disorder. Their existence challenges the distinction between bipolar and major depressive disorders. The challenges involved in identifying the underlying physiological mechanisms go to the heart of these questions.

Lurasidone for major depressive disorder with mixed features and irritability: a post-hoc analysis.

OBJECTIVE: The aim of this post-hoc analysis was to evaluate the efficacy of lurasidone in treating major depressive disorder (MDD) with mixed features including irritability. METHODS: The data in this analysis were derived from a study of patients meeting DSM-IV-TR criteria for unipolar MDD, with a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥26, presenting with two or three protocol-defined manic symptoms, and who were randomized to 6 weeks of double-blind treatment with either lurasidone 20-60 mg/d (n=109) or placebo (n=100). We defined "irritability" as a score ≥2 on both the Young Mania Rating Scale (YMRS) irritability item (#5) and the disruptive-aggressive item (#9). Endpoint change in the MADRS and YMRS items 5 and 9 were analyzed using a mixed model for repeated measures for patients with and without irritability. RESULTS: Some 20.7% of patients met the criteria for irritability. Treatment with lurasidone was associated with a significant week 6 change vs. placebo in MADRS score in both patients with (-22.6 vs. -9.5, p<0.0001, effect size [ES]=1.4) and without (-19.9 vs. -13.8, p<0.0001, ES=0.7) irritability. In patients with irritable features, treatment with lurasidone was associated with significant week 6 changes vs. placebo in both the YMRS irritability item (-1.4 vs. -0.3, p=0.0012, ES=1.0) and the YMRS disruptive-aggressive item (-1.0 vs. -0.3, p=0.0002, ES=1.2). CONCLUSIONS: In our post-hoc analysis of a randomized, placebo-controlled, 6-week trial, treatment with lurasidone significantly improved depressive symptoms in MDD patients with mixed features including irritability. In addition, irritability symptoms significantly improved in patients treated with lurasidone.

Heightened early-attentional stimulus orienting and impulsive action in men with antisocial personality disorder.

We tested whether enhanced stimulus orienting operationalized as N1 and P2 auditory evoked potentials to increasing loudness (50-90 dB clicks) could be associated with trait impulsivity (Barratt Impulsiveness Scale, BIS-11), impulsive action (commission error on the Immediate Memory Task), or impulsive choice (immediate responses on temporal discounting tasks). We measured N1 and P2 loudness sensitivity in a passive listening task as linear intensity-sensitivity slopes in 36 men with antisocial personality disorder with a history of conviction for criminal conduct and 16 healthy control men. Across all subjects, regression analyses revealed that a steeper P2 slope predicted higher IMT commission error/correct detection ratio, and lower stimulus discriminability (A-prime). These associations were also found within both groups. These relationships suggest an association between enhanced early stimulus orienting (P2), impulsive action (response inhibition), and impaired signal-noise discriminability (A-prime).

Effects of Intranasal Oxytocin on Aggressive Responding in Antisocial Personality Disorder.

The oxytocin receptor is important in several domains of social behavior, and administration of oxytocin modulates social responding in several mammalian species, including humans. Oxytocin has both therapeutic and scientific potential for elucidating the neural and behavioral mechanisms governing social behavior. In the present study, operationally-defined aggressive behavior of six males with Antisocial Personality Disorder (ASPD) was measured following acute intranasal oxytocin dosing (12, 24, and 48 international units) and placebo, using a well-validated laboratory task of human aggression (Point-Subtraction Aggression Paradigm, or PSAP). The PSAP provides participants with concurrently available monetary-earning and operationally-defined aggressive response options, maintained by fixed ratio schedules of consequences. Shifts in response rates and inter-response time (IRT) distributions were observed on the aggressive response option following oxytocin doses, relative to placebo. Few changes were observed in monetary-reinforced responding. However, across participants the direction and magnitude of changes in aggressive responding were not systematically related to dose. No trends were observed between psychometric or physiological data and oxytocin dosing or aggressive behavior. While this report is to our knowledge the first to examine the acute effects of oxytocin in this population at high risk for violence and other forms of antisocial behavior, several limitations in the experimental design and the results cast the study as a preliminary report. Strategies for more extensive future projects are discussed.

First manic episode associated with use of human chorionic gonadotropin for obesity: a case report.

BACKGROUND: Although highly controversial, the treatment of obesity with exogenous human chorionic gonadotropin (HCG) remains popular in the USA. We report the case of a patient whose first manic episode was associated with the use of HCG for weight loss. CASE REPORT: A 32-year-old female patient was admitted to our psychiatric inpatient unit due to a two-week history of manic symptoms. She had no previous history of manic or hypomanic episodes and had completed a 45-day course of sublingual HCG for weight loss immediately prior to the onset of the manic episode. The patient was treated with lithium carbonate and aripiprazole, and progressed with improvement in the symptoms. CONCLUSION: While it is not possible to definitively link the HCG use to the development of mania, available evidence suggests that HCG may have a contributing role in triggering manic symptomatology.

A randomized, double-blind, placebo-controlled trial of quetiapine in patients with bipolar disorder, mixed or depressed phase, and alcohol dependence.

BACKGROUND: Alcohol dependence is common in bipolar disorder (BPD) and associated with treatment nonadherence, violence, and hospitalization. Quetiapine is a standard treatment for BPD. We previously reported improvement in depressive symptoms, but not alcohol use, with quetiapine in BPD and alcohol dependence. However, mean alcohol use was low and a larger effect size on alcohol-related measures was observed in those with higher levels of alcohol consumption. In this study, efficacy of quetiapine in patients with BPD and alcohol dependence was examined in patients with higher mean baseline alcohol use than in the prior study. METHODS: Ninety outpatients with bipolar I or II disorders, depressed or mixed mood state, and current alcohol dependence were randomized to 12 weeks of sustained release quetiapine (to 600 mg/d) add-on therapy or placebo. Drinking was quantified using the Timeline Follow Back method. Additional assessment tools included the Hamilton Rating Scale for Depression, Inventory of Depressive Symptomatology-Self-Report, Young Mania Rating Scale, Penn Alcohol Craving Scale, liver enzymes, and side effects. Alcohol use and mood were analyzed using a declining-effects random-regression model. RESULTS: Baseline and demographic characteristics in the 2 groups were similar. No significant between-group differences were observed on the primary outcome measure of drinks per day or other alcohol-related or mood measures (p > 0.05). Overall side effect burden, glucose, and cholesterol were similar in the 2 groups. However, a significant weight increase was observed with quetiapine at week 6 (+2.9 lbs [SE 1.4] quetiapine vs. -2.0 lbs [SE 1.4], p = 0.03), but not at week 12. Scores on the Barnes Akathisia Scale increased significantly more (p = 0.04) with quetiapine (+0.40 [SE 0.3]) than placebo (-0.52 [SE 0.3]) at week 6 but not week 12. Retention (survival) in the study was similar in the groups. CONCLUSIONS: Findings suggest that quetiapine does not reduce alcohol consumption in patients with BPD and alcohol dependence.

Phenomenological subtypes of severe bipolar mixed states: a factor analytic study.

OBJECTIVE: The correct identification of bipolar mixed states (MS) has important implications for clinical practice. The aim of the study was to define the multidimensional psychopathological structure of severe MS. To our knowledge, no factor analytical studies including only patients with MS, have been conducted before. METHODS: In the first week of hospitalization, we evaluated by HAM-D-17, YMRS, BPRS and CGI, 202 Bipolar I inpatients with MS according to DSM-IV criteria referred for an ECT trial. A Principal-component analysis followed by Varimax rotation was performed on the 24-item BPRS. The relationships among different symptomatological subtypes and other clinical characteristics were explored. RESULTS: Six interpretable factors were extracted: Psychotic-positive symptoms, Mania, Disorientation-Unusual Motor Behaviour, Depression, Negative Symptoms and Anxiety. On the basis of the highest z-scores, we found 6 "dominant" BPRS factor groups, that were statistically distinct and without significant overlap in the main symptomatological presentation. Only 29 (14.4%) of our patients could be described as "Dominant Manic" and 48 (23.8%) as "Dominant Depressive"; most importantly 125 (61.9%) were neither predominately-manic nor predominately-depressive. Variables including age, number of previous episodes, suicidal behavior and HAM-D and YMRS scores significantly differentiated the subtypes. CONCLUSION: At least in the most severe forms, MS appears to represent more than the superposition of affective symptoms of opposite polarity. Anxiety, perplexity, psychotic experiences, motor disturbances and grossly disorganized behavior seem to arise from protracted intra-episodic instability and presence of a drive state influencing the mood state and the emotional resonance.

Impulsivity in children and adolescents with mood disorders and unaffected offspring of bipolar parents.

OBJECTIVE: Increased impulsivity seems to be present across all phases of bipolar disorder (BD). Impulsivity may therefore represent an endophenotype for BD, if it is also found among normal individuals at high genetic risk for mood disorders. In this study, we assessed impulsivity across four different groups of children and adolescents: patients with BD, major depressive disorder (MDD) patients, unaffected offspring of bipolar parents (UO), and healthy controls (HC). SUBJECTS AND METHODS: 52 patients with BD, 31 with MDD, 20 UO, and 45 HC completed the Barratt Impulsiveness Scale (BIS-11), an instrument designed to measure trait impulsivity. RESULTS: UO displayed significantly higher total BIS-11 impulsivity scores than HC (p=0.02) but lower scores than BD patients (F=27.12, p<0.01). Multiple comparison analysis revealed higher BIS-11 total scores among BD patients when compared to HC (p<0.01) and UO (p<0.01). MDD patients had higher BIS-11 scores when compared to HC (p<0.01). Differences between MDD patients and UO, as well as between MDD and BD patients, were not statistically significant. CONCLUSION: Our findings suggest that trait impulsivity is increased among children and adolescents with mood disorders, as well as in unaffected individuals at high genetic risk for BD.

Anti-suicidal effects of IV ketamine in a real-world setting.

The current study evaluated the effectiveness of intravenous ketamine treatment for suicidality in a community-based clinical sample of 295 outpatients (mean age=  40.37; 58.6 % male). We conducted growth mixture modeling to estimate latent classes of changes in symptoms of suicidality measured by the Concise Health Risk Tracking - Self-Report (CHRT-SR) across five infusions in a two-week course of treatment. Best-fit indices indicated three trajectory groups demonstrating non-linear, quadratic changes in CHRT-SR scores during ketamine treatment. The largest group of patients (n=  170, 57.6 %) had moderate CHRT-SR scores at baseline and showed gradual improvement during treatment. The other two groups of patients had severe CHRT-SR scores at baseline and diverged into one group with no improvement throughout treatment (n = 63, 21  %) and one group with rapid improvement (n = 62, 21 %). Of the clinical and demographic variables available and tested, only higher scores pertaining to active thoughts of death and/or plan were found to predict which of the patients with severe CHRT-SR scores at baseline would not benefit from treatment. The present study provides an important contribution to the knowledge of ketamine's effects on symptoms related to suicide over time. providing support for the possible effectiveness of ketamine in a proportion of patients.

Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort.

Importance: Many psychiatric outcomes share a common etiologic pathway reflecting behavioral disinhibition, generally referred to as externalizing (EXT) disorders. Recent genome-wide association studies (GWASs) have demonstrated the overlap between EXT disorders and important aspects of veterans' health, such as suicide-related behaviors and substance use disorders (SUDs). Objective: To explore correlates of risk for EXT disorders within the Veterans Health Administration (VA) Million Veteran Program (MVP). Design, Setting, and Participants: A series of phenome-wide association studies (PheWASs) of polygenic risk scores (PGSs) for EXT disorders was conducted using electronic health records. First, ancestry-specific PheWASs of EXT PGSs were conducted in the African, European, and Hispanic or Latin American ancestries. Next, a conditional PheWAS, covarying for PGSs of comorbid psychiatric problems (depression, schizophrenia, and suicide attempt; European ancestries only), was performed. Lastly, to adjust for unmeasured confounders, a within-family analysis of significant associations from the main PheWAS was performed in full siblings (European ancestries only). This study included the electronic health record data from US veterans from VA health care centers enrolled in MVP. Analyses took place from February 2022 to August 2023 covering a period from October 1999 to January 2020. Exposures: PGSs for EXT, depression, schizophrenia, and suicide attempt. Main Outcomes and Measures: Phecodes for diagnoses derived from the International Statistical Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification, codes from electronic health records. Results: Within the MVP (560 824 patients; mean [SD] age, 67.9 [14.3] years; 512 593 male [91.4%]), the EXT PGS was associated with 619 outcomes, of which 188 were independent of risk for comorbid problems or PGSs (from odds ratio [OR], 1.02; 95% CI, 1.01-1.03 for overweight/obesity to OR, 1.44; 95% CI, 1.42-1.47 for viral hepatitis C). Of the significant outcomes, 73 (11.9%) were significant in the African results and 26 (4.5%) were significant in the Hispanic or Latin American results. Within-family analyses uncovered robust associations between EXT PGS and consequences of SUDs, including liver disease, chronic airway obstruction, and viral hepatitis C. Conclusions and Relevance: Results of this cohort study suggest a shared polygenic basis of EXT disorders, independent of risk for other psychiatric problems. In addition, this study found associations between EXT PGS and diagnoses related to SUDs and their sequelae. Overall, this study highlighted the potential negative consequences of EXT disorders for health and functioning in the US veteran population.

Is impulsivity a common trait in bipolar and unipolar disorders?

OBJECTIVES: Impulsivity is increased in bipolar and unipolar disorders during episodes and is associated with substance abuse disorders and suicide risk. Impulsivity between episodes predisposes to relapses and poor therapeutic compliance. However, there is little information about impulsivity during euthymia in mood disorders. We sought to investigate trait impulsivity in euthymic bipolar and unipolar disorder patients, comparing them to healthy individuals and unaffected relatives of bipolar disorder patients. METHODS: Impulsivity was evaluated by the Barratt Impulsiveness Scale (BIS-11A) in 54 bipolar disorder patients, 25 unipolar disorder patients, 136 healthy volunteers, and 14 unaffected relatives. The BIS-11A mean scores for all four groups were compared through the Games-Howell test for all possible pairwise combinations. Additionally, we compared impulsivity in bipolar and unipolar disorder patients with and without a history of suicide attempt and substance abuse disorder. RESULTS: Bipolar and unipolar disorder patients scored significantly higher than the healthy controls and unaffected relatives on all measures of the BIS-11A except for attentional impulsivity. On the attentional impulsivity measures there were no differences among the unaffected relatives and the bipolar and unipolar disorder groups, but all three of these groups scored higher than the healthy participant group. There was no difference in impulsivity between bipolar and unipolar disorder subjects with and without suicide attempt. However, impulsivity was higher among bipolar and unipolar disorder subjects with past substance use disorder compared to patients without such a history. CONCLUSIONS: Questionnaire-measured impulsivity appears to be relatively independent of mood state in bipolar and unipolar disorder patients; it remains elevated in euthymia and is higher in individuals with past substance abuse. Elevated attentional and lower non-planning impulsivity in unaffected relatives of bipolar disorder patients distinguished them from healthy participants, suggesting that increased attentional impulsivity may predispose to development of affective disorders, while reduced attentional impulsivity may be protective.

Aggression, impulsivity, and psychopathic traits in combined antisocial personality disorder and substance use disorder.

Aggression, impulsivity, and psychopathic traits are prominent in both antisocial personality disorder (ASPD) and substance use disorders (SUD), but have rarely been examined collectively. The authors' results show that all three variables were elevated in adults with comorbid ASPD/SUD, relative to SUD-only and control subjects.

Activated depression: mixed bipolar disorder or agitated unipolar depression?

The combination of depression and activation presents clinical and diagnostic challenges. It can occur, in either bipolar disorder or major depressive disorder, as increased agitation as a dimension of depression. What is called agitation can consist of expressions of painful inner tension or as disinhibited goal-directed behavior and thought. In bipolar disorder, elements of depression can be combined with those of mania. In this case, the agitation, in addition to increased motor activity and painful inner tension, must include symptoms of mania that are related to goal-directed behavior or manic cognition. These diagnostic considerations are important, as activated depression potentially carries increased behavioral risk, especially for suicidal behavior, and optimal treatments for depressive episodes differ between bipolar disorder and major depressive disorder.

The medical alliance: from placebo response to alliance effect.

The natural human response to illness is to seek to understand what is happening and to look for help from others. In all cultures, one finds healers, who provide explanations and offer care. Their interventions often have a placebo effect through activation of natural healing processes in the patient. Although placebo effects are relatively large and robust, physicians generally consider placebo treatment prescientific and deceptive. We review the determinants of the placebo response and show how a particular professional alliance between a patient and a caregiver is apt to equally affect treatment outcome. We distinguish the alliance effect from the placebo effect. We develop a comprehensive model of the medical alliance, on the basis of the concept of concordance, and review its relevance for clinical practice and medical education. The alliance effect represents a professional and ethical way of activating a patient's natural healing mechanisms.

Overdiagnosis of bipolar disorder: a critical analysis of the literature.

Bipolar disorder (BD) is considered one of the most disabling mental conditions, with high rates of morbidity, disability, and premature death from suicide. Although BD is often misdiagnosed as major depressive disorder, some attention has recently been drawn to the possibility that BD could be overdiagnosed in some settings. The present paper focuses on a critical analysis of the overdiagnosis issue among bipolar patients. It includes a review of the available literature findings, followed by some recommendations aiming at optimizing the diagnosis of BD and increasing its reliability.

Neuroanatomical Correlates of the Late Positive Potential in Youth with Pediatric Bipolar Disorder.

BACKGROUND: The late positive potential (LPP) could be a marker of emotion dysregulation in youth with pediatric bipolar disorder (PBD). However, the neuroanatomical correlates of the LPP are still not clarified. OBJECTIVE: To provide cortical and deep gray matter correlates of the LPP in youth, specifically, youth with PBD. METHODS: Twenty-four 7 to 17 years-old children with PBD and 28 healthy controls (HC) underwent cortical thickness and deep gray matter volumes measurements through magnetic resonance imaging and LPP measurement elicited by passively viewing emotional faces through electroencephalography. T-tests compared group differences in LPP, cortical thickness, and deep gray matter volumes. Linear regressions tested the relationship between LPP amplitude and cortical thickness/deep gray matter volumes. RESULTS: PBD had a more pronounced LPP amplitude for happy faces and a thinner cortex in prefrontal areas than HC. While considering both groups, a higher LPP amplitude was associated with a thicker cortex across occipital and frontal lobes, and with a smaller right globus pallidus volume. In addition, a higher LPP amplitude for happy faces was associated with smaller left caudate and left globus pallidus volumes across both groups. Finally, the LPP amplitude correlated negatively with right precentral gyrus thickness across youth with PBD, but positively across HC. CONCLUSION: Neural correlates of LPP in youth included fronto-occipital areas that have been associated also with emotion processing and control. The opposite relationship between BPD and HC of LPP amplitude and right precentral gyrus thickness might explain the inefficacy of the emotional control system in PBD.

Replication of distinct trajectories of antidepressant response to intravenous ketamine.

BACKGROUND: The goal of this study was to replicate previous findings of three distinct treatment response pathways associated with repeated intravenous (IV) ketamine infusions among patients with major depressive disorder (MDD). METHODS: We conducted growth mixture modeling to estimate latent classes of change in depression (Quick Inventory of Depressive Symptomatology-Self Report, QIDS-SR) across six treatment visits in 298 patients with MDD treated with IV ketamine in an outpatient community clinic. Mean age was 40.36 and patients were primarily male (58.4 %). The sample had relatively severe depression (QIDS-SR = 16.61) at pre-treatment and the majority had not responded to at least two prior medications. RESULTS: Best-fit indices indicated three trajectory groups to optimally demonstrate non-linear, quadratic changes in depressive symptoms during ketamine treatment. Two groups had severe depression at baseline but diverged into a group of modest improvement over the treatment course (n = 78) and a group of patients with rapid improvement (n = 103). A third group had moderate depression at baseline with moderate improvement during the treatment course (n = 117). Additional planned trajectory comparisons showed that suicidality at entry was higher in the high depression groups and that change in suicidality severity followed that of depression. LIMITATIONS: This was a retrospective analysis of a naturalistic sample. Patients were unblinded and more heterogenous than those included in most controlled clinical trial samples. CONCLUSIONS: This replication study in an independent community-based ketamine clinic sample revealed similar response trajectories, with only about a third of depressed patients benefitting substantially from an acute induction course of ketamine infusions.