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.

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).

Influence of empathetic pain processing on cognition in schizophrenia.

Deficits in both empathy and cognition have been reported widely in patients with schizophrenia. However, little is known about how these deficits interact among such patients. In the present study, we used pain portraying pictures preceding a color-word Stroop task to investigate the effect of empathetic pain observation on cognition among patients with schizophrenia. Twenty patients with schizophrenia and twenty healthy controls were included. The control group showed increased Stroop facilitation and decreased interference during the empathetic pain condition compared with the non-empathetic condition. Although patients with schizophrenia exhibited deficits in cognition, they demonstrated a similar empathy effect to controls on Stroop facilitation, but a somewhat larger empathy effect on Stroop interference (a more decreased effect). In particular, the groups did not differ in either automatic or controlled processing during the non-empathetic condition, suggesting general rather than specific cognitive deficits in schizophrenia. Together, we interpret our findings in terms of two opposing effects of empathy on cognition in schizophrenia, with possible neuromodulatory mechanism. Whereas prior studies showed empathy to be impaired, our outcomes indicate that at least some components of empathetic pain processing are preserved in such patients.

Alterations in attentional processing in youth with misophonia: A phenotypical cross-comparison with anxiety patients.

BACKGROUND: Misophonia is a complex condition characterized by extreme emotional distress in response to specific sounds or specific visual stimuli. Despite a growing body of clinical and neuroscientific literature, the etiology of this condition remains unclear. Hyperarousal, that is, a state of heightened alertness and disinhibition, as a core feature of misophonia is supported by behavioral and neuroimaging literature and might represent a viable clinical target for the development of both behavioral and pharmacological interventions. The aim of this study was to investigate how hyperarousal might be linked to neurocognitive processes associated with vigilance and stimulus discrimination in youth with misophonia. METHODS: We compared 72 children and adolescents with misophonia (13.74 ± 2.44 years) (64 % female) and 89 children and adolescents with anxiety (12.35 ± 2.57 years) (58.4 % female) on behavioral and signal detection performance of the immediate memory task (IMT). Anxiety patients were used as a clinical control group to distinguish attentional processes specific for misophonia. RESULTS: Both groups demonstrated similar behavioral performance, including response rate and reaction time. However, misophonia was associated with elevated stimulus discrimination (d prime), which in turn was positively correlated with the severity of misophonia trigger reports. CONCLUSIONS: Our findings are in line with previous cognitive and neuroimaging studies, and support an arousal-based model of misophonia, where individuals with misophonia experience a state of heightened vigilance, being more aware of stimuli in the environment. Our findings provide a neurocognitive basis for future study of neurochemical imaging that might further progress towards clinical targets.

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.

Neural complexity EEG biomarkers of rapid and post-rapid ketamine effects in late-life treatment-resistant depression: a randomized control trial.

Ketamine is an effective intervention for treatment-resistant depression (TRD), including late-in-life (LL-TRD). The proposed mechanism of antidepressant effects of ketamine is a glutamatergic surge, which can be measured by electroencephalogram (EEG) gamma oscillations. Yet, non-linear EEG biomarkers of ketamine effects such as neural complexity are needed to capture broader systemic effects, represent the level of organization of synaptic communication, and elucidate mechanisms of action for treatment responders. In a secondary analysis of a randomized control trial, we investigated two EEG neural complexity markers (Lempel-Ziv complexity [LZC] and multiscale entropy [MSE]) of rapid (baseline to 240 min) and post-rapid ketamine (24 h and 7 days) effects after one 40-min infusion of IV ketamine or midazolam (active control) in 33 military veterans with LL-TRD. We also studied the relationship between complexity and Montgomery-Åsberg Depression Rating Scale score change at 7 days post-infusion. We found that LZC and MSE both increased 30 min post-infusion, with effects not localized to a single timescale for MSE. Post-rapid effects of reduced complexity with ketamine were observed for MSE. No relationship was observed between complexity and reduction in depressive symptoms. Our findings support the hypothesis that a single sub-anesthetic ketamine infusion has time-varying effects on system-wide contributions to the evoked glutamatergic surge in LL-TRD. Further, changes to complexity were observable outside the time-window previously shown for effects on gamma oscillations. These preliminary results have clinical implications in providing a functional marker of ketamine that is non-linear, amplitude-independent, and represents larger dynamic properties, providing strong advantages over linear measures in highlighting ketamine's effects.

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.

Clinical characteristics, impairment, and psychiatric morbidity in 102 youth with misophonia.

BACKGROUND: There is little information on the clinical presentation, functional impact, and psychiatric characteristics of misophonia in youth, an increasingly recognized syndrome characterized by high emotional reactivity to certain sounds and associated visual stimuli. METHOD: One-hundred-two youth (8-17 years-old) with misophonia and their parents were recruited and compared with 94 youth with anxiety disorders. Participants completed validated assessments of misophonia severity, quality of life, as well as psychiatric symptoms and diagnoses. RESULTS: The most common misophonia triggers included eating (96 %), breathing (84 %), throat sounds (66 %), and tapping (54 %). Annoyance/irritation, verbal aggression, avoidance behavior, and family impact were nearly universal. Misophonia severity was associated with internalizing symptoms, child-reported externalizing behaviors, and poorer quality of life. High rates of comorbidity with internalizing and neurodevelopmental disorders were found. Quality of life and externalizing behaviors were not significantly different between misophonia and anxiety samples; internalizing symptoms and autism characteristics were significantly higher among youth with anxiety disorders. LIMITATIONS: This self-selected sample was characterized by limited multicultural diversity. CONCLUSIONS: This study presents misophonia as a highly impairing psychiatric syndrome. Future interdisciplinary work should clarify the mechanisms of misophonia, establish evidence-based treatments, and extend these findings to randomly sampled and more culturally diverse populations.

Measuring misophonia in youth: A psychometric evaluation of child and parent measures.

BACKGROUND: Misophonia is characterized by intense emotional reactions to specific sounds or visual stimuli and typically onsets during childhood. An obstacle for research and clinical practice is that no comprehensively evaluated measures for pediatric misophonia exist. METHODS: In a sample of 102 youth meeting the proposed diagnostic criteria of misophonia, we evaluated the child and parent-proxy versions of the self-reported Misophonia Assessment Questionnaire (MAQ; assessing broad aspects of misophonia) and the child version of the Amsterdam Misophonia Scale (A-MISO-S; assessing misophonia severity). Confirmatory and exploratory factor analysis were used to examine factor structures of the measures. Further, child-parent agreement on the MAQ and associations between both measures and misophonia-related impairment, quality of life, and misophonia-related school interference were examined to evaluate aspects of convergent validity. RESULTS: For both youth- and parent-ratings, four MAQ factors emerged: pessimism, distress, interference, and non-recognition. A-MISO-S showed a unidimensional structure, but the item 'effort to resist' did not load significantly onto the unidimensional factor. Good child-parent agreement on the MAQ scales were found and both MAQ and A-MISO-S were moderately to strongly associated with misophonia-related impairment, quality of life (inverse association), and misophonia-related school interference. LIMITATIONS: MAQ and A-MISO-S assess sensitivity to auditory but not visual stimuli, the sample size was modest, and repeated assessments were not conducted. CONCLUSIONS: The combination of MAQ and A-MISO-S shows promise as a multidimensional assessment approach for pediatric misophonia. Future evaluations should include known-groups validity, screening performance, and sensitivity to change in symptom severity.

Amygdala structure and function in paediatric bipolar disorder and high-risk youth: A systematic review of magnetic resonance imaging findings.

OBJECTIVE: Converging evidence from structural and functional magnetic resonance imaging (MRI) studies points to amygdala alteration as crucial in the development of paediatric bipolar disorder (pBP). The high number of recent studies prompted us to comprehensively evaluate findings. We aimed to systematically review structural and functional MRI studies investigating the amygdala in patients with pBP and in youth at high-risk (HR) for developing pBP. METHODS: We searched PubMed from any time to 25 September 2020 using: 'amygdala AND (MRI OR magnetic resonance imaging) AND bipolar AND (pediatr* OR child OR children OR childhood OR adolescent OR adolescents OR adolescence OR young OR familial OR at-risk OR sibling* OR offspring OR high risk)'. In this review, we adhered to the PRISMA statement. RESULTS: Amygdala hyperactivity to emotional stimuli is the most commonly reported finding in youth with pBP and HR compared to healthy peers (HC), whereas findings from structural MRI studies are inconsistent. CONCLUSIONS: Hyperactivation of the amygdala might be an endophenotype of pBP.

Does mismatch negativity have utility for NMDA receptor drug development in depression?

CLINICAL TRIAL REGISTRATION: Rapid antidepressant effects associated with ketamine have shifted the landscape for the development of therapeutics to treat major depressive disorder (MDD) from a monoaminergic to glutamatergic model. Treatment with ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, may be effective, but has many non-glutamatergic targets, and clinical and logistical problems are potential challenges. These factors underscore the importance of manipulations of binding mechanics to produce antidepressant effects without concomitant clinical side effects. This will require identification of efficient biomarkers to monitor target engagement. The mismatch negativity (MMN) is a widely used electrophysiological signature linked to the activity of NMDA receptors (NMDAR) in humans and animals and validated in pre-clinical and clinical studies of ketamine. In this review, we explore the flexibility of the MMN and its capabilities for reliable use in drug development for NMDAR antagonists in MDD. We supplement this with findings from our own research with three distinct NMDAR antagonists. The research described illustrates that there are important distinctions between the mechanisms of NMDAR antagonism, which are further crystallized when considering the paradigm used to study the MMN. We conclude that the lack of standardized methodology currently prevents MMN from being ready for common use in drug discovery. This manuscript describes data collected from the following National Institutes of Health (NIH) and Veterans Affairs (VA) studies: AV-101, NCT03583554; lanicemine, NCT03166501; ketamine, NCT02556606.

Identification of an optimal dose of intravenous ketamine for late-life treatment-resistant depression: a Bayesian adaptive randomization trial.

Evidence supporting specific therapies for late-life treatment-resistant depression (LL-TRD) is necessary. This study used Bayesian adaptive randomization to determine the optimal dose for the probability of treatment response (≥50% improvement from baseline on the Montgomery-Åsberg Depression Rating Scale) 7 days after a 40 min intravenous (IV) infusion of ketamine 0.1 mg/kg (KET 0.1), 0.25 mg/kg (KET 0.25), or 0.5 mg/kg (KET 0.5), compared to midazolam 0.03 mg/kg (MID) as an active placebo. The goal of this study was to identify the best dose to carry forward into a larger clinical trial. Response durability at day 28, safety and tolerability, and effects on cortical excitation/inhibition (E/I) ratio using resting electroencephalography gamma and alpha power, were also determined. Thirty-three medication-free US military veterans (mean age 62; range: 55-72; 10 female) with LL-TRD were randomized double-blind. The trial was terminated when dose superiority was established. All interventions were safe and well-tolerated. Pre-specified decision rules terminated KET 0.1 (N = 4) and KET 0.25 (N = 5) for inferiority. Posterior probability was 0.89 that day-seven treatment response was superior for KET 0.5 (N = 11; response rate = 70%) compared to MID (N = 13; response rate = 46%). Persistent treatment response at day 28 was superior for KET 0.5 (response rate = 82%) compared to MID (response rate = 37%). KET 0.5 had high posterior probability of increased frontal gamma power (posterior probability = 0.99) and decreased posterior alpha power (0.89) during infusion, suggesting an acute increase in E/I ratio. These results suggest that 0.5 mg/kg is an effective initial IV ketamine dose in LL-TRD, although further studies in individuals older than 75 are required.

Criminal conviction, impulsivity, and course of illness in bipolar disorder.

OBJECTIVE: Criminal behavior in bipolar disorder may be related to substance use disorders, personality disorders, or other comorbidities potentially related to impulsivity. We investigated relationships among impulsivity, antisocial personality disorder (ASPD) or borderline personality disorder symptoms, substance use disorder, course of illness, and history of criminal behavior in bipolar disorder. METHODS: A total of 112 subjects with bipolar disorder were recruited from the community. Diagnosis was by Structured Clinical Interview for DSM-IV (SCID-I and SCID-II); psychiatric symptom assessment by the Change version of the Schedule for Affective Disorders and Schizophrenia (SADS-C); severity of Axis II symptoms by ASPD and borderline personality disorder SCID-II symptoms; and impulsivity by questionnaire and response inhibition measures. RESULTS: A total of 29 subjects self-reported histories of criminal conviction. Compared to other subjects, those with convictions had more ASPD symptoms, less education, more substance use disorder, more suicide attempt history, and a more recurrent course with propensity toward mania. They had increased impulsivity as reflected by impaired response inhibition, but did not differ in questionnaire-measured impulsivity. On logit analysis, impaired response inhibition and ASPD symptoms, but not substance use disorder, were significantly associated with criminal history. Subjects convicted for violent crimes were not more impulsive than those convicted for nonviolent crimes. CONCLUSIONS: In this community sample, a self-reported history of criminal behavior is related to ASPD symptoms, a recurrent and predominately manic course of illness, and impaired response inhibition in bipolar disorder, independent of current clinical state.

Distinct trajectories of antidepressant response to intravenous ketamine.

BACKGROUND: The N-methyl-D-aspartate receptor antagonist ketamine is potentially effective in treatment resistant depression. However, its antidepressant efficacy is highly variable, and there is little information about predictors of response. METHODS: We employed growth mixture modeling (GMM) analysis to examine specific response trajectories to intravenous (IV) ketamine (three infusions; mean dose 0.63 mg/kg, SD 0.28, range 0.30 - 2.98 mg/kg over 40 min) in 328 depressed adult outpatients referred to a community clinic. The Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) assessed depression severity at baseline and before each infusion, up to three infusions for four total observations. RESULTS: GMM revealed three QIDS-SR response trajectories. There were two groups of severely depressed patients, with contrasting responses to ketamine. One group (n=135, baseline QIDS-SR=18.8) had a robust antidepressant response (final QIDS-SR=7.3); the other group (n=97, QIDS-SR=19.8) was less responsive (final QIDS-SR=15.6). A third group (n=96) was less severely depressed at baseline (QIDS-SR=11.7), with intermediate antidepressant response (final QIDS-SR=6.6). Comparisons of demographic and clinical characteristics between groups with severe baseline depression revealed higher childhood physical abuse in the group with robust ketamine response (p=0.01). LIMITATIONS: This was a retrospective analysis on a naturalistic sample. Patients were unblinded and more heterogenous than those included in most controlled clinical trial samples. Information pertaining to traumatic events occurring after childhood and pre-existing or concurrent medical conditions that may have affected outcomes was not available. CONCLUSIONS: Overall, ketamine's effect in patients with severe baseline depression and history of childhood maltreatment may be consistent with ketamine-induced blockade of behavioral sensitization.

A randomized cross-over trial to define neurophysiological correlates of AV-101 N-methyl-D-aspartate receptor blockade in healthy veterans.

The kynurenine pathway (KP) is a strategic metabolic system that combines regulation of neuronal excitability via glutamate receptor function and neuroinflammation via other KP metabolites. This pathway has great promise in treatment of depression and suicidality. The KP modulator AV-101 (4-chlorokynurenine, 4-Cl-KYN), an oral prodrug of 7-chlorokynurenic acid (7-Cl-KYNA), an N-methyl-D-aspartate receptor (NMDAR) glycine site antagonist, and of 4-chloro-3-hydroxyanthranilic acid (4-Cl-3-HAA), a suppressor of NMDAR agonist quinolinic acid (QUIN), is a promising potential antidepressant that targets glutamate functioning via the KP. However, a recent placebo-controlled clinical trial of AV-101 in depression found negative results. This raises the question of whether AV-101 can penetrate the brain and engage the NMDAR and KP effectively. To address this problem, ten healthy US military veterans (mean age = 32.6 years ± 6.11; 1 female) completed a phase-1 randomized, double-blind, placebo-controlled, crossover study to examine dose-related effects of AV-101 (720 and 1440 mg) on NMDAR engagement measured by γ-frequency band auditory steady-state response (40 Hz ASSR) and resting EEG. Linear mixed models revealed that 1440 mg AV-101, but not 720 mg, increased 40 Hz ASSR and 40 Hz ASSR γ-inter-trial phase coherence relative to placebo. AV-101 also increased 4-Cl-KYN, 7-Cl-KYNA, 4-Cl-3-HAA, 3-HAA, and KYNA in a dose-dependent manner, without affecting KYN and QUIN. AV-101 was safe and well tolerated. These results corroborate brain target engagement of 1440 mg AV-101 in humans, consistent with blockade of interneuronal NMDAR blockade. Future studies should test higher doses of AV-101 in depression. Suicidal behavior, which has been associated with high QUIN and low KYNA, is also a potential target for AV-101.

The Neurobiology of Mixed States.

Interest in the coexistence of manic and depressive symptoms fostered hypotheses on neurobiological underpinnings of mixed states. Neurobiological properties of mixed states, however, have not been comprehensively described. The authors searched databases for articles on neurobiological markers related to mixed states. Results showed that mixed states are characterized by elevated central and peripheral monoamine levels, greater alterations in hypothalamic-pituitary-adrenal axis, increased inflammation, and greater circadian rhythms dysfunction than nonmixed forms. Furthermore, the magnitude of pathophysiologic alterations in mixed states exceeds those associated with nonmixed mania or depression and suggest that hyperactivation and hyperarousal are core features of mixed states.

Temporal Structure of Mixed States: Does Sensitization Link Life Course to Episodes?

Susceptibility to combined depressive and manic syndromes correlates strongly with arousal-related symptoms including impulsivity, anxiety and agitation. This relationship to a driven, "mixed" activation-depression state, generated by a life-long process, was described in classical times. Course of illness in mixed states includes increased episode frequency, duration, earlier onset, and association with addiction- and trauma/stress-related disorders. Mixed episodes have catecholamine and hypothalamic-pituitary-adrenocortical activity increased beyond nonmixed states of similar symptom severity. These properties resemble behavioral sensitization, where salient, survival-related stimuli (traumatic or rewarding) can generate persistently exaggerated responses with disrupted arousal and reward, with potential for suicide and other severe consequences.

Impulsivity and Suicidal Behavior.

Suicide is the leading cause of injury mortality in the United States and the second-leading cause of death in people aged 10-34 years. While many long-term risk factors are known, the short-term prediction of suicidal behavior remains elusive. Many characteristics of suicidal behavior cut across diagnoses, but suicide is increased in recurrent psychiatric disorders, addictive disorders, and trauma-related disorders. Suicide results from the interaction of short-term and long-term behavioral regulation. The shorter the time-course of the mechanism, the closer it is to actual suicidal behavior, and the harder it is to prevent. We will discuss the manner in which impulsivity, a major determinant of short-term suicide risk, interacts with longer-term risk factors, especially sensitization to addictive or traumatic stimuli. Impulsivity predisposes to sensitization; in turn, impulsivity is a prominent component of sensitized behavior. Impulsivity can be described as a general pattern of behavior ("trait" impulsivity), as responses that are not conformed to their context (action-impulsivity), or as inability to delay reward or to take future consequences into account (choice-impulsivity). Each of these contributes to suicidal behavior. The neural mechanisms of impulsivity and sensitization are analogous, and sensitization can produce rapidly fluctuating patterns of impulsive behavior, arousal, and anhedonia. In order to recognize and prevent suicidal behavior, it is necessary to identify factors associated with susceptibility to bouts of impulsive behavior in people at elevated long-term risk.

Psychotherapy for Mixed Depression and Mixed Mania.

Treatment guidelines for mixed states of depression or (hypo)mania focus almost exclusively on psychopharmacologic intervention without tapping into the benefits of psychotherapy. The authors highlight the complex clinical picture and illness course of mixed states, and discuss the benefit of taking a patient-centered approach to treatment incorporating techniques from a variety of evidence-based psychotherapies. A careful assessment of suicide risk as well as interventions designed specifically for anxiety are also recommended.

Increased trait-like impulsivity and course of illness in bipolar disorder.

BACKGROUND: Impulsivity as a trait characteristic is increased in bipolar disorder and may be a core factor of the illness. We have investigated relationships between trait-like impulsivity, measured by the Barratt Impulsiveness Scale (BIS-11), and demographic and illness-course characteristics of bipolar disorder. METHODS: We studied 114 subjects with bipolar disorder and 71 healthy comparison subjects. Diagnoses were based on the Structured Clinical Interview for DSM-IV. In addition to impulsivity, we examined age, education, gender, psychiatric symptoms, and characteristics related to course of illness. We used general linear mixed model analysis to evaluate the manner in which the variables contributed to BIS-11 scores. RESULTS: All BIS-11 subscale scores were higher in bipolar disorder than in comparison subjects. There were less consistent independent effects of education and age. Elevated BIS-11 scores were associated with early onset, more frequent episodes of illness, and a history of suicide attempts. These relationships persisted when age, gender, and education were taken into account. DISCUSSION: These results show that, after accounting for common confounding factors, trait-like impulsivity was substantially higher in subjects with bipolar disorder than in nonbipolar comparison subjects, regardless of symptoms. Within subjects with bipolar disorder, high trait impulsivity was associated with a more severe course of illness.