Nathan J. Kolla

Greater Monoamine Oxidase A Binding in Perimenopausal Age as Measured With Carbon 11–Labeled Harmine Positron Emission Tomography

IMPORTANCE Perimenopause is a period of high risk for mood disorders, and it has been proposed that perimenopause is also a window of risk for processes linked to later dementia. However, in human perimenopause, the neurobiological changes implicated in the genesis of mood disorders or dementia have not been identified. Monoamine oxidase A (MAO-A) is an important brain enzyme that creates oxidative stress, influences apoptosis, and metabolizes monoamines. After declines in estrogen level, MAO-A density may be elevated for a month or longer, and repeated declines in estrogen level occur with greater magnitude during perimenopause. OBJECTIVE To investigate whether MAO-A total distribution volume (VT), an index of MAO-A density, is elevated in women of perimenopausal age (41-51 years). DESIGN, SETTING, AND PARTICIPANTS In a cross-sectional study at a tertiary care psychiatric hospital, 58 women underwent carbon 11-labeled harmine positron emission tomography. These included 19 young women of reproductive age (mean [SD], 28.26 [5.05] years), 27 women of perimenopausal age (mean [SD] age, 45.21 [3.41] years; including 14 women with change in menstrual cycle length with a mean [SD] age of 45.50 [4.00] years and 13 women with no change in menstrual cycle length with a mean [SD] age of 44.92 [2.81] years), and 12 women in menopause (mean [SD] age, 56.25 [3.19] years). MAIN OUTCOMES AND MEASURES Values of MAO-A VT in the prefrontal cortex, anterior cingulate cortex, dorsal striatum, ventral striatum, thalamus, hippocampus, and midbrain. RESULTS On average, MAO-A VT in perimenopausal age was elevated by 34% compared with reproductive age and by 16% compared with menopause (multivariate analysis of variance, group effect, F16,94 = 3.03; P < .001). Within the perimenopausal age group, meeting Stages of Reproductive Aging Workshop criteria for perimenopause, which is mainly based on menstrual cycle length, was not associated with MAO-A VT (F8,18 = 0.548; P = .81) but tendency to cry was positively correlated with MAO-A VT in the prefrontal cortex (r = 0.54; P = .008). CONCLUSIONS AND RELEVANCE To our knowledge, this is the first report of a change in a central biomarker during perimenopausal age that is also present during major depressive episodes and high-risk states for major depressive episodes. The functions of MAO-A influence oxidative stress and apoptosis, 2 processes implicated as excessive in both mood disorders and dementia. Hence, greater MAO-A VT during perimenopause may represent a new target for assessing novel interventions to prevent mood disorders and reduce longer-term risk of neurodegenerative disease.

Elevated Monoamine Oxidase A Binding During Major Depressive Episodes Is Associated with Greater Severity and Reversed Neurovegetative Symptoms

Inadequate treatment response occurs in approximately 40% of major depressive episodes (MDEs), and one approach to solve this is careful matching of treatment to the specific pathologies of MDE. One such biological abnormality is elevated monoamine oxidase A (MAO-A) levels, which occurs in the prefrontal and anterior cingulate cortex (PFC and ACC) during MDE; however, the subtypes for which this abnormality is most prominent are unknown. We hypothesized that MAO-A levels in the PFC and ACC are most elevated in MDE with greater severity and reversed neurovegetative symptoms (hypersomnia and either hyperphagia or weight gain). MAO-A VT (an index of MAO-A density) was measured using [11C]harmine positron emission tomography (PET) in 42 subjects with MDEs secondary to major depressive disorder and 37 healthy controls. The effect of severity and reversed neurovegetative symptoms on MAO-A VT in the PFC and ACC was analyzed using a multivariate analysis of variance (MANOVA). Greater severity and reversed neurovegetative symptoms were associated with elevated MAO-A VT in the PFC and ACC (MANOVA, severity: F(2,38)=5.44, p=0.008; reversed neurovegetative symptoms: F(2,38)=5.13, p=0.01). Increased MAO-A level, when greater severity and reversed neurovegetative symptoms are present, may explain the association of these clinical features with a preferential response to MAO inhibitors, which is especially well-evidenced for reversed neurovegetative symptoms in MDE. As MAO-A creates oxidative stress, facilitates apoptosis, and metabolizes monoamines, therapeutics opposing these processes are predicted to best treat MDE with greater severity and reversed neurovegetative symptoms.

Childhood Maltreatment and Aggressive Behaviour in Violent Offenders with Psychopathy

Objective: To document experiences of childhood maltreatment among violent offenders with antisocial personality disorder (ASPD) distinguishing between those with and without the syndrome of psychopathy (+P and –P), and to determine whether maltreatment is associated with proactive and reactive aggression. Method: The sample included 10 violent offenders with ASPD+P, 15 violent offenders with ASPD-P, and 15 nonoffenders. All participants completed interviews with the same forensic psychiatrist focusing on physical, sexual, and emotional abuse prior to age 18 using the Early Trauma Inventory. Aggression was assessed using the Reactive-Proactive Questionnaire. Results: Violent offenders with ASPD+P reported significantly more severe childhood physical abuse, but not more sexual or emotional abuse, than violent offenders with ASPD-P and nonoffenders. Psychopathy Checklist—Revised (PCL-R) scores, but not childhood physical abuse, were associated with proactive aggression. Childhood physical abuse was associated with reactive aggression, as was an interaction term indicating that when both PCL-R scores and childhood physical abuse were high, so was reactive aggression. Conclusions: Among violent offenders, PCL-R scores were positively associated with proactive aggression, while experiences of childhood maltreatment were not. This finding concurs with previous studies of children and adults and suggests that proactive aggression may be a behavioural marker of psychopathic traits. By contrast, childhood physical abuse was associated with reactive aggression, even among violent offenders with high PCL-R scores. This latter finding suggests a strong influence of childhood physical abuse on the development of reactive aggression that persists over the lifespan.

Epidemiology, Risk Factors, and Psychopharmacological Management of Suicidal Behavior in Borderline Personality Disorder

Borderline personality disorder (BPD) is a chronic psychiatric condition characterized by a pervasive pattern of instability in affect regulation and impulse control. These maladaptive coping strategies predispose individuals with BPD to suicidal behavior, and this diagnosis increases the risk for completed suicide. Empirical data indicate that adverse life events; a history of childhood trauma; and the presence of comorbid psychiatric conditions, in particular major depressive disorder and substance use disorders; confer an elevated risk of suicidal behavior in patients with BPD. Psychopharmacological interventions, including the use of antidepressants, anti-psychotics, and mood stabilizers, are considered in this review in terms of the evidence for their utility in reducing the risk of suicidal behavior in BPD.

Lower Monoamine Oxidase-A Total Distribution Volume in Impulsive and Violent Male Offenders with Antisocial Personality Disorder and High Psychopathic Traits: An [ 11 C] Harmine Positron Emission Tomography Study

Antisocial personality disorder (ASPD) often presents with highly impulsive, violent behavior, and pathological changes in the orbitofrontal cortex (OFC) and ventral striatum (VS) are implicated. Several compelling reasons support a relationship between low monoamine oxidase-A (MAO-A), an enzyme that regulates neurotransmitters, and ASPD. These include MAO-A knockout models in rodents evidencing impulsive aggression and positron emission tomography (PET) studies of healthy subjects reporting associations between low brain MAO-A levels and greater impulsivity or aggression. However, a fundamental gap in the literature is that it is unknown whether brain MAO-A levels are low in more severe, clinical disorders of impulsivity, such as ASPD. To address this issue, we applied [11C] harmine PET to measure MAO-A total distribution volume (MAO-A VT), an index of MAO-A density, in 18 male ASPD participants and 18 age- and sex-matched controls. OFC and VS MAO-A VT were lower in ASPD compared with controls (multivariate analysis of variance (MANOVA): F2,33=6.8, P=0.003; OFC and VS MAO-A VT each lower by 19%). Similar effects were observed in other brain regions: prefrontal cortex, anterior cingulate cortex, dorsal putamen, thalamus, hippocampus, and midbrain (MANOVA: F7,28=2.7, P=0.029). In ASPD, VS MAO-A VT was consistently negatively correlated with self-report and behavioral measures of impulsivity (r=−0.50 to −0.52, all P-values<0.05). This study is the first to demonstrate lower brain MAO-A levels in ASPD. Our results support an important extension of preclinical models of impulsive aggression into a human disorder marked by pathological aggression and impulsivity.

Patient Characteristics by Type of Hypersexuality Referral: A Quantitative Chart Review of 115 Consecutive Male Cases

Hypersexuality remains an increasingly common but poorly understood patient complaint. Despite diversity in clinical presentations of patients referred for hypersexuality, the literature has maintained treatment approaches that are assumed to apply to the entire phenomenon. This approach has proven ineffective, despite its application over several decades. The present study used quantitative methods to examine demographic, mental health, and sexological correlates of common clinical subtypes of hypersexuality referrals. Findings support the existence of subtypes, each with distinct clusters of features. Paraphilic hypersexuals reported greater numbers of sexual partners, more substance abuse, initiation to sexual activity at an earlier age, and novelty as a driving force behind their sexual behavior. Avoidant masturbators reported greater levels of anxiety, delayed ejaculation, and use of sex as an avoidance strategy. Chronic adulterers reported premature ejaculation and later onset of puberty. Designated patients were less likely to report substance abuse, employment, or finance problems. Although quantitative, this article nonetheless presents a descriptive study in which the underlying typology emerged from features most salient in routine sexological assessment. Future studies might apply purely empirical statistical techniques, such as cluster analyses, to ascertain to what extent similar typologies emerge when examined prospectively.

Elevated Monoamine Oxidase-A Distribution Volume in Borderline Personality Disorder Is Associated With Severity Across Mood Symptoms, Suicidality, and Cognition

BACKGROUND Monoamine oxidase-A (MAO-A) is a treatment target in neurodegenerative illness and mood disorders that increases oxidative stress and predisposition toward apoptosis. Increased MAO-A levels in prefrontal cortex (PFC) and anterior cingulate cortex (ACC) occur in rodent models of depressive behavior and human studies of depressed moods. Extreme dysphoria is common in borderline personality disorder (BPD), especially when severe, and the molecular underpinnings of severe BPD are largely unknown. We hypothesized that MAO-A levels in PFC and ACC would be highest in severe BPD and would correlate with symptom magnitude. METHODS [(11)C] Harmine positron emission tomography measured MAO-A total distribution volume (MAO-A VT), an index of MAO-A density, in severe BPD subjects (n = 14), moderate BPD subjects (n = 14), subjects with a major depressive episode (MDE) only (n = 14), and healthy control subjects (n = 14). All subjects were female. RESULTS Severe BPD was associated with greater PFC and ACC MAO-A VT compared with moderate BPD, MDE, and healthy control subjects (multivariate analysis of variance group effect: F6,102 = 5.6, p < .001). In BPD, PFC and ACC MAO-A VT were positively correlated with mood symptoms (PFC: r = .52, p = .005; ACC: r = .53, p = .004) and suicidality (PFC: r = .40, p = .037; ACC: r = .38, p = .046), while hippocampus MAO-A VT was negatively correlated with verbal memory (r = -.44, p = .023). CONCLUSIONS These results suggest that elevated MAO-A VT is associated with multiple indicators of BPD severity, including BPD symptomatology, mood symptoms, suicidality, and neurocognitive impairment.

Prospective Risk Factors for Suicide Attempts in a Treated Sample of Patients with Borderline Personality Disorder

Objective: People with borderline personality disorder (BPD) are at high risk for attempting suicide. There are some data to suggest that risk factors for suicide attempts change over time. We conducted a prospective cohort study to examine risk factors for suicide attempts in a treated sample of patients with BPD. Method: One hundred eighty participants with BPD were followed over a year-long course of dialectical behaviour therapy or general psychiatric management and then for 2 more years in naturalistic follow-up. Participants were assessed for suicidal and self-injurious behaviours at baseline, every 4 months over the 1-year treatment phase, and every 6 months over a 2-year follow-up period. Participants were classified as suicide or nonsuicide attempters based on their behaviour at the end of the 1-year treatment phase and after the 2-year follow-up period. Groups were then compared on baseline clinical and demographic variables. Results: Nearly 26% of participants made a suicide attempt during the 1-year treatment phase, while 16.7% reported a suicide attempt over the 2-year follow-up period. Baseline number of suicide attempts during the 4 months prior to study and severity of childhood sexual abuse predicted suicide attempts during the treatment year. Similarly, baseline suicide attempts, severity of childhood sexual abuse, and number of hospitalizations in the 4 months prior to study entry predicted suicide attempts during the 2-year follow-up. Conclusions: Risk factors for suicide attempts in this treated sample of patients with BPD were fairly stable, largely nonmodifiable, and unrelated to psychopathology or psychosocial functioning at baseline.

Demonstrating adherence to guidelines for the treatment of patients with borderline personality disorder.

Objective: To describe the development and implementation of General Psychiatric Management (GPM), a dynamically informed psychotherapeutic and case management approach along with symptom-targeted pharmacological interventions for the treatment of borderline personality disorder (BPD), derived from the American Psychiatric Associations (APA) guidelines for treating BPD. Method: Clinician adherence to GPM was assessed using the General Psychiatric Management Adherence Scale (GPMAS), which measured the amount of emphasis accorded to therapeutic tools and strategies during individual therapy sessions. GPMAS surveys were completed by 9 different therapists every 6 weeks during 1 year for 50 patients. Results: GPMAS displayed excellent internal consistency and good-to-excellent test–retest reliability. The convergence between patient- and therapist-rated sessions was excellent. Mean levels of emphasis were significantly greater for GPM interventions than prohibited ones across all time points. The mean number of prescribed psychotropic medications was 2.3, and the most frequently prescribed class of medication was antidepressants, followed by neuroleptics. Conclusions: From these results, we conclude that the clinicians were adherent to the outlined protocol and that the GPMAS is a valuable measure for demonstrating adherence to therapies based on the APA guidelines.

Attention Deficit Hyperactivity Disorder Symptoms, Comorbidities, Substance Use, and Social Outcomes among Men and Women in a Canadian Sample

Background. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that can persist in adolescence and adulthood. Aim. To examine prevalence of ADHD symptoms and correlates in a representative sample of adults 18 years and older living in Ontario, Canada. Method. We used the Centre for Addiction and Mental Health Monitor, an ongoing cross-sectional telephone survey, to examine the relationships between ADHD positive symptoms and comorbidities, substance use, medication use, social outcomes, and sociodemographics. Results. Of 4014 residents sampled in 2011-2012, 3.30% (2.75%–3.85%) screened positively for ADHD symptoms (women = 3.6%; men = 3.0%). For men, distress, antisocial symptoms, cocaine use, antianxiety medication use, antidepressant medication use, and criminal offence arrest were associated with positive ADHD screen. For women, distress, cocaine use, antianxiety medication use, antidepressant medication use, pain medication use, and motor vehicle collision in the past year were associated with positive ADHD screen. Conclusions. ADHD symptoms are associated with adverse medical and social outcomes that are in some cases gender specific.