James M. Bolton

Nix and Nip3 Form a Subfamily of Pro-apoptotic Mitochondrial Proteins

We have identified Nix, a homolog of the E1B 19K/Bcl-2 binding and pro-apoptotic protein Nip3. Human and murine Nix have a 56 and 53% amino acid identity to human and murine Nip3, respectively. The carboxyl terminus of Nix, including a transmembrane domain, is highly homologous to Nip3 but it bears a longer and distinct asparagine/proline-rich N terminus. Human Nip3 maps to chromosome 14q11.2–q12, whereas Nix/BNip3L was found on 8q21. Nix encodes a 23.8-kDa protein but it is expressed as a 48-kDa protein, suggesting that it homodimerizes similarly to Nip3. Following transfection, Nix protein undergoes progressive proteolysis to an 11-kDa C-terminal fragment, which is blocked by the proteasome inhibitor lactacystin. Nix colocalizes with the mitochondrial matrix protein HSP60, and removal of the putative transmembrane domain (TM) results in general cytoplasmic and nuclear expression. When transiently expressed, Nix and Nip3 but not TM deletion mutants rapidly activate apoptosis. Nix can overcome the suppressers Bcl-2 and Bcl-XL, although high levels of Bcl-XL expression will inhibit apoptosis. We propose that Nix and Nip3 form a new subfamily of pro-apoptotic mitochondrial proteins.

Self-medication of mood disorders with alcohol and drugs in the National Epidemiologic Survey on Alcohol and Related Conditions

BACKGROUND Using alcohol or drugs to reduce emotional distress (self-medication) has been proposed as an explanation for the high comorbidity rates between anxiety and substance use disorders. Self-medication has been minimally studied in mood disorders despite equally high rates of alcohol and drug use. METHODS Data came from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a large (n=43,093, age 18 years and older) nationally representative survey of mental illness in community-dwelling adults. Prevalence rates of self-medication were determined for DSM-IV mood disorders: dysthymia, major depressive disorder, bipolar I disorder, and bipolar II disorder. Multiple logistic regression generated odds ratios for the association between each category of self-medication and anxiety and personality disorders. RESULTS Almost one-quarter of individuals with mood disorders (24.1%) used alcohol or drugs to relieve symptoms. The highest prevalence of self-medication was seen in bipolar I disorder (41.0%). Men were more than twice as likely as women to engage in self-medication (Adjusted Odds Ratio=2.18; 95% Confidence Interval 1.90-2.49). After controlling for the effects of substance use disorders, self-medication was associated with higher odds of comorbid anxiety and personality disorders when compared to individuals who did not self-medicate. LIMITATIONS Cross-sectional design. CONCLUSIONS The use of alcohol and drugs to relieve affective symptoms is common among individuals with mood disorders in the general population, yet is associated with substantial psychiatric comorbidity. These findings may help clinicians identify a subgroup of people with mood disorders who suffer from a higher mental illness burden.

The relationship between anxiety disorders and suicide attempts: findings from the National Epidemiologic Survey on Alcohol and Related Conditions

Background: Previous work has suggested that anxiety disorders are associated with suicide attempts. However, many studies have been limited by lack of accounting for factors that could influence this relationship, notably personality disorders. This study aims to examine the relationship between anxiety disorders and suicide attempts, accounting for important comorbidities, in a large nationally representative sample. Methods: Data came from the National Epidemiologic Survey on Alcohol and Related Conditions Wave 2. Face‐to‐face interviews were conducted with 34,653 adults between 2004 and 2005 in the United States. The relationship between suicide attempts and anxiety disorders (panic disorder, agoraphobia, social phobia, specific phobia, generalized anxiety disorder, posttraumatic stress disorder (PTSD)) was explored using multivariate regression models controlling for sociodemographics, Axis I and Axis II disorders. Results: Among individuals reporting a lifetime history of suicide attempt, over 70% had an anxiety disorder. Even after adjusting for sociodemographic factors, Axis I and Axis II disorders, the presence of an anxiety disorder was significantly associated with having made a suicide attempt (AOR=1.70, 95% confidence interval (CI): 1.40–2.08). Panic disorder (AOR=1.31, 95% CI: 1.06–1.61) and PTSD (AOR=1.81, 95% CI: 1.45–2.26) were independently associated with suicide attempts in multivariate models. Comorbidity of personality disorders with panic disorder (AOR=5.76, 95% CI: 4.58–7.25) and with PTSD (AOR=6.90, 95% CI: 5.41–8.79) demonstrated much stronger associations with suicide attempts over either disorder alone. Conclusion: Anxiety disorders, especially panic disorder and PTSD, are independently associated with suicide attempts. Clinicians need to assess suicidal behavior among patients presenting with anxiety problems. Depression and Anxiety, 2010.

Use of alcohol and drugs to self-medicate anxiety disorders in a nationally representative sample

This study examined the prevalence and correlates of self-medication of anxiety disorders with alcohol and drugs in a nationally representative sample (N = 5877). A modified version of the Composite International Diagnostic Interview was used to make DSM-III-R mental disorder diagnoses. Frequencies of self-medication ranged from 7.9% (social phobia, speaking subtype) to 35.6% (generalized anxiety disorder). Among respondents with an anxiety disorder, self-medication was significantly associated with an increased likelihood of comorbid mood disorders, substance use disorders, distress, suicidal ideation, and suicide attempts. Self-medication behavior remained significantly associated with an increased likelihood of suicidal ideation (adjusted odds ratio = 1.66; 1.17–2.36) as well as suicide attempts (adjusted odds ratio = 2.23; 1.50–3.31), even after adjusting for a number of sociodemographic and psychiatric variables. These results suggest that individuals with anxiety disorders who self-medicate their symptoms with alcohol or drugs may be at increased risk for mood and substance use disorders and suicidal behavior.

Self-medication of anxiety disorders with alcohol and drugs: Results from a nationally representative sample.

Self-medication--the use of alcohol or drugs in an attempt to reduce anxiety--has often been invoked as an explanatory mechanism for the high co-occurrence of anxiety and substance use disorders (for reviews, see Allan, C. A. (1995). Alcohol problems and anxiety disorders-A critical review. Alcohol & Alcoholism, 30(2), 145-151; Kushner, M. G., Abrams, K., & Borchardt. (2000). The relationship between anxiety disorders and alcohol use disorders: A review of major perspectives and findings. Clinical Psychology Review, 20(2), 149-171). The current study expands upon previous self-medication research by: (1) examining prevalence and comorbidity of self-medication for anxiety disorders (panic disorder, social phobia, specific phobia, and generalized anxiety disorder); (2) using a nationally representative sample (National Epidemiologic Survey on Alcohol and Related Conditions; N=43,093) to do so; and (3) by differentiating self-medication with alcohol from self-medication with drugs. Prevalence rates ranged from 18.3% (self-medication with alcohol for generalized anxiety disorder) to 3.3% (self-medication with both alcohol and drugs for specific phobia and panic disorder without agoraphobia). Multiple logistic regression analyses determined that self-medication with alcohol was associated with increased likelihood of any mood or personality disorder diagnosis, while self-medication with both alcohol and drugs further increased these associations over and above self-medication with alcohol alone. Findings remained significant after adjusting for sociodemographic and substance use disorder variables, which suggests that independently of substance use disorders, self-medication can be viewed as a marker of severity.

The use of alcohol and drugs to self-medicate symptoms of posttraumatic stress disorder.

Background: Self‐medication has been proposed as an explanation for the high rates of comorbidity between posttraumatic stress disorder (PTSD) and substance use disorders; however, knowledge of self‐medication in PTSD is scarce. We describe the prevalence and correlates of self‐medication in PTSD in the general population. Methods: Data came from the National Epidemiologic Survey on Alcohol and Related Conditions Wave 2 (N=34,653; response rate: 70.2%), a nationally representative survey of mental illness in community‐dwelling adults. Self‐medication was assessed separately for alcohol and drugs. Prevalence rates were determined for self‐medication among individuals with DSM‐IV PTSD. Regression analyses determined associations between self‐medication and a variety of correlates, including sociodemographic factors, comorbid mental disorders, suicide attempts, and quality of life. Results: Approximately 20% of individuals with PTSD used substances in an attempt to relieve their symptoms. Men were significantly more likely than women to engage in self‐medication behavior. In adjusted models, using illicit drugs or misusing prescription medications to control PTSD symptoms was associated with a substantially higher likelihood of dysthymia and borderline personality disorder. After controlling for mental disorder comorbidity, self‐medication was independently associated with higher odds of suicide attempts (adjusted odds ratio=2.46; 95% confidence interval 1.53–3.97) and lower mental health‐related quality of life. Conclusions: Self‐medication is a common behavior among people with PTSD in the community, yet has potentially hazardous consequences. Health care practitioners should assess reasons for substance use among people with PTSD to identify a subgroup with higher psychiatric morbidity. Depression and Anxiety, 2010.  © 2010 Wiley‐Liss, Inc.

Comorbidity of borderline personality disorder and posttraumatic stress disorder in the U.S. population

While placed on different axes of the DSM classification system, borderline personality disorder (BPD) and posttraumatic stress disorder (PTSD) have important relationships with trauma, and overlap between these disorders has long been recognized. The current study is the first to examine comorbidity of PTSD and BPD in a large nationally representative sample using a reliable and valid method of assessing Axis I and II mental disorders. Data came from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) Wave II (N = 34,653; response rate 70.2%). Multiple regression models were used to examine differences in psychopathology, traumatic events and health-related quality of life across individuals with PTSD alone (n = 1820), BPD alone (n = 1290) and those with comorbid PTSD-BPD (n = 643). The lifetime prevalence of PTSD and BPD were 6.6% and 5.9%, respectively. Of individuals with BPD, 30.2% were also diagnosed with PTSD, whereas 24.2% of individuals with PTSD were also diagnosed with BPD. Individuals with comorbid PTSD-BPD had a poorer quality of life, more comorbidity with other Axis I conditions, increased odds of a lifetime suicide attempt, and a higher prevalence of repeated childhood traumatic events than individuals with either condition alone. These results show that PTSD and BPD have a high degree of lifetime co-occurrence but are not entirely overlapping. Their concurrence is associated with poorer functioning compared to either diagnosis alone, emphasizing the clinical utility of diagnosing both conditions. Future research should explore the determinants of having either or both diagnoses with an aim toward improved identification, prevention, and intervention.

Population-Attributable Fractions of Axis I and Axis II Mental Disorders for Suicide Attempts: Findings From a Representative Sample of the Adult, Noninstitutionalized US Population

OBJECTIVES We aimed to determine the percentage of suicide attempts attributable to individual Axis I and Axis II mental disorders by studying population-attributable fractions (PAFs) in a nationally representative sample. METHODS Data were from the National Epidemiologic Survey on Alcohol and Related Conditions Wave 2 (NESARC; 2004-2005), a large (N = 34 653) survey of mental illness in the United States. We used multivariate logistic regression to compare individuals with and without a history of suicide attempt across Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I disorders (anxiety, mood, psychotic, alcohol, and drug disorders) and all 10 Axis II personality disorders. PAFs were calculated for each disorder. RESULTS Of the 25 disorders we examined in the model, 4 disorders had notably high PAF values: major depressive disorder (PAF = 26.6%; 95% confidence interval [CI] = 20.1, 33.2), borderline personality disorder (PAF = 18.1%; 95% CI = 13.4, 23.5), nicotine dependence (PAF = 8.4%; 95% CI = 3.4, 13.7), and posttraumatic stress disorder (PAF = 6.3%; 95% CI = 3.2, 10.0). CONCLUSIONS Our results provide new insight into the relationships between mental disorders and suicide attempts in the general population. Although many mental illnesses were associated with an increased likelihood of suicide attempt, elevated rates of suicide attempts were mostly attributed to the presence of 4 disorders.

Fracture risk from psychotropic medications: a population-based analysis.

Background: Selective serotonin reuptake inhibitors (SSRIs), benzodiazepines, and antipsychotics have each been associated with an increased risk of fracture in older individuals. The aim of this study was to better define the magnitude of fracture risk with psychotropic medications and to determine whether a dose-effect relationship exists. Methods: Population-based administrative databases were used to examine psychotropic medication exposure and fractures in persons aged 50 years and older in Manitoba between 1996 and 2004. Persons with osteoporotic fractures (vertebral, wrist, or hip [n = 15,792]) were compared with controls (3 controls for each case matched for age, sex, ethnicity, and comordibity [n = 47,289]). Medications examined included antidepressants (SSRIs vs other monoamines), antipsychotics, lithium, and benzodiazepines. Results: Selective serotonin reuptake inhibitors were associated with the highest adjusted odds of osteoporotic fractures (odds ratio [OR] = 1.45; 95% confidence interval [CI], 1.32-1.59). Other monoamine antidepressants (OR = 1.15; 95% CI, 1.07-1.24) and benzodiazepines (OR = 1.10; 95% CI, 1.04-1.16) were also associated with greater fracture risk, although the relationship was weaker. Lithium was associated with lower fracture risk (OR = 0.63; 95% CI, 0.43-0.93), whereas the relationship with antipsychotics was not significant in the models that adjusted for diagnoses. A dose-effect relationship was seen with SSRIs and benzodiazepines. Conclusions: This study provides novel insight into the relationship between fractures and psychotropic medications in the elderly. Selective serotonin reuptake inhibitors seem to have a greater risk than other psychotropic classes, and higher doses may further increase that risk. Lithium seems to be protective against fractures.

A population-based longitudinal study of risk factors for suicide attempts in major depressive disorder

No longitudinal study has examined risk factors for future suicide attempts in major depressive disorder in a nationally representative sample. The objective of this study was to investigate baseline sociodemographic characteristics, comorbid mental disorders, specific depressive symptoms, and previous suicidal behavior as potential risk factors for suicide attempts at 3 years follow-up. Data came from the national epidemiologic survey on alcohol and related conditions (NESARC), a large nationally representative longitudinal survey of mental illness in adults [Wave 1 (2001-2002); Wave 2 (2004-2005) n=34,653]. Logistic regression examined associations between risk factors present at Wave 1 and suicide attempts at Wave 2 (n=169) among individuals with major depressive disorder at baseline assessment (n=6004). Risk factors for incident suicide attempts at Wave 2 (n=63) were identified among those with major depressive disorder at Wave 1 and no lifetime history of suicide attempts (n=5170). Results revealed specific comorbid anxiety, personality, and substance use disorders to be associated with incident suicide attempts at Wave 2. Comorbid borderline personality disorder was strongly associated with suicide attempts in all models. Several comorbid disorders were strongly associated with suicide attempts at Wave 2 even after adjusting for previous suicidal behavior, notably posttraumatic stress disorder (adjusted odds ratio (AOR)=2.20; 95% confidence interval (95% CI) 1.27-3.83) and dependent personality disorder (AOR=4.43; 95% CI 1.93-10.18). These findings suggest that mental illness comorbidity confers an increased risk of future suicide attempts in major depressive disorder that is not solely accounted for by past suicidal behavior.