Scott A. West

Differences and similarities in mixed and pure mania

The aim of this study was to examine the relationship between mixed and pure mania using both narrow (DSM-III-R) and broad (Cincinnati) operational diagnostic criteria to define mixed mania regarding the degree of associated depression. Hospitalized patients aged > or = 12 years and meeting DSM-III-R criteria for bipolar disorder, manic or mixed, were compared regarding demographics, phenomenology, course of illness, comorbidity, family history, and short-term outcome. Seventy-one patients were recruited during a 1-year period. Twenty-four patients (34%) met DSM-III-R criteria for mixed bipolar disorder; 28 (40%) met the broader definition (which required three associated depressive symptoms rather than full syndromal DSM-III-R depression). Compared with pure manic patients, DSM-III-R mixed patients had significantly more depressive symptoms, were more likely to be female, experienced more prior mixed episodes, displayed higher rates of comorbid obsessive-compulsive disorder, and had longer hospitalizations. However, when mixed mania was defined more broadly, differences in gender and hospitalization length were lost. Also, regardless of the definition used, mixed and pure manic patients were similar on most other variables assessed. We conclude that mixed and pure mania differ in some respects but have many similarities, especially when mixed mania is defined by lesser degrees of depression. The use of dimensional rather than categoric systems to describe the degree of associated depression may be a more meaningful method of classifying mania.

ABT-089, A Neuronal Nicotinic Receptor Partial Agonist, for the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults: Results of a Pilot Study

BACKGROUND This pilot study was designed to evaluate ABT-089, a neuronal nicotinic receptor partial agonist, as treatment for adult attention-deficit/hyperactivity disorder (ADHD). METHODS Adults with ADHD received placebo, 2 mg, 4 mg, or 20 mg of ABT-089 for 2 weeks each in a randomized, double-blind, placebo-controlled, 4 x 4 Latin square design for a total of 8 weeks. In addition to the primary outcome, the Conners Adult ADHD Rating Scale (CAARS), secondary rating scales, and neuropsychological and safety assessments were completed. RESULTS A total of 11 adults with well-characterized ADHD completed this crossover study. ABT-089 b.i.d. was superior to placebo for the CAARS Total Symptom Score, which was the primary endpoint (placebo: 38.0 +/- 1.9; 2 mg b.i.d.: 32.2 +/- 1.9, one-tail p = .021; 4 mg b.i.d.: 33.2 +/- 1.9, p = .047; 20 mg b.i.d.: 33.5 +/- 1.9, p = .056). ABT-089 was also superior to placebo for the CAARS ADHD Index and Hyperactive/Impulsive scores and the Clinical Global Impression-ADHD Severity score. On the clinical efficacy endpoints, CAARS Total Symptom Score and CAARS Hyperactive/Impulsive score, a shallow inverted U-shaped dose-response curve was observed; however, the dose-response curve for attention and memory effects as measured by computerized cognitive testing seemed dose-linear. No clinically meaningful findings in safety assessments or side effect profile were observed. CONCLUSIONS Data from this pilot study suggest that ABT-089 might be effective in treating adult ADHD and that it is well tolerated. On the basis of these promising results, larger, parallel-group ABT-089 studies of longer duration are warranted.

Chronology of comorbid and principal syndromes in first-episode psychosis

Psychiatric comorbidity is common in psychotic disorders, but the chronology of comorbid and principal diagnoses has not been closely examined. Understanding chronology may be important for identifying risk factors, or alternatively, prodromal syndromes, for some patients with psychosis. To address this issue, we examined the rates of antecedent comorbid syndromes in patients with first-episode psychoses. Patients aged > or = 12 years presenting with psychosis were recruited from inpatient and outpatient treatment sites. Patients were excluded if they had been previously hospitalized or if symptoms resulted entirely from substance abuse or medical illness. All diagnoses were made using the Structural Clinical Interview for DSM-III-R-Patient Version (SCID-P). Comorbidity was defined as antecedent if the age of onset of the comorbidity predated the age of the onset of the psychotic disorder by more than 1 year. Seventy-one patients were recruited during a 1-year period and included 39 with bipolar disorder, 18 with schizophrenia spectrum disorders, and 14 with psychotic depression. Comorbidity was present in 69% of patients. This comorbidity was antecedent in over 80% of the patients with concurrent syndromes. Patients with psychotic depression had the highest rates of comorbidity, in particular alcohol abuse and antecedent posttraumatic stress disorder (PTSD). Comorbidity is common in first-episode psychosis and is often antecedent to the psychotic disorder. These antecedent comorbidities may represent risk factors or prodromal syndromes for the psychotic disorder.

Racial influence on diagnosis in psychotic mania

In a sample of 100 patients with psychotic mania, we examined whether African-Americans were more likely than Caucasians to present with Schneiderian first-rank symptoms, potentially contributing to a misdiagnosis of schizophrenia. In this sample, African-American patients were significantly more likely than Caucasian patients to have received a clinical diagnosis other than bipolar or schizoaffective disorder. There were no racial differences in affective symptoms, but there were differences in psychotic symptom profiles, primarily due to increased hallucinations in African-Americans and increased persecutory delusions in Caucasians. Racial differences in the clinical diagnosis of patients with mania were not due to differences in symptomatic expression, however.

Attention and formal thought disorder in mixed and pure mania

The Continuous Performance Test (CPT) (Rosvold et al 1956) is a quantitative measure of sustained attention (or vigilance) that has been used primarily in studies examining cognitive deficits in schizophrenia (Cornblatt et al 1989; Nuechterlein et al 1984; Orzack and Kornetsky 1966; Wohlberg and Kornetsky 1973). Although it has been used less frequently in manic-depressive samples, results indicate that patients with mania are also significantly impaired on this measure (Nuechterlein et al 1991; Rund et al 1992). One question that has not been addressed, however, is whether this deficit differs among subtypes of mania. Since the issue of heterogeneity has been a potential source of variability in studies of schizophrenia, it is important to determine whether performance differs among various subtypes of mania. A number of studies suggest that mixed and pure mania represent distinct affective states with different clinical and phenomenological profiles (McElroy et al 1992). Mixed states of mania are concurrent or cyclical manic and depressive syndromes which appear to be associated with a more chronic course of illness relative to pure mania (McElroy et al 1992, 1993). In contrast to studies examining clinical and phenomenological factors, there is limited information about differences in cognitive functioning between the two groups. Efforts to identify symptom correlates of impaired CPT performance in schizophrenia have resulted in a possible association with formal thought disorder (Neuchterlein et al 1986; Pandurangi et al 1994). One prominent feature of formal thought disorder is

Cerebrospinal fluid and plasma β-endorphin in combat veterans with post-traumatic stress disorder

Abstract Opioid-mediated analgesia develops in experimental animals following traumatic stress and increased opioid-mediated analgesia has been observed in combat veterans with post-traumatic stress disorder (PTSD). These observations have led to the hypothesis that increased central nervous system (CNS) opioidergic activity exists in patients with PTSD. However, direct CNS data on opioid peptide concentrations and dynamics in patients with PTSD are lacking. We withdrew cerebrospinal fluid (CSF) via a flexible, indwelling subarachnoid catheter over a 6-h period and determined hourly CSF concentrations of immunoreactive β-endorphin (irβEND) in 10 well-characterized combat veterans with PTSD and nine matched normal volunteers. Blood was simultaneously withdrawn to obtain plasma for irβEND. PTSD symptom clusters, as measured by the CAPS, were correlated with neuroendocrine data. Mean CSF irβEND was significantly greater in patients with PTSD compared with normals and there was a negative correlation between the irβEND and PTSD intrusive and avoidant symptoms of PTSD. No intergroup difference between plasma ieβEND was found, nor was there a significant correlation between CSF and plasma irβEND. Immunoreactive β-lipotropin (irβLPH) and pro-opiomelanocortin (irPOMC), both precursors of βEND, were much more plentiful in human CSF than was β-endorphin itself, as has been previously reported. It remains to be determined whether the increased CNS opioid concentrations predate traumatic stress, thereby conferring a vulnerability to dissociative states and PTSD itself, or result from the trauma. The negative correlation between CSF irβEND and avoidant and intrusive symptoms suggests that CNS hypersecretion of opioids might constitute an adaptive response to traumatic experience. Poor correlation between CSF and plasma irβEND limits use of plasma measures to assess CNS opioid activity.

Outcome and comorbidity in first- compared with multiple-episode mania.

The aim of this study was to examine the outcome and comorbidity of patients with bipolar disorder presenting with first-episode as compared with multiple-episode mania. Based on studies from the prepharmacological era and the sensitization model of bipolar disorder, we hypothesized that compared with multiple-episode mania, first-episode mania would be associated with better outcome, milder severity, and less psychiatric comorbidity. Seventy-one hospitalized patients, age 12 years and older and meeting DSM-III-R criteria for bipolar disorder, were recruited over a 1-year period. Thirty-four (48%) first-episode and 37 (56%) multiple-episode patients were compared regarding demographics, phenomenology, comorbidity, family history, and short-term course. Compared with multiple-episode mania, first-episode mania was associated with significantly shorter hospitalization and a higher rate of comorbid impulse control disorders. These data provide indirect support for the sensitization model of bipolar disorder.

The Co-Occurrence of Mania with Medical and other Psychiatric Disorders

Objective: The co-occurrence of mania with other medical and psychiatric disorders has been little studied. The authors reviewed the literature in order to clarify the current state of knowledge of this subject and to identify possible areas of future research. Methods: Published articles which specifically addressed associations of mania with medical disorders and other psychiatric syndromes were identified using the Paperchase® medical literature search system and by cross-referencing from other published work. The articles were then organized into three categories: 1) medical disorders associated with secondary mania; 2) medical comorbidity in bipolar disorder; and 3) psychiatric comorbidity in bipolar disorder. Results: The review of medical illness and secondary mania supports the hypothesis that injuries involving right-side and mid-line brain structures are associated with so-called secondary mania. Additionally, an association between bipolar disorder and migraine is identified. Several psychiatric disorders appear to occur with mania at rates higher than expected including obsessive-compulsive disorder, bulimia nervosa, panic disorder, impulse control disorders, and substance abuse. Conclusions: The authors discuss the potential implications of these findings and suggest research approaches to further examine the relationships between mania and other medical and psychiatric syndromes.

The effects of antecedent substance abuse on the development of first-episode psychotic mania

We examined associations of antecedent drug and alcohol abuse with age of onset of bipolar disorder and the time to hospitalization in a sample of 59 patients presenting with their first episode of psychotic mania. Patients with first-episode manic or mixed bipolar disorder with psychotic features were recruited from consecutive hospitalizations and evaluated using structured diagnostic instruments. Antecedent alcohol abuse was present in 12 patients (20%), and antecedent drug abuse in 19 (32%). Antecedent alcohol abuse was associated with a later age of onset of the bipolar disorder, although antecedent drug abuse was not associated with age of onset. Patients with antecedent drug or alcohol abuse required hospitalization sooner than those without. These preliminary findings suggest that patients with bipolar disorder and antecedent alcohol abuse may have a later onset of their affective illness, perhaps representing a subgroup of patients in whom previous alcohol abuse is necessary to precipitate an affective episode. Regardless, the presence of antecedent substance abuse leads to more rapid hospitalization in these patients. Our results should be considered preliminary, given the small sample size and the post-hoc design of the study. Additional prospective studies of patients with new onset bipolar disorder and antecedent substance abuse syndromes are needed to further clarify the complex relationships between substance abuse and bipolar disorder.

Changes in symptoms and adverse events after discontinuation of atomoxetine in children and adults with attention deficit/hyperactivity disorder: A prospective, placebo-controlled assessment

Abstract: Drugs that affect neurotransmitter release can induce changes in neuroregulation during chronic administration. Thus, in addition to recurrence of symptoms of the illness, discontinuation of treatment can be associated with clinical signs and symptoms related to these changes. Atomoxetine, a new drug approved in the United States for treatment of attention deficit/hyperactivity disorder (ADHD), is associated with blockade of the presynaptic norepinephrine transporter. Because treatment of ADHD typically involves chronic treatment, the potential for production of a discontinuation syndrome as well as recurrence of symptoms upon drug discontinuation were assessed as part of the clinical development process. The effects of discontinuation of atomoxetine were assessed in children and adults with ADHD following 9 to 10 weeks of continuous therapy in 4 large studies. Symptoms of ADHD worsened following drug discontinuation but did not return to pretreatment levels. The incidence of discontinuation-emergent adverse events was low and there were no statistically significant differences between the patients abruptly discontinuing from atomoxetine and those continuing on placebo. Discontinuation of atomoxetine did not result in the development of an acute discontinuation syndrome and was well tolerated. It appears that atomoxetine may be discontinued without risk for symptom rebound or discontinuation-emergent adverse effects. Tapering of doses is not necessary when atomoxetine is discontinued.