Steven D. Targum

Prevalence of seasonal affective disorder at four latitudes.

The Seasonal Pattern Assessment Questionnaire (SPAQ) was mailed to a sample population balanced for sex and randomly selected from local telephone directories in four areas: Nashua, NH, New York, NY, Montgomery County, MD, and Sarasota, FL. On the basis of responses to this questionnaire, prevalence rates of winter seasonal affective disorder (winter SAD), summer seasonal affective disorder (summer SAD), and subsyndromal winter SAD were estimated for the four areas. Rates of winter SAD and subsyndromal SAD were found to be significantly higher at the more northern latitudes, while no correlation was found between latitude and summer SAD. The positive correlation between latitude and prevalence of winter SAD applied predominantly to the age groups over 35.

A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder.

Pregabalin is a novel compound under development for the treatment of several types of anxiety disorders. To obtain an initial evaluation of the efficacy and safety of pregabalin in the treatment of generalized anxiety disorder (GAD), we conducted a double-blind, fixed-dose, parallel-group, placebo and active-controlled multicenter 4-week study that compared 271 patients randomized to receive pregabalin 50 mg tid (N = 70), pregabalin 200 mg tid (N = 66), placebo (N = 67), or lorazepam 2 mg tid (N = 68), followed by a 1-week double-blind taper. The primary efficacy parameter was change from baseline to endpoint (last observation carried forward) in the Hamilton Anxiety Scale (HAM-A) total score; adjusted mean change scores on the HAM-A were significantly improved for pregabalin 200 mg tid (difference of 3.90 between drug and placebo; p = 0.0013 [ANCOVA], df = 252) and for lorazepam (difference of 2.35; p = 0.0483 [ANCOVA], df = 252), with the significant difference between the pregabalin 200 mg tid and placebo groups seen at week 1 of treatment (p = 0.0001 [ANCOVA], df = 238). Safety analysis, which included assessment of spontaneously reported adverse events, laboratory monitoring, and withdrawal symptoms, showed pregabalin to be generally well-tolerated. The most common adverse events seen with pregabalin 200 mg tid were somnolence and dizziness. They were usually mild or moderate in intensity and were often transient. Pregabalin-treated patients had a higher completion rate than lorazepam-treated patients. This study supports the hypothesis that pregabalin is effective and safe in short-term therapy for GAD. More studies are needed to determine the best dosing regimen to optimize efficacy and tolerability.

Fenfluramine Provocation of Anxiety in Patients With Panic Disorder

Fenfluramine, and indirect serotonergic agonist, was administered to nine women with panic disorder, nine women with major depressive disorder, and nine women controls. Panic disorder patients revealed significantly greater anxiogenic responses to fenfluramine administration at all 5 hourly measurement points than either depressed patients or control subjects. Prolactin and cortisol responses to fenfluramine were also significantly greater in panic disorder patients than in either depressed patients or control subjects. Placebo administration did not elicit robust or significantly different anxiety or hormonal responses in panic disorder patients or control subjects. These data offer evidence that serotonergic hyperresponsivity must be considered as an important factor in the mechanism of events provoking overt panic attacks.

Efficacy of quetiapine in Parkinson's patients with psychosis.

Eleven patients with Parkinsons disease (PD) and acute psychosis received flexible doses of quetiapine between 25 and 300 mg/day based on clinical response and tolerance. Ten patients were receiving dopaminergic agents at baseline. Serial efficacy ratings (Brief Psychiatric Rating Scale, Clinical Global Impressions Scale), neuromuscular symptom assessments (Abnormal Involuntary Movement Scale, Simpson-Angus Scale, Unified Parkinsons Disease Rating Scale [UPDRS]), and adverse events monitoring were performed for up to 52 weeks. The patients had moderate hallucinations and/or delusions at baseline before the initiation of quetiapine. Nine of the 11 patients completed at least 12 weeks of treatment. Quetiapine was well tolerated in all but one patient, who became dizzy within the first week and withdrew from the study. Ten patients presented with moderate visual hallucinations. Quetiapine was markedly effective in controlling visual hallucinations in six of these patients. Symptoms of paranoia or delusions were less responsive to quetiapine. Four patients withdrew because of adverse events or comorbid medical problems, two withdrew because of a lack of efficacy, and five completed 52 weeks of treatment. The introduction of quetiapine did not exacerbate parkinsonian symptoms. Motor dysfunction, as measured by the UPDRS, revealed a slow, gradual worsening consistent with the progression of PD. Atypical antipsychotic medications such as quetiapine have a reduced likelihood of causing adverse drug-induced parkinsonism and therefore a possible role in treating psychotic symptoms in patients with PD.

A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease

Background: Deep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown. Objective: To assess DBS of memory circuits as a treatment for patients with mild Alzheimer’s disease (AD). Methods: We evaluated active “on” versus sham “off” bilateral DBS directed at the fornix-a major fiber bundle in the brain’s memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation. Results: Surgery and electrical stimulation were safe and well tolerated. There were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the “on” versus “off” stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patients <65 years old (n = 12) whose results trended toward being worse with DBS ON versus OFF, in patients≥65 (n = 30) DBS-f ON treatment was associated with a trend toward both benefit on clinical outcomes and a greater increase in cerebral glucose metabolism. Conclusion: DBS for AD was safe and associated with increased cerebral glucose metabolism. There were no differences in cognitive outcomes for participants as a whole, but participants aged≥65 years may have derived benefit while there was possible worsening in patients below age 65 years with stimulation.

RESEARCH: Validation of the Massachusetts General Hospital Antidepressant Treatment History Questionnaire (ATRQ)

The low rate of response to antidepressants in treatment resistant depression (TRD) justifies studies of next‐step therapies following a treatment failure. In TRD clinical trials, it is important to verify the accurate diagnosis of treatment resistance for all enrolled subjects using a reliable and valid instrument. Self‐rated scales can reduce the impact of investigator bias and reduce the time burden for clinical researchers. The Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ) is a self‐rated scale used to determine treatment resistance in major depressive disorder (MDD). The ADAPT‐A study is a multi‐center double‐blind, placebo‐controlled study of low‐dose aripiprazole adjunctive to ADT among outpatients with TRD. At the screening assessment, potential subjects completed the MGH ATRQ. The ADAPT‐A medical monitors subsequently performed remote patient interviews and obtained detailed medication histories. The data obtained from the MGH ATRQ and by the medical monitors were compared for congruency. Of the 186 patients enrolled by the local sites, no subjects deemed treatment resistant by the MGH ATRQ were found to be nonresistant by the medical monitors. In 76.3% (n = 142) of the subjects, the number of failed adequate antidepressant trials reported by the MGH ATRQ was concordant with the data collected by medical monitors. In 16.1% (n = 30) of all cases, the medical monitors found a greater number of failed trials; in 7.5% (n = 14) of cases, the medical monitors found fewer failed medication trials. The discrepancy was by more than one medication trial in only 4.0% (n = 7) of cases. We found the MGH ATRQ to be relatively concordant in its assessment of treatment resistance in depression compared with independent clinical researchers. Although the MGH ATRQ tended to underreport the number of unsuccessful treatment trials relative to the clinical interviews, its accuracy in cases it detected was confirmed by raters.

Evidence for a null allele at the esterase D (EC 3.1.1.1) locus.

SummaryElectrophoretic and quantitative assays of esterase D in a Caucasian family demonstrate the inheritance of a null allele, which was observed in the heterozygous state in six individuals.

Lurasidone for the Treatment of Major Depressive Disorder With Mixed Features: A Randomized, Double-Blind, Placebo-Controlled Study

OBJECTIVE Accumulating evidence indicates that manic symptoms below the threshold for hypomania (mixed features) are common in individuals with major depressive disorder. This form of depression is often severe and is associated with an increased risk for recurrence, suicide attempts, substance abuse, and functional disability. This study evaluated the efficacy and safety of lurasidone in major depressive disorder with mixed features. METHODS Patients meeting DSM-IV-TR criteria for major depressive disorder who presented with two or three protocol-defined manic symptoms were randomly assigned to 6 weeks of double-blind treatment with either lurasidone at 20-60 mg/day (N=109) or placebo (N=100). Changes from baseline in Montgomery-Åsberg Depression Rating Scale score (MADRS; primary outcome measure) and Clinical Global Impressions severity subscale score (CGI-S; key secondary outcome measure) were evaluated using a mixed model for repeated-measures analysis. RESULTS Lurasidone significantly improved depressive symptoms and overall illness severity, assessed by least squares mean change at week 6 in the MADRS and CGI-S scores: -20.5 compared with -13.0 (effect size, 0.80) and -1.8 compared with -1.2 (effect size, 0.60), respectively. Significant improvement in manic symptoms, assessed by the Young Mania Rating Scale, was also observed, in addition to other secondary efficacy endpoints. Rates of discontinuation due to adverse events were low. The most common adverse events were nausea (6.4% and 2.0% in the lurasidone and placebo groups, respectively) and somnolence (5.5% and 1.0%). CONCLUSIONS Lurasidone was effective and well tolerated in this study involving patients with major depressive disorder associated with subthreshold hypomanic symptoms (mixed features).

Redefining Affective Disorders: Relevance for Drug Development

The evaluation of new drug entities with specific modes of action may be hampered by rigid diagnostic classification systems and patient selection processes that do not focus on the anticipated symptomatic, behavioral, and functional outcomes to be achieved. Patients enrolled in central nervous system (CNS) clinical trials may present with a heterogeneous group of symptoms representing several syndromes or subtypes, subsumed under the same diagnosis in the DSM‐IV classification system. As a result, enrolled patients may not have the valid illness characteristics of interest to the particular study. We propose that clinical drug development needs to focus on the primary nosological entity likely to be affected by a new drug entitys mode of action. Ideally, a valid patient will have the acute primary symptoms that the novel drug is supposed to influence. In this article, we propose operational criteria to delineate a more symptom‐specific and ecologically valid approach to the identification of the valid patient for clinical trials.

Compensatory pituitary-thyroid mechanisms in major depressive disorder.

The thyrotropin-releasing hormone (TRH) stimulation test was administered to 47 patients meeting DSM-III criteria for major depressive disorder (with melancholia) and to 19 nondepressed patients. The wide variability of pituitary responses to TRH stimulation noted in the depressed patients provides evidence for the dysregulation of compensatory hypothalamic-pituitary-thyroid function in acute depression. Blunted thyroid-stimulating hormone (TSH) responses to TRH injection were found in 16 depressed (34%) and no nondepressed patients (p less than 0.01). Depressed patients who revealed blunted TSH responses also had blunted prolactin responses to TRH relative to other depressed and nondepressed patient groups (p less than 0.01). These patients (with blunted TSH and prolactin responses) may represent a psychobiologically distinct subgroup of endogenously depressed patients. Augmented (high normal) TSH responses to TRH stimulation were found in eight depressed patients (all women), in contrast to no nondepressed patients. These patients may have a subtle thyroidal dysfunction affecting the underlying endogenous depressive diathesis.