John T. Little

N-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial.

BACKGROUND Brain glutathione levels are decreased in schizophrenia, a disorder that often is chronic and refractory to treatment. N-acetyl cysteine (NAC) increases brain glutathione in rodents. This study was conducted to evaluate the safety and effectiveness of oral NAC (1 g orally twice daily [b.i.d.]) as an add-on to maintenance medication for the treatment of chronic schizophrenia over a 24-week period. METHODS A randomized, multicenter, double-blind, placebo-controlled study. The primary readout was change from baseline on the Positive and Negative Symptoms Scale (PANSS) and its components. Secondary readouts included the Clinical Global Impression (CGI) Severity and Improvement scales, as well as general functioning and extrapyramidal rating scales. Changes following a 4-week treatment discontinuation were evaluated. One hundred forty people with chronic schizophrenia on maintenance antipsychotic medication were randomized; 84 completed treatment. RESULTS Intent-to-treat analysis revealed that subjects treated with NAC improved more than placebo-treated subjects over the study period in PANSS total [-5.97 (-10.44, -1.51), p = .009], PANSS negative [mean difference -1.83 (95% confidence interval: -3.33, -.32), p = .018], and PANSS general [-2.79 (-5.38, -.20), p = .035], CGI-Severity (CGI-S) [-.26 (-.44, -.08), p = .004], and CGI-Improvement (CGI-I) [-.22 (-.41, -.03), p = .025] scores. No significant change on the PANSS positive subscale was seen. N-acetyl cysteine treatment also was associated with an improvement in akathisia (p = .022). Effect sizes at end point were consistent with moderate benefits. CONCLUSIONS These data suggest that adjunctive NAC has potential as a safe and moderately effective augmentation strategy for chronic schizophrenia.

Frequency dependence of antidepressant response to left prefrontal repetitive transcranial magnetic stimulation (rTMS) as a function of baseline cerebral glucose metabolism.

BACKGROUND Recent studies suggest that both high frequency (10-20 Hz) and low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) have an antidepressant effect in some individuals. Electrophysiologic data indicate that high frequency rTMS enhances neuronal firing efficacy and that low frequency rTMS has the opposite effect. METHODS We investigated the antidepressant effects of 10 daily left prefrontal 1 Hz versus 20 Hz rTMS with the hypothesis that within a given subject, antidepressant response would differ by frequency and vary as a function of baseline cerebral glucose metabolism. After baseline PET scans utilizing [18F]-Fluorodeoxyglucose, thirteen subjects participated in a randomized crossover trial of 2 weeks of 20 Hz paired with 2 weeks 1 Hz or placebo rTMS. RESULTS We found a negative correlation between degree of antidepressant response after 1 Hz compared to 20 Hz rTMS (r = -0.797, p < .004). Additionally, better response to 20 Hz was associated with the degree of baseline hypometabolism, whereas response to 1 Hz rTMS tended to be associated with baseline hypermetabolism. CONCLUSIONS These preliminary results suggest that antidepressant response to rTMS might vary as a function of stimulation frequency and may depend on pretreatment cerebral metabolism. Further studies combining rTMS and functional neuroimaging are needed.

Regional cerebral glucose utilization in Patients with a range of severities of unipolar depression

BACKGROUND Patients with unipolar depression are most often reported to have decreased regional cerebral glucose metabolism (rCMRglu) in dorsal prefrontal and anterior cingulate cortices compared with healthy control subjects, often correlating inversely with severity of depression. METHODS We measured rCMRglu with fluorine-18 deoxyglucose positron emission tomography (PET) in 38 medication-free patients with unipolar depression and 37 healthy control subjects performing an auditory continuous performance task to further investigate potential prefrontal and anterior paralimbic rCMRglu abnormalities in patients attending to this task. RESULTS Compared with control subjects, the subgroup of patients with Hamilton depression scores of 22 or greater demonstrated decreased absolute rCMRglu in right prefrontal cortex and paralimbic/amygdala regions as well as bilaterally in the insula and temporoparietal cortex (right > left); they also exhibited increased normalized metabolic activity bilaterally in the cerebellum, lingula/cuneus, and brain stem. Severity of depression negatively correlated with absolute rCMRglu in almost the entire extent of the right cingulate cortex as well as bilaterally in prefrontal cortex, insula, basal ganglia, and temporoparietal cortex (right > left). CONCLUSIONS Areas of frontal, cingulate, insula, and temporal cortex appear hypometabolic in association with different components of the severity and course of illness in treatment-resistant unipolar depression.

Prevalence of Psychotic Symptoms in a Community-Based Parkinson Disease Sample

OBJECTIVES : To determine the prevalence of psychotic phenomena, including minor symptoms, in a Parkinson disease (PD) sample and compare the clinical correlates associated with the various psychotic phenomena. To evaluate the extent to which cases met National Institute of Neurological Diseases and Stroke (NINDS)/National Institute of Mental Health (NIMH)-proposed criteria for PD-associated psychosis. METHODS : A total of 250 patients with idiopathic PD and Mini Mental State Exam scores greater than 23 from three community-based movement disorder clinics underwent comprehensive research diagnostic evaluations by a geriatric psychiatrist as part of a study on mood disorders in PD. Psychotic symptoms were categorized using a checklist, which included a breakdown of hallucinations, delusions, and minor symptoms. Clinical characteristics of groups with minor and other psychotic symptoms were compared. The NINDS/NIMH criteria for PD-psychosis were retrospectively applied. RESULTS : Of the total sample, 26% of patients were found to have any current psychotic symptoms, with 47.7% of those having isolated minor symptoms, and 52.3% having hallucinations and/or delusions. Compared to those with no current psychiatric symptoms, minor symptoms were associated with more depressive symptoms and worse quality of life, and 90.8% of those with psychotic symptoms fulfilled the NINDS/NIMH proposed criteria. CONCLUSIONS : Psychotic symptoms are common in PD patients, with minor psychotic phenomena present in nearly half of affected patients in a community-based sample. Psychotic symptoms, including minor phenomena, were clinically significant. The NINDS/NIMH PD-psychosis criteria captured the clinical characteristics of psychosis as it relates to PD. Longitudinal studies are needed to determine whether minor psychotic symptoms represent a precursor to hallucinations and delusions, and to further validate diagnostic criteria.

Implications of Kindling And Quenching For the Possible Frequency Dependence Of rTMS

Kindling involves repeated administration of brief high-frequency electrophysiological stimulation of the brain at initially subthreshold intensities that eventually evoke full-blown seizures. It has thus been used not only as a model of epileptogenesis, but of long-term neuronal memory. Quenching is a phenomenon that utilizes low-frequency stimulation for much longer periods of time (eg, 1 Hz for 15 minutes), and appears to exert preventive effects on the development of kindling and inhibit the manifestation of full-blown kindled seizures by markedly increasing the amygdala afterdischarge and seizure threshold. (See also “Kindling and Quenching: Conceptual Implications for rTMS,” by Weiss and Post, page 32). The parameters of kindling and quenching with intracerebral stimulation of the amygdala in vivo are highly similar to those achieved in vitro in hippocampai slice preparations for inducing long-term potentiation (LTP) and longterm depression (LTD), respectively. These neuroplastic changes are relatively long lasting and appear reversible at the level of synaptic function with either LTD or LTP capable of countering the effects of the other.

Venlafaxine but not bupropion decreases cerebrospinal fluid 5-hydroxyindoleacetic acid in unipolar depression

BACKGROUND While the antidepressants venlafaxine and bupropion are known to have different neurochemical profiles in vitro, their effects on human cerebral metabolism in vivo have not been directly compared. METHODS Cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), serotonin, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were examined in 14 never-hospitalized outpatients with unipolar depression and 10 age-similar healthy controls. Patients received a baseline lumbar puncture (LP), which was repeated after at least 6 weeks of randomized monotherapy with either venlafaxine or bupropion, while controls received only a baseline LP. RESULTS Patients (n = 9) receiving venlafaxine showed a significant decrease (42%) in their CSF 5-HIAA concentrations after treatment, but no change in other CSF measures. In contrast, patients receiving bupropion (n = 8) showed no change in CSF measures compared to pretreatment values. CONCLUSIONS While the mechanism for this differential effect of venlafaxine remains to be determined, the current study provides confirmation of the different aminergic effects of venlafaxine and bupropion.

The Influence of Ondansetron and m-Chlorophenylpiperazine on Scopolamine-Induced Cognitive, Behavioral, and Physiological Responses in Young Healthy Controls

BACKGROUND There is evidence from animal and human experiments that learning and memory come under the separate influence of both cholinergic and serotonergic pathways. We were interested in learning whether serotonergic drugs could attenuate or exacerbate the memory-impairing effects of anticholinergic blockade in humans. METHODS The selective serotonin 5-HT3 receptor antagonist ondansetron (0.15 mg/kg i.v.) and the serotonergic agent m-chlorophenylpiperazine (m-CPP; 0.08 mg/kg i.v.) were administered in combination with the anticholinergic agent scopolamine (0.4 mg PO) and compared to scopolamine alone in 10 young, healthy volunteers. Testing occurred on three separate days. RESULTS As expected, i.v. administration of scopolamine induced significant impairments in episodic memory and processing speed; however, these scopolamine-induced cognitive deficits were not attenuated by pretreatment with i.v. ondansetron (0.15 mg/kg), nor were they exacerbated by administration of i.v. m-CPP (0.8 mg/kg) in addition to scopolamine; however, administration of i.v. m-CPP was followed by a significant increase of self-rated functional impairment, altered self-reality, and dysphoria ratings, and scopolamines effect on pupil size was potentiated. CONCLUSIONS Together, these results suggest that in young, healthy volunteers scopolamine-induced changes of cognitive performance are only minimally modulated by the serotonergic effects on ondansetron and m-CPP. Further studies with older controls are needed to test whether these findings may be influenced by age.

Fluvoxamine Pharmacotherapy of Anxiety Disorders in Later Life: Preliminary Open-Trial Data

The authors present data from an open trial of fluvoxamine (median daily dosage: 200 mg) in the treatment of generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder in 19 older outpatients (mean age = 66.8). Of the 12 subjects completing the 21-week trial, 8 achieved a good response (50% reduction in symptom measures) and 7 were rated as much or very much improved. Fluvoxamine pharmacotherapy also had a significant effect in reducing comorbid depressive symptoms and in increasing levels of functioning. These data support the effectiveness of fluvoxamine in older subjects with anxiety disorders (particularly generalized anxiety disorder) and warrant further double-blind, placebo-controlled evaluation. (J Geriatr Psychiatry Neurol 2000; 13:43—48).

Application of Depression Rating Scales in Patients with Parkinson's Disease with and without Co-Occurring Anxiety

BACKGROUND In patients with Parkinsons disease (PD), depressive symptom rating scales facilitate identification of depressive disorders, which are common and disabling. Anxiety disturbances in PD, which lack valid assessment scales, frequently co-occur with PD-depression, are under-recognized, and require different interventions than depressive disorders. Whether high anxiety rates in PD confound depression scale performance or if any depression scales also predict anxiety disturbances is not known. OBJECTIVE To test the impact of co-occurring anxiety disorders on psychometric properties of depression rating scales in depressed PD patients and compare disability between PD patients with anxiety, depression, and comorbid anxiety and depressive disorders. METHODS PD subjects (n = 229) completed self-report and clinician-administered depression scales. Receiver operating characteristic curves were developed to estimate psychometric properties of each scale in those with depression alone, anxiety alone, and comorbid depression and anxiety. Between-group differences on all measures were examined. RESULTS Comorbid anxiety did not affect the psychometric properties of any scale when identifying depressive disorders, but is associated with greater symptom severity and disability. Depression-scale scores were not significantly different between subjects with anxiety disorders only and those without depressive or anxiety diagnoses. CONCLUSIONS Co-occurring anxiety disorders do not impact performance of depression rating scales in depressed PD patients. However, depression rating scales do not adequately identify anxiety disturbances alone or in patients with depression.

339. CSF neuropeptide y correlates with anxiety in patients with affective disorders

present in humanswith seasonrdaffectivedisorder(SAD)and if their olfactoryperformancecorrelateswithdepressivescores.Becausepreviousstudiessuggesta predominant righthemisphericdysfunctionin SAD and olfactoryneurons’primaryprojectionsare largely ipsilatersf,we tested olfactory identificationperformance on each side of the nose. Twenty-fourSAD patients and twenty-fourmatched controls were studied using bilateraJphenyl ethyl alcohol detectionthresholdsand urrilaterrdUniversityof PennsylvaniaSmellIdentificationTestwithtwo booklets randorrdypresentedto each nostril, the contrafaterrdnostril beingoccluded.Subjectsratedtheirmoodon the SelfAssessmentMood ScaIe for SAD. Patients’ testing was performedin “depressed”and “improvedon light” state. We foundno differencein olfactoryperformancebetweenpatientaandcontrols,norbetweenpatientsbeforevsatler light treatment. A negative correlationemerged between right-sided identification scores and “typical” depression scores (r=–O.56, p=o.006).A similarnegativecorrelationbetwmr the asymmetryindex (Right -Left)/(Right+Left)and typical depressive scores (r=–O.64, p< O.001)was found.These results add to previousevidenceof right hemisphericinvolvementin mood dysregulation.