Rehybridization dynamics into the pericyclic minimum of an electrocyclic reaction imaged in real-time.

Electrocyclic reactions are characterized by the concerted formation and cleavage of both σ and π bonds through a cyclic structure. This structure is known as a pericyclic transition state for thermal reactions and a pericyclic minimum in the excited state for photochemical reactions. However, the structure of the pericyclic geometry has yet to be observed experimentally. We use a combination of ultrafast electron diffraction and excited state wavepacket simulations to image structural dynamics through the pericyclic minimum of a photochemical electrocyclic ring-opening reaction in the molecule α-terpinene. The structural motion into the pericyclic minimum is dominated by rehybridization of two carbon atoms, which is required for the transformation from two to three conjugated π bonds. The σ bond dissociation largely happens after internal conversion from the pericyclic minimum to the electronic ground state. These findings may be transferrable to electrocyclic reactions in general.

Conformer-specific photochemistry imaged in real space and time.

Conformational isomers (conformers) of molecules play a decisive role in biology and organic chemistry. However, experimental methods for investigating chemical reaction dynamics are typically not conformer-sensitive. We report on a gas-phase megaelectronvolt ultrafast electron diffraction investigation of α-phellandrene undergoing an electrocyclic ring-opening reaction. We directly imaged the evolution of a specific set of α-phellandrene conformers into the product isomer predicted by the Woodward-Hoffmann rules in real space and time. Our experimental results are in quantitative agreement with nonadiabatic quantum molecular dynamics simulations, which provide considerable detail of how conformation influences the time scale and quantum efficiency of photoinduced ring-opening reactions.

Space-time resolved approach for interacting quantum field theories.

An alternative approach to the usual perturbative S-matrix evaluation of quantum field theories is presented which is nonperturbative and provides full space-time resolution. We study the dynamical development of the force between two fermion wave packets for the Yukawa system. The spatial distribution of the virtual bosons that act as mediators of the force can be analyzed along with the fermionic densities. Using a potential function for the fermion-fermion interaction is a good approximation to the field theoretical calculations when the Fock space is restricted to only one boson, but in the full quantum field theory the fermion-fermion force is enhanced by higher-order multiboson processes. Furthermore, the normally attractive fermion-fermion Yukawa force can, in principle, be manipulated to even be repulsive if the momentum modes available to the virtual bosons are restricted.

Neuroleptic malignant syndrome due to olanzapine.

Neuroleptic malignant syndrome (NMS) is a rare and potentially fatal complication precipitated by the use of antipsychotic medications, most notably haloperidol. Criteria previously described include: exposure to the neuroleptic class of medications; hyperthermia; muscle rigidity; a cluster of laboratory and physical findings that may include mental status changes, autonomic instability, creatine phosphokinase elevation and leukocytosis, and exclusion of other causes for the patient's condition. A prodrome of mental status changes, autonomic instability, tremors, diaphoresis, excess salivation, and extrapyramidal signs may precede NMS. Prior reports of NMS linked to olanzapine have been in patients who had been previously treated with other neuroleptic agents or in patients who had previous episodes of NMS precipitated by other neuroleptics. Several cases included patients treated with olanzapine in addition to another neuroleptic. This report describes a case of NMS associated with olanzapine in a patient who had not previously been exposed to the neuroleptic drug class. At the time this patient presented, there were no reports in the literature of NMS associated with olanzapine alone. Treatment of NMS includes: immediate withdrawal of all neuroleptics; supportive care; fever control; management of autonomic instability (tachycardia, tachypnea, blood pressure fluctuations); and pharmacologic management with dantrolene and bromocriptine.

Evaluation of the efficacy, safety and physiological effects of fluvoxamine in social phobia.

There is no US Food and Drug Administration (FDA) approved treatment for social phobia although data suggest efficacy for several drug classes, including beta-blockers, benzodiazepines, monoamine oxidase inhibitors, and selective serotonin reuptake inhibitors (SSRIs). The SSRIs are particularly attractive due to their favourable tolerance and safety profile. An open label trial of fluvoxamine was conducted to evaluate its efficacy and safety in the treatment of social phobia (DSM-III-R) and to assess physiological changes that may accompany treatment. Fifteen non-depressed patients, aged 22-44 years (mean 31.6 years), entered the study. A 5-min performance task (public speaking simulation) preceded and concluded the active treatment period. Cardiovascular monitoring was performed during this time and blood sampled for plasma cortisol and steady-state plasma fluvoxamine concentration (at week 7). Ten patients (5 men and 5 women) completed an active 6 week treatment period of flexible dosing (50-150 mg/day). Five patients failed to complete the study due to drowsiness (n = 2), nausea (n = 1), or were lost to follow-up (n = 2). Analysis of clinical ratings indicated a statistically significant decrease in all scales from baseline to week 7 at the conclusion of the active treatment period. Clinical benefits were still evident at follow-up 1 week after drug discontinuation. Neither physiological effects nor plasma drug concentration correlated with clinical change. Fluvoxamine appeared to be effective and well tolerated in completers. Randomized clinical trials are needed to further demonstrate the efficacy of fluvoxamine in the treatment of social phobia.

Once-weekly dosing of fluoxetine in the maintenance of remission in panic disorder.

BACKGROUND: Fluoxetine and its active metabolite norfluoxetine have long half-lives of 4-6 days and 4-16 days, respectively. We postulated that, owing to the long elimination half-life, patients diagnosed with panic disorder might be maintained on fluoxetine taken once a week, after being treated initially with daily doses of fluoxetine. METHOD: Ten patients with DSM-III-R panic disorder were treated openly with fluoxetine, 20-40 mg daily. Once panic free, these patients were switched to once-weekly dosing of fluoxetine, and dosage was titrated as needed. RESULTS: All 10 patients successfully switched to once-weekly dosing. One patient reported recurrence of panic attacks 18 months after the switch. After a brief treatment for 4 weeks with benzodiazepines and daily fluoxetine, the patient was once again maintained on once-weekly dosing when rechallenged. Patients have been maintained in a panic-free state for up to 26 months with a single weekly dose of fluoxetine ranging from 10 to 60 mg. The medication was well tolerated. CONCLUSION: Fluoxetine at doses ranging from 10 to 60 mg administered once weekly appears to be effective maintenance treatment for patients with panic disorder who were initially treated successfully with daily fluoxetine. A once-weekly regimen may allow for considerable cost savings and may serve as a convenient alternative method for treating panic disorder.

Abnormal peripheral benzodiazepine receptor density associated with generalized social phobia.

BACKGROUND: Peripheral benzodiazepine receptors (PBRs) are involved in regulating stress responses. Abnormally low numbers of platelet PBRs have been found in patients with panic disorder, posttraumatic stress disorder, and generalized anxiety disorder, but not in patients with obsessive-compulsive disorder (OCD) or major depressive disorder (MDD). The purpose of this study was to evaluate the PBR density on platelets from patients with generalized social phobia (GSP). METHODS: The density (Bmax) and dissociation constant (Kd) of platelet PBRs was determined for 53 medication-free patients with GSP and an equal number of control subjects (NC). RESULTS: The GSP group was found to have a significantly lower PBR Bmax than the NC group (GSP = 2764 +/- 1242 vs. NC = 4327 +/- 1850 fmol/mg protein, df = 1,100, F = 22.7, p = .00001). CONCLUSIONS: GSP shares this PBR abnormality with some other anxiety disorders but not with OCD or MDD. PBRs may play a role in the pathophysiology of some anxiety disorders.

Effects of the cholecystokinin agonist pentagastrin in patients with generalized anxiety disorder.

OBJECTIVE: The anxiogenic and panicogenic effects of peripheral administration of the cholecystokinin-B receptor agonist pentagastrin and placebo were evaluated in patients with generalized anxiety disorder and normal comparison subjects. METHODS: Seven patients with generalized anxiety disorder and seven age- and sex-matched normal subjects received an intravenous bolus of placebo and pentagastrin. RESULTS: Panic attacks occurred in five patients with generalized anxiety disorder (71%) and in one normal subject (14%). Patients with generalized anxiety disorder were more likely to report more nonpanic anxiety than were normal subjects. CONCLUSIONS: Patients with generalized anxiety disorder appear to exhibit greater subjective sensitivity to pentagastrin than do normal subjects.

Fluvoxamine: a review of the controlled trials in depression.

Fluvoxamine, a serotonin selective reuptake inhibitor, has been available as an antiobsessional agent in the United States since 1995. However, it has been utilized as an effective antidepressant for many years in various European countries. The controlled trials of fluvoxamine in the pharmacotherapy of depression are reviewed. The drug compares well with a variety of other antidepressants. It appears safe and well tolerated in daily doses of 50 to 300 mg. The most common adverse events are gastrointestinal complaints, particularly nausea. Initiating pharmacotherapy at lower doses and increasing over the period of 1 to 2 weeks minimizes this discomfort.

The practical use of carbon dioxide-induced anxiety in the diagnosis and care of patients with panic disorder.

The authors utilized inhalation of 35% carbon dioxide and 65% oxygen as a diagnostic tool in the evaluation of suspected panic disorder. In two inpatients admitted for a medical evaluation for pheochromocytoma and carcinoid syndrome, respectively, a positive response to the double-blind administration of CO2/O2 or room air was consistent with a diagnosis of panic disorder by psychiatric history. In two additional patients in whom denial of mental illness was a psychological impediment to proper treatment, a positive CO2/O2 challenge resulted in therapeutic benefit.

Tetanus, pseudotetanus, or conversion disorder: a diagnostic dilemma?

Failure to consider conversion disorder in a patient with acute, tetanus-like symptoms led to unnecessary medical expenditures and delayed appropriate psychiatric intervention. Patients presenting these clinical symptoms need a comprehensive evaluation, with careful attention to details in the psychosocial history. While tetanus is rarely encountered now in the United States, conversion disorder is commonly encountered in both medical and psychiatric populations.

Panic disorder. Recognizing and managing the 'real thing'.

Panic disorder is a severe anxiety disease frequently encountered in primary care. Although it is associated with potentially serious medical and psychiatric complications and is often difficult to diagnose, the condition is highly treatable. Initial pharmacotherapy may include alprazolam (Xanax), imipramine hydrochloride (Janimine, Tofranil), or phenelzine (Nardil). Correct diagnosis and treatment can alleviate much suffering and expense and promote both mental and physical health.

Polypharmacy in psychiatry: three case studies and methods for prevention.

OBJECTIVE: To illustrate problems of overprescribing in the elderly and to make practical suggestions for prevention of polypharmacy. DESIGN: Three cases of polypharmacy in psychiatric patients admitted to the hospital between January and March 1990 are described. Intervention to correct drug-related problems in these patients is described and methods of preventing polypharmacy are discussed. SETTING: Inpatient psychiatry service in a tertiary-care center. PATIENTS: Elderly psychiatry patients (n = 3) taking an excessive number of medications. This polypharmacy was believed to contribute to decreased cognitive and/or physical function. INTERVENTIONS: Medication regimens were reviewed by the physician and pharmacist. Those considered unnecessary or believed to be adversely affecting the patient were discontinued. RESULTS: All patients were discharged on a reduced number of medications, with improvement in cognitive and/or physical function. CONCLUSIONS: Polypharmacy contributes to an increased incidence of adverse reactions in the elderly. Implementation of practical methods for reducing polypharmacy can lead to a reduction in the number of drug-related adverse effects and improved care of the elderly patient.

The role of psychological factors in the report of building-related symptoms in sick building syndrome.

Sick building syndrome (SBS) is an increasingly common problem, although continued skepticism exists regarding its validity. Because of this, the attribution of complaints to psychogenic causes or mas hysteria persists. In this study (N = 111), self-report measures of psychopathology (Minnesota Multiphasic Personality Inventory [Hathaway & McKinley, 1983] and SCL-90-R [Derogatis, 1983]) and physical symptom reports failed to discriminate symptomatic from nonsymptomatic workers in an affected building but could more generally differentiate workers in the target building from control subjects. These results suggest that SBS cannot be justifiably attributed to psychological factors alone, although working in a contaminated environment appeared to have deleterious psychological consequences for some workers. Smoking history (in pack/years [packs per day x number of years smoked]) was reliably associated with the development of symptoms in exposed workers. Issues related to the assessment of psychological complaints in SBS are discussed.

Effect of electroconvulsive therapy on serum concentration of alpha-1-acid glycoprotein.

Recent studies have shown significant alterations in serum alpha-1-acid glycoprotein (AGP) concentration in epileptic patients, the major protein to which basic drugs bind in serum. To date, there have been no reports in the literature investigating the effects of generalized seizures as a result of repeatedly administered electroconvulsive therapy (ECT) on this serum protein. As the cyclic antidepressants are basic drugs that bind avidly to AGP, an alteration of AGP concentration by ECT could represent a mechanism of interaction between two somatic treatments for depression. We therefore determined the serial AGP concentrations of 10 patients undergoing repeated ECT. AGP concentrations were determined by radial immunodiffusion on serum samples obtained at each treatment session (course of treatment ranged from 4 to 12 sessions over 8 to 32 days). The mean (SD) AGP concentrations prior to and at the end of ECT were 88.7 (18.3) mg/dl and 97.8 (24.8) mg/dl, respectively. Variability in AGP concentration was observed over the course of treatments with no consistent trend (intrapatient coefficients of variation averaged 11.5%). These data suggest that serial ECT does not produce consistent, significant changes in serum AGP concentrations and should have limited effects on altering the serum protein binding and, therefore, pharmacological effects of concurrently administered cyclic antidepressants.

Pharmacokinetics, pharmacodynamics, and treatment issues of benzodiazepines: alprazolam, adinazolam, and clonazepam.

Alprazolam, adinazolam, and clonazepam share the typical pharmacological effects of benzodiazepines yet are diverse in their pharmacokinetic properties. Alprazolam has an average terminal elimination half-life of 12 hours, whereas adinazolam generates a metabolite responsible for its benzodiazepine effects whose half-life is less than 3 hours. Clonazepam shows a much slower elimination with a half-life of 20 to 80 hours. The rate of decline of plasma benzodiazepine concentration may be an important factor in determining the number of daily doses necessary to maintain optimal anti-panic effects and to minimize rebound anxiety and withdrawal effects. Clonazepam, which has a longer half-life, would be expected to have some advantages over the other drugs. The limited data available do not provide evidence for any substantial advantages of one benzodiazepine over another. The potential disadvantage of the rapid elimination half-life of adinazolam and its metabolite may be offset by formulation in a sustained release capsule. When discontinuing therapy abruptly, a benzodiazepine with a longer half-life may be advantageous; however, when pharmacotherapy is discontinued gradually, the importance of half-life is diminished. Studies of the pharmacodynamics of drug-receptor interactions suggest new approaches to minimizing the adverse effects of discontinuing benzodiazepine therapy. Preliminary data relating plasma alprazolam concentrations to anxiolytic and adverse effects are presented.

Sick building syndrome.

"Sick building syndrome" (SBS) is one of the more colorful terms describing an increasingly common pattern of symptoms found among workers in modern office buildings. Core symptoms include lethargy, mucous membrane irritation, headache, eye irritation, and dry skin. To prompt a diagnosis of SBS, these otherwise common symptoms must be "excessively" reported and primarily "work-related." The World Health Organization now estimates that 30% of new or remodeled office buildings show signs of SBS, and that between 10% and 30% of the occupants of these buildings are affected by SBS. Despite such figures, SBS remains poorly researched and even more poorly understood. The following review provides the clinician an overview of SBS that will allow a more accurate differential diagnosis and will help to prevent the widespread suffering that can accrue when SBS is not quickly recognized.