Antidepressant drug interactions in the elderly. Understanding the P-450 system is half the battle in reducing risks.

Antidepressant treatment in patients 65 years of age or older carries increased risks of adverse drug events because of age-related physiologic changes, polypharmacy, and individual variability in drug metabolism (due to genetic factors, concurrent disease, diet, and consumption habits). Reduction of total drug burden, adjustment of dose levels, and careful selection of an appropriate agent are important steps toward avoiding adverse drug interactions, In addition, the documented and potential drug interactions of the various classes of antidepressants, and specific agents within each class, should be considered. Each elderly patient should be treated individually and monitored carefully during the initiation and maintenance of antidepressant therapy.

Practical management of treatment-resistant depression.

Patients receiving antidepressant monotherapy may be partially or totally resistant to treatment in 10 to 30 percent of cases. In patients who have experienced only partial treatment results, the clinician should first consider optimizing antidepressant dosage or lengthening therapy. Antidepressant drug substitution should generally be reserved for use in patients who haven't responded at all (nonresponders). Combining two or more antidepressants is generally not recommended, as this approach may obscure adequate monotherapy evaluation and lead to significant adverse effects or drug-drug interactions. Use of electroconvulsive therapy is recommended in patients with psychotic and severe refractory depression. Augmentation therapy is often efficacious in patients who exhibit a partial antidepressant response. Lithium and thyroid hormone have been the most extensively studied augmentative agents but, more recently, pindolol and buspirone have also been used for this purpose.

Azapirones: an alternative to benzodiazepines for anxiety.

The azapirones are a relatively new class of psychotherapeutic drugs with both anxiolytic and antidepressant properties and a favorable benefit-to-risk ratio. They represent a significant advance in psychotherapeutic drug development. Buspirone, the only azapirone currently in clinical use, is a partial serotonin agonist with low abuse potential, no sedative effects, no cognitive or psychomotor impairment properties and no significant withdrawal symptoms. It is well-tolerated by elderly patients. Clinical indications for which buspirone is particularly appropriate are chronic anxiety and mixed anxiety/depression states. Buspirone has demonstrated some efficacy in the treatment of a broad range of other serotonin-related disorders.

Geriatric psychopharmacology. A primary care challenge.

Optimum therapy with psychopharmacologic agents in geriatric patients requires an appreciation of the elderly's increased predisposition to emotional disorders and their unique sensitivity to adverse drug-drug interactions. Although nonpharmacologic approaches should be considered, adjunctive use of psychoactive medications can assist the physician to break the "negative cycle" of emotional distress that often goes untreated in this age-group. Knowledge of which psychotropic medications are preferred for use in the elderly allows primary care physicians to make timely and successful therapeutic interventions. Consultation with a psychiatrist should be considered for complicated cases.

Sleep disorders in older patients. Conservative treatment is usually enough.

Sleep disorders in older patients can be caused by the changes of aging, physical disorders, psychological problems, certain drugs, or a combination of these. A complete physical examination and a thorough sleep history help in selecting appropriate treatment. Pharmacologic or surgical therapy may be needed, but one or more sleep-hygiene measures are adequate to improve most patients' quality of life when they are asleep--and awake.

Early differentiation of senile dementias.

Neurologic causes of dementia include cortical and subcortical pathology, as well as intracranial space-occupying lesions. The elderly are particularly prone to metabolic and toxic encephalopathies with associated delirium, dementia, or both. Many of these disorders are potentially reversible, but appropriate management requires comprehensive assessment.

Drug interactions in the elderly. How multiple drug use increases risk exponentially.

Adverse drug reactions occur more often in the elderly because of alterations in pharmacokinetics and tissue sensitivity and the increased prevalence of chronic disease. The elderly take many more prescription and nonprescription drugs than do younger people. When multiple drugs are administered, the incidence of drug interactions rises exponentially. Therefore, following the "rule of five" is recommended to minimize interaction in this vulnerable population.

Morphology of the uvula in obstructive sleep apnea.

Alterations in pharyngeal structure and function are considered fundamental in the pathogenesis of obstructive sleep apnea (OSA). However, little is known about morphologic features of the pharynx in patients with OSA. We therefore studied the tissue composition of the uvula (midsagittal section) in patients with OSA, using a quantitative, morphometric point-counting technique. Uvula tissue was obtained by uvulopalatopharyngoplasty (UPPP) in 33 patients (mean number of apneas per hour of sleep = 32.7 +/- 5.2) and by autopsy in 22 normal subjects not known to have OSA. All statistical comparisons were controlled for differences caused by age and body mass index. Patients with OSA had a significantly greater percentage of muscle in the uvula (18.1 +/- 1.9% versus 9.3 +/- 2.1%, p = 0.02) than did normal subjects. A significant difference in fat content was also found (9.5 +/- 1.4% in patients versus 4.0 +/- 1.0% in normal subjects, p less than 0.02). These differences between patients with OSA and control subjects could not be accounted for by anthropometric or sex differences. The percentage of uvula fat tissue was significantly related to the frequency of apneas and hypopneas in sleep (r = 0.43, p less than 0.01). Uvula morphology in 6 nonapneic snorers undergoing UPPP was similar to that of patients with OSA. We conclude that the uvula in patients with OSA contains more muscle and fat than the uvula in control subjects, possibly contributing to pharyngeal narrowing in OSA.

Effects of nadolol on blood pressure, sleep efficiency, and sleep stages.

The effects of nadolol (20 and 80 mg) on blood pressure and sleep parameters were assessed in six patients with mild hypertension. A 32-night experimental protocol in the sleep laboratory was instituted consisting of four placebo-baseline nights followed by 4 weeks of drug administration. Both doses of nadolol had a clear-cut and consistent lowering effect on blood pressure throughout the night and during the day, with a greater reduction noted with the 80 mg dose. In fact, blood pressure values were reduced to normotensive levels. Neither dose had a disrupting effect on sleep, whereas the 80 mg dose improved sleep efficiency and also had a rapid eye movement-enhancing effect. This absence of sleep-disrupting effects is attributed to nadolol's low level of lipophilicity and lack of intrinsic sympathomimetic activity. The clinical significance of the lack of sleep disruption and possible improvement of sleep with nadolol is discussed in light of the well-recognized sleep disturbances produced by other beta-blockers.

Uvulopalatopharyngoplasty as a treatment of obstructive sleep apnea precipitated by uvular prolapse.

Two patients are discussed in whom obstructive sleep apnea was precipitated by uvular prolapse into the larynx and successfully treated by uvulopalatopharyngoplasty. Although tracheostomy has been the definitive treatment for obstructive sleep apnea, uvulopalatopharyngoplasty has also been used as an alternative surgical procedure. However, indications for its successful use have not been clearly defined. Our experience illustrates that the surgical approach to obstructive sleep apnea is dependent on a thorough diagnostic evaluation that includes a sleep history, head and neck examination, hypnopolygraphic recording and, if indicated, nocturnal fiberoptic endoscopy.

Disorders of excessive sleepiness: narcolepsy and hypersomnia.

Besides sleep apnea, the main disorders of excessive daytime sleepiness include narcolepsy and hypersomnia. Narcolepsy is characterized by periods of irresistible sleepiness and sleep attacks of brief duration and, most often, by one or more of the auxiliary symptoms: cataplexy, sleep paralysis, and hypnogogic hallucinations. Generally, sleepiness and sleep attacks in hypersomnia are of longer duration and are more resistible than in narcolepsy; also, the auxiliary symptoms are absent. There are three types of hypersomnia: idiopathic, secondary, and periodic. Nocturnal sleep is typically disrupted in narcolepsy, whereas in idiopathic hypersomnia it is prolonged and in secondary hypersomnia it is variable. The exact causes of narcolepsy and idiopathic hypersomnia are unknown; however, there is evidence for genetic predisposition for either disorder. In secondary hypersomnia causative factors include: neurologic, such as head injuries, cerebrovascular insufficiency, and brain tumors; general medical, such as metabolic disorders, various intoxications, and conditions leading to brain hypoxia; and psychiatric, most notably depression. Although the cause of periodic hypersomnia is unclear, most research supports the notion of underlying organic disease. Often, the evaluation of patients with excessive daytime sleepiness can be completed in the office setting, based on the sleep history and a thorough neurologic, general medical, and psychiatric assessment. Whenever indicated, ancillary laboratory studies, such as computed tomography and magnetic resonance scans, should be performed. Sleep laboratory recordings generally are not necessary unless there is suspicion of sleep apnea or narcolepsy in the absence of auxiliary symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharyngeal size and resistance in obstructive sleep apnea.

Although anatomic and physiologic abnormalities of the upper airway are thought to be important in the pathogenesis of obstructive sleep apnea (OSA), the relative contributions of these factors have not been elucidated. We therefore measured pharyngeal cross-sectional area (PCSA) and pharyngeal air-flow resistance (Rp) in 12 overweight men with severe symptomatic OSA (mean apnea plus hypopnea index [AHI], 66.9 +/- 6.0 events per hour) and in 17 age- and weight-matched control subjects without spontaneous complaints of OSA symptoms (mean AHI, 4.9 +/- 1.6 events per hour). During wakefulness, PCSA was assessed during breath cessation at FRC by computed tomography (CT) and Rp by measuring inspiratory air-flow resistance between the choanae and epiglottis. No measure of PCSA differed significantly between patients and control subjects, and only 1 measure of PCSA, minimal pharyngeal area, correlated with AHI in all subjects (r = -0.38, p less than 0.05). In contrast, Rp was significantly higher (p less than 0.05) in patients (6.9 +/- 1.0 cm H2O/L/s) than in all control subjects (4.2 +/- 0.5 cm H2O/L/s) and correlated significantly with AHI (r = 0.53, p less than 0.01). We conclude that increased inspiratory resistance to air flow in the naso-oropharynx is present during wakefulness in overweight men with OSA, when compared with matched control subjects without symptomatic OSA, and is associated with disordered breathing during sleep. This occurs even though computed tomography is unable to demonstrate that pharyngeal size during wakefulness at FRC is significantly different between patients and control subjects. These observations suggest that the ability to dilate the pharynx during inspiration may be defective in patients with OSA.

Further clinical experience with the silicone tracheal cannula in obstructive sleep apnea.

We report on the perioperative and postoperative course of 47 patients with severe obstructive sleep apnea, who underwent tracheostomy by use of a silicone tracheal cannula developed by Dr. William Montgomery. Our initial experience with the first 20 of these patients (presented in 1982) was quite favorable because of the ease of insertion and care, a high degree of patient acceptance, and infrequent complications. With our current sample, larger experience, and more prolonged follow-up, we noted that symptomatic granulation tissue formation, with or without wound infection, occurred more frequently than was initially appreciated. In 21% (10 of 47) of the cases, the only way to resolve this problem was to remove this device and replace it permanently with a metal (or other type) tracheostomy tube. Other complications included tracheal narrowing and cannula malpositioning and fragmentation. This full report lists in detail the incidence of complications associated with our use of this cannula and modifications which may lessen these.

Narcolepsy/cataplexy. IV: Diagnostic value of daytime nap recordings.

Sleep and wakefulness patterns in daytime naps of 50 patients with narcolepsy/cataplexy were compared with those of 50 controls. Each subject was monitored polygraphically during 2 one-hour nap periods. A sleep-onset REM period in either of the 2 daytime naps was observed to have a higher diagnostic sensitivity (78%) than an abnormally shortened sleep latency (68%). However, the specificities of a sleep-onset REM period (88%) or abnormally shortened sleep latency (90%) were quite similar. When the occurrence of either a sleep-onset REM period or a shortened sleep latency was evaluated in either of the two naps, the overall sensitivity was increased to 84% while the specificity was decreased only to 80%. The limitations of and indications for the use of testing for sleep and REM latencies in the diagnosis of narcolepsy in clinical practice are discussed.

Effects of oral narcotics on sleep-disordered breathing in healthy adults.

Alcohol and benzodiazepines may increase sleep-disordered breathing by decreasing activity of pharyngeal dilating muscles, favoring the development of obstructive apneas and hypopneas. Narcotics cause greater depression of wakeful respiration than the previously mentioned drugs; however, the influence of narcotics on the upper airway and breathing during sleep has not been studied. We, therefore, examined, in 12 healthy adults, the effects of oral hydromorphone hydrochloride (2 and 4 mg) on breathing during sleep and on a variety of awake respiratory variables (minute ventilation, gas exchange, and chemoresponsiveness). In addition, awake pharyngeal inspiratory airflow resistance was determined before and after narcotic administration to assess the drug's influence on patency of the upper airway. Following both doses, minute ventilation decreased, and carbon dioxide pressure increased. The 4-mg dose of hydromorphone hydrochloride also produced a significant decrement in the hypoxic ventilatory response, whereas hypercapnic responsiveness and pharyngeal resistance did not change following either dose of the drug. Despite the respiratory depression during wakefulness described previously, no significant change was observed in any measure of sleep-disordered breathing after either dose of narcotic. We conclude that in healthy individuals without suspected sleep apnea, oral hydromorphone in standard dosages does not significantly increase sleep-disordered breathing. This result may be due to a lack of selective depression of upper-airway muscular function by the doses of narcotic used.

The effects of nasal anesthesia on breathing during sleep.

Inability to breathe through the nose is an increasingly recognized cause of disordered breathing during sleep. To test the hypothesis that this respiratory dysrhythmia could result from loss of neuronal input to respiration from receptors located in the nose, we anesthetized the nasal passages of 10 normal men during sleep. Each subject spent 4 consecutive nights in the sleep laboratory while sleep stages, breathing patterns, respiratory effort, and arterial oxygen saturation were monitored. Night 1 was for acclimatization with Nights 3 and 4 being randomized to nasal spraying with either 4% lidocaine or placebo. On the lidocaine and placebo nights (Nights 3 and 4) the nasal passages were also sprayed with a decongestant to prevent increased nasal air-flow resistance resulting from mucosal swelling. To control for the possible effects of this decongestant, an additional night (Night 2) was included during which the nasal passages were sprayed with room air. Parallel studies conducted during wakefulness demonstrated low nasal resistance during the lidocaine-decongestant regimen. Because of the short duration of anesthesia with lidocaine, spraying was done at lights out and 2.5 and 5 h later. On the placebo night (decongestant plus saline) there were 6.4 +/- 1.8 (SEM) disordered breathing events (apneas plus hypopneas) per subject, whereas with lidocaine (plus decongestant) this increased fourfold to 25.8 +/- 7.8 events per subject (p less than 0.05). The majority of the disordered breathing events were apneas and were fairly evenly distributed between central and obstructive events. The magnitude of these changes is similar to that previously reported with complete nasal obstruction. These results suggest that nasal receptors sensitive to air flow may be important in maintaining breathing rhythmicity during sleep.

Pharmacologic and psychotherapeutic issues in coexistent paranoid schizophrenia and narcolepsy: case report.

The case of a 32-year-old man with schizophrenia and narcolepsy, two seemingly unrelated disorders, is discussed from the perspective of the diagnostic and therapeutic challenges raised by their coexistence. In addition, the development of tardive dyskinesia and its subsequent amelioration with a depot form of a high-potency neuroleptic are discussed in relation to these disorders. Consistent and supportive psychotherapy for such patients is recommended for maintaining compliance, for pharmacotherapy, and an optimal level of personal, occupational, and interpersonal functioning.