Early individualization of tricyclic antidepressant dosing using a Bayesian pharmacokinetic model.

Existing methods to prospectively dose tricyclic antidepressants (TCAs) require either specific test doses, precisely timed serum sampling, or both. We prospectively tested a new pharmacokinetic model that allows flexible dosing and sampling to determine maintenance requirements in patients receiving TCAs. Thirty-four patients entered the study. Drug concentrations were measured on the third day after starting TCA therapy. These values were analyzed using a Bayesian pharmacokinetic model to determine drug clearance and volume of distribution. This information was then used to predict the serum concentration resulting from a maintenance dose chosen by the psychiatrist. In phase I (n = 17), patients received imipramine without specific starting doses. Phase II (n = 17) was performed to provide a preliminary evaluation of the method in the usual clinical environment. In this phase, patients received either amitriptyline, imipramine, desipramine, doxepin (75 mg on day 1,100 mg on day 2), or nortriptyline (50 mg on day 1, 75 mg on day 2). Lower doses were allowed if clinically indicated. The predictability of future serum concentrations was then compared between the two phases. The mean prediction errors (model bias) in phases I and II were -15.5 +/- 27.3 and -12.3 +/- 21.8 ng/mL and were not different (p greater than 0.05). The absolute prediction errors (model precision) were 18.5 +/- 25.1 and 18.8 +/- 16.0 ng/mL and were not different (p greater than 0.05). Two slow metabolizers were identified (clearance less than 0.10 L/kg/h). This new method allows the determination of maintenance dose requirements early in therapy without standard test doses or specifically timed serum sampling.(ABSTRACT TRUNCATED AT 250 WORDS)

Benefit of nasal CPAP in obstructive sleep apnea is due to positive pharyngeal pressure.

The purpose of this study was to determine if the mechanism of nasal continuous positive airway pressure's (CPAP's) effectiveness is to act as a pneumatic splint or to increase functional residual capacity (FRC) and consequently, upper airway caliber. Four subjects with obstructive sleep apnea underwent 3 nights of polysomnography: night 1, control; night 2, nasal CPAP; night 3, external subatmospheric pressure (ESAP). ESAP, a negative pressure body suit, increases FRC. We measured the changes in FRC with nasal CPAP and ESAP using the weighted spirometer technique. The dose used for the ESAP night was the dose that produced the same FRC as the subject's prescribed nasal CPAP dose. The mean number of arousals and the respiratory events index were higher on ESAP and control nights. Less severe oxygen desaturation occurred during non-rapid-eye-movement sleep on the nasal CPAP and ESAP nights. These preliminary results show that increasing FRC alone does not account for the effectiveness of nasal CPAP, and splinting of the collapsible upper airway is necessary.

Rate of forgetting in mild Alzheimer's-type dementia.

Patients with mild dementia of the Alzheimer's type (DAT) and matched controls were examined for rate of forgetting line drawings of common objects. DAT patients demonstrated rapid forgetting in the first 10 min after learning to criterion. This finding is discussed with respect to memory consolidation and neuropathologic changes in dementia of the Alzheimer's type.

Productive naming and memory in depression and Alzheimer's type dementia.

Patients with mild to moderate dementia of the Alzheimer's type (DAT), patients with major depression, and normal controls completed tests of productive naming and verbal recall memory. Both depressed and DAT patients demonstrated reduced verbal fluency on productive naming tasks, indicating limited utility of such tasks in differential diagnosis. There was a stronger relationship between verbal fluency and memory in DAT patients than in depressed patients. The linguistic component as well as the requirement for cognitive speed may be important in explaining the deficit of DAT patients on productive naming tasks. In contrast, the speed component may be particularly important for depressed patients whose poor performance may reflect a motivational deficit.

Effects of protriptyline on vigilance and information processing in narcolepsy.

Vigilance, memory function, and response latency on the Sternberg short-term memory scanning task were examined in eight narcoleptic patients on and off medication. Off medication, half of the patients demonstrated reduced vigilance and all displayed diminished automatic memory encoding and longer response latencies on the Sternberg memory scanning procedure relative to the treated condition. Protriptyline normalized vigilance in half of the patients, while response latency and automatic information processing significantly improved in all. These findings are discussed with regard to the potential effect of the medication on central nervous system arousal.

Psychomotor slowing and subcortical-type dysfunction in depression.

Elderly patients with major depression and normal controls completed the Sternberg short-term memory scanning procedure and WAIS Digit Symbol. Depressed patients demonstrated psychomotor slowing on both tasks, but normal response latency as a function of memory set size on the Sternberg procedure. While cognitive-behavioural slowing may be observed in both depressive illness and subcortical neurological disorders, a normal rate of processing information centrally appears to distinguish depression from certain of these disorders. Psychomotor slowing in the presence of normal information processing speed might be explained by a deficit in motivational state associated with depression.

Normal pressure hydrocephalus presenting as mania.

A case of normal pressure hydrocephalus presented as a secondary mania. The patient responded to neurosurgical intervention. Psychiatric aspects of diagnosis and management of normal pressure hydrocephalus are discussed.

Selective reminding procedure in depression and dementia.

Patients with mild dementia of the Alzheimer's type (DAT), patients with major depression, and normal elderly control subjects were administered a verbal learning task using the selective reminding procedure. Depressed patients were impaired on total recall and the proportion of items retained from one trial to the next without reminding and did not benefit from imagery in retaining items over consecutive trials. The DAT patients were impaired on all measures derived from the test, including storage and recognition memory. With the exception of the ability to benefit from imagery, all of the measures distinguished depressed and mild DAT patients. These findings are consistent with deficient encoding in DAT and performance deficits as a function of effortful cognitive processing in depression.

Natural history of Klüver-Bucy syndrome after treated herpes encephalitis.

We present the natural history of three patients with features of Klüver-Bucy syndrome after treated herpes encephalitis. Although cognitive and behavioral disturbances following herpes encephalitis are often severe, improvement can occur over an extended period, and chronic residual sequelae may be relatively mild. The pattern of memory impairment is consistent with the current hypothesis that medial temporal lobe structures mediate memory consolidation.

Gastric surgery for respiratory insufficiency of obesity.

Morbid obesity is often associated with severe respiratory insufficiency, commonly known as the pickwickian syndrome. This can be divided into the following two primary breathing disorders which can affect patients alone or in combination: the obstructive sleep apnea syndrome (SAS); and the obesity-hypoventilation syndrome (OHS). Thirty-eight (14 percent) of 263 morbidly obese patients with respiratory insufficiency of obesity underwent gastric surgery for weight reduction. Ten had OHS, nine has SAS, and 19 had both. Of these patients, one died of postoperative complications, one died at five weeks with an inconclusive autopsy, one was lost to follow-up, and the time since surgery was too short (less than three months) in three. A total of 30 patients lost 45 +/- 25 percent (p less than 0.0001) of excess body weight within 3 to 12 months following surgery, when repeat pulmonary studies were done. Most patients continued to lose additional weight until two years, when they had lost 62 +/- 26 percent of excess weight. Nine patients failed initial surgery (gastroplasty); seven of these were successfully converted to gastric bypass. Weight loss was associated with a significant decrease in the percentage of sleep apnea from 44 +/- 15 to 8 +/- 11 (p less than 0.0001). In patients with OHS, the arterial oxygen pressure (PaO2) increased from 53 +/- 9 to 68 +/- 11 mm Hg (p less than 0.0001), and the arterial carbon dioxide tension decreased from 51 +/- 7 to 41 +/- 4 mm Hg (p less than 0.0001). Pulmonary function tests in the patients with OHS revealed significant increases, as a percentage of predicted normal, in the forced vital capacity, forced expiratory volume in one second, expiratory reserve volume, functional residual capacity, and total lung capacity. Secondary polycythemia, defined as a hemoglobin level greater than 16 g/dl associated with a PaO2 less than 60 mm Hg, was noted in 13 of 29 patients with OHS. This fell from 16.9 +/- 1.1 to 14.9 +/- 1.7 g/dl (p less than 0.001) after weight loss and improved pulmonary function.

Information processing speed of children with Friedreich's ataxia.

Two children with Friedreich's ataxia and six controls matched for age and Verbal IQ were administered a measure of short-term memory scanning and tests of attention, memory, language and abstraction. The patients demonstrated a deficit in information processing speed, decreased sustained attention and variable memory performance. The findings suggest that a deficit in information processing speed occurs early in the clinical course of Friedreich's ataxia and progresses as neurological status deteriorates.

Effect of estrogens on the dexamethasone suppression test in nondepressed women.

It is often suggested that estrogens may cause false-positive dexamethasone suppression test (DST) results. In this study of nine healthy, non-depressed women, DSTs were performed at baseline, immediately following administration of 21 days of oral contraceptives containing either 50 or 80 micrograms of mestranol (a synthetic estrogen) in combination with 1 mg of norethindrone (a synthetic progesterone), and 1 month after discontinuing the oral contraceptives. All subjects had post-dexamethasone cortisol levels less than or equal to 5 micrograms/dl during the study with the exception of two subjects in the mestranol 80 microgram group who had positive DSTs immediately following oral contraceptive administration; one of these subjects continued to have a positive DST 1 month later. DST results should be interpreted with caution if high dose estrogens are taken concurrently or have been recently discontinued.

Information processing speed in Friedreich's ataxia.

Three patients with Friedreich's ataxia and six controls matched by age and vocabulary and information scores on the Wechsler Adult Intelligence Scale-Revised were administered a measure of short-term memory scanning. Patients with Friedreich's ataxia demonstrated a deficit in information processing speed in the relative absence of impairment in attention, memory, language, judgment, reasoning, and other cognitive functions. The short-term memory scanning procedure may be useful in documenting cognitive slowing and in distinguishing this impairment from the motor abnormality often associated with a subcortical brain disorder.