A naturalistic assessment of protriptyline for attention-deficit hyperactivity disorder.

OBJECTIVE: To evaluate the potential benefit of the tricyclic antidepressant, protriptyline, in the treatment of children and adolescents with attention-deficit hyperactivity disorder (ADHD). METHOD: All clinic patients in an outpatient pediatric psychopharmacology unit treated with protriptyline for ADHD were monitored for response to treatment. Thirteen subjects (11 male, 2 female) were treated naturalistically with protriptyline for ADHD and were administered the ADHD Symptom Rating Scale and Clinical Global Impression of Severity (CGI-S) and improvement (CGI-I) at baseline and while taking medication. All patients had failed to respond to at least one previous medication trial, and 46% had psychiatric comorbidity. RESULTS: Patients received an average protriptyline dose of 17 mg (range 5 to 30 mg) for 11.5 +/- 6.8 weeks. Of the 11 patients who continued to take protriptyline for at least 4 weeks, there was a modest reduction in the ADHD symptom checklist (p < .004) and the CGI-S (p = .032). However, using a predefined criteria of response, only 45% of patients were considered positive responders. Adverse effects were prominent, with 46% of patients reporting clinically significant problems and 38% of patients discontinuing treatment because of intolerable side effects. CONCLUSION: These findings do not support the clinical utility of protriptyline in the routine management of complex cases of ADHD in children and adolescents. However, the usefulness in noncomorbid, medication-naive ADHD individuals remains unclear.

Effect of protriptyline, 10 mg daily, on chronic hypoxaemia in chronic obstructive pulmonary disease.

A daily dose of 20 mg of protriptyline can improve daytime arterial blood gas tensions in chronic obstructive pulmonary disease (COPD). Its usefulness is limited by anticholinergic side-effects. This study examined whether a daily dose of 10 mg of protriptyline improved daytime arterial oxygen tension (PaO2) and quality of life in patients with stable mild or moderate hypoxaemia caused by COPD. Twenty six patients were randomized to receive protriptyline or placebo in a double-blind parallel-group trial for 12 weeks, following a run-in period of 4 weeks, in order to assess the stability of hypoxaemia. Patients with a change in PaO2 of > 0.7 kPa during the run-in were excluded. Spirometry, quality of life and dyspnoea score were measured at randomization and after 12 weeks, whilst arterial blood gas tensions were also measured 2 and 6 weeks after randomization. No improvement in arterial blood gas tensions, spirometry values, dyspnoea score, or quality of life was found in either the protriptyline or the placebo group. The majority of patients receiving protriptyline experienced anticholinergic side-effects, which necessitated the withdrawal of the drug in one patient. We conclude that there was no evidence that a daily dose of 10 mg of protriptyline had a significant effect on daytime arterial oxygen tension in stable mild and moderate hypoxaemia caused by COPD. Despite the low dose, anticholinergic side-effects occurred in most patients.

Effects of protriptyline on snoring characteristics.

We evaluated the effects of protriptyline on snoring characteristics in 14 nonapneic snorers (age range, 23 to 54 years; body mass index, 27.4 +/- 0.9 kg/m2, mean +/- SEM). The study design was a double-blind placebo-controlled crossover trial. Patients were evaluated during a polysomnographic study after each 2 weeks of treatment. Breathing sounds were recorded with two microphones symmetrically placed on each side of the bed, the signal being preamplified, equalized, and analyzed by using a real time analyzer. A snoring event was defined as a breathing sound with a sound pressure level (SPL) greater than 60 dB SPL. The snoring index (number/sleep hour) and the sound intensity of each event were automatically determined. Mild side effects were observed in ten subjects, but no subject interrupted the study because of them. The REM sleep time decreased with protriptyline with a parallel increase in stages 1 to 2. There was no difference in body position during sleep between the placebo and protriptyline trials. The snoring index decreased from 335 +/- 40 with placebo to 238 +/- 41 with protriptyline (p < 0.05) with important individual differences. Among the different sleep stages, the highest values of the snoring index were observed in slow-wave sleep with placebo. The snoring index decreased in each sleep stage with protriptyline, the highest decrease occurring in slow-wave sleep. The percentage of total sleep time (TST) spent above 60 dB SPL was significantly lower with protriptyline (6.1 +/- 1.2 percent TST) than with placebo (8.6 +/- 1.2 percent TST). Changes in snoring characteristics were not correlated with snoring severity, the drug blood level, the body mass index, or the drug-induced modifications in sleep architecture. We conclude that protriptyline can improve both snoring frequency and loudness in some nonapneic snorers, and that this improvement occurs mostly in the sleep stages where snoring is worst.

Protriptyline as an alternative stimulant medication in patients with brain injury: a series of case reports.

The results of a series of eight individual case reports in which protriptyline, an activating tricyclic antidepressant, was used as a 'stimulant' medication are presented. For some patients with head injury, traditional stimulants, such as methylphenidate, or dopaminergic stimulants, such as levodopa-carbidopa, amantadine, or bromocriptine, may be partially or totally ineffective or not tolerated. Protriptyline can be a very effective alternative and, for some patients, may be the most effective stimulant tried. In low to moderate doses, protriptyline should be considered for trials as an activating/stimulant medication in patients with head injury.

Role of protriptyline and acetazolamide in the sleep apnea/hypopnea syndrome.

The role of drug therapy in the treatment of the sleep apnea/hypopnea syndrome is unclear. In a randomised, double-blind, placebo-controlled study, we investigated the value of 14-day therapy with protriptyline (20 mg daily) or acetazolamide (250 mg 4 times per day) on symptoms and on the frequency of apneas, hypopneas, arousals, and 4% desaturations in 10 patients with obstructive sleep apnea/hypopnea syndrome. Overall, protriptyline did not have a significant effect either on symptoms or on any of the above polysomnographic criteria. Acetazolamide reduced the apnea/hypopnea frequency [placebo 50 +/- 26 (SD); acetazolamide 26 +/- 20/h of sleep, p less than 0.03] and tended to decrease the frequency of 4% desaturations (placebo 29 +/- 20; acetazolamide 19 +/- 16/h of sleep, p = 0.06). Despite these physiological improvements, acetazolamide did not significantly improve symptoms and paraesthesiae were common. Contrary to earlier studies, we conclude that protriptyline may have a limited role in the treatment of the sleep apnea syndrome. The reason why acetazolamide produced a physiological, but not a symptomatic, response requires further investigation.

Bethanechol chloride can reverse erectile and ejaculatory dysfunction induced by tricyclic antidepressants and mazindol: case report.

A 43-year-old man who experienced profound dose-related erectile and ejaculatory dysfunction without loss of libido on three separate antidepressants and on the anorectic agent mazindol is described. Bethanechol chloride 20 mg p.o., taken 1 to 2 hours prior to sexual activity, permitted satisfactory erection and ejaculation during sexual intercourse, while the patient continued to take protriptyline or mazindol. Bethanechol chloride may prove to be of use in treating sexual dysfunction associated with drugs or conditions which increase sympathetic tone.

Diagnosis and management of obstructive sleep apnea. Part II.

Snoring has been shown to be the primary sign of a potentially serious medical condition, ie, obstructive sleep apnea. Traditionally, the otolaryngologist has been the primary resource for patients with snoring problems although, until recently, little was known about the now-acknowledged serious complications of this phenomenon. Among the primary treatments for this condition, the most commonly used to-date involve surgical procedures routinely performed by the otolaryngologist, ie, tracheostomy and uvulopalatopharyngoplasty. Thus, the practicing otolaryngologist has been thrust into the forefront of diagnosis and management of obstructive sleep apnea, and it behooves the modern practitioner to be cognizant of the multidisciplinary approach to the diagnosis and management of this problem. The utilization of information obtained during the sleep study determines the management of the sleep apneic patient.

The role of protriptyline in obstructive sleep apnea.

Protriptyline, a non-sedating tricyclic agent, was evaluated in a double blind drug-placebo crossover trial in five obese patients with obstructive sleep apnea. Four of the five patients had improvement in somnolence. Protriptyline improved oxygenation. This seemed related primarily to a reduction (from 23% to 11%) in REM, with fewer of the more severe REM apneas. Arousal frequency remained quite high; thus the reason for the reduction in somnolence remains unclear. In three patients, at six months the improvement in clinical status and oxygenation persisted. We have now attempted long term treatment in nine patients. In five, anticholinergic side-effects necessitated stopping therapy. Four patients continue to do well. A trial of protriptyline is thus indicated in treatment of mild to moderate obstructive apnea or when the patient refuses more invasive treatment.

Tricyclic antidepressants and delirium.

Some patients who take tricyclic antidepressants (TCAs) develop delirium. Charts were reviewed of 125 inpatients whose TCA plasma levels had been assayed. Delirium was documented in 10 cases. The occurrence of delirium was statistically related to age, race, and loge plasma TCA levels.

The effects of protriptyline in sleep-disordered breathing.

The effects of therapy with the tricyclic antidepressant protriptyline were studied in 12 patients with hypersomnolence and moderately severe sleep apnea. After treatment there was no significant change in the duration or frequency of sleep-disordered breathing (SDB) during non-REM sleep, but there was an alteration in the breathing pattern characterized by a decrease in the amount of apnea during SDB events. Apnea, as a percent of disordered breathing time, fell from 60.4 +/- 27.2% to 35.5 +/- 26.7% (p less than 0.01) and was accompanied by a reduction in the peak fall in oxygen saturation from 16.2 +/- 6.2% to 9.2 +/- 4.7% (p less than 0.01). During REM sleep there was no change in the pattern, duration, or frequency of SDB, or reduction in the peak fall in oxygen saturation. However, there was a reduction in the amount of Stage REM sleep, thereby reducing the more severe SDB events (p less than 0.01) and further improving nocturnal oxygenation. In 10 of 12 patients, there was subjective improvement in daytime hypersomnolence, which was associated with an increase in median sleep onset time from 3.3 +/- 2.2 to 5.1 +/- 2.1 min (p less than 0.01). Although all patients developed mild side effects from the anticholinergic properties of protriptyline manifested by a dry mouth, 4 patients noted additional side effects including urinary hesitancy, mild constipation, and difficulty in maintaining an erection. One patient developed intolerable constipation that necessitated discontinuation of the drug. We conclude that protriptyline reduced daytime hypersomnolence and altered the pattern of SDB, thus improving gas exchange and oxygenation during sleep. Therefore, in selected patients with moderately severe obstructive sleep apnea, therapy with protriptyline is an alternative to surgical treatment with a tracheostomy.

Protriptyline in the treatment of sleep apnoea.

Nine patients with obstructive sleep apnoea were treated with 5 to 20 mg of protriptyline each night for two to 18 months. In four patients, there was dramatic, sustained improvement in symptoms and measured sleep quality and apnoea frequency and duration. There was no improvement in two patients and three developed intolerable side-effects preventing adequate treatment. Apnoea frequency was the only apparent predictor of responsiveness. Those with fewer than 30 episodes of apnoea per hour consistently improved. Only two of four patients with more than 60 episodes per hour improved. These results provide additional evidence that a carefully monitored trial of protriptyline may benefit selected patients with mild to moderate obstructive sleep apnoea.

Phototoxicity mechanisms: chlorpromazine photosensitized damage to DNA and cell membranes.

Photosensitized damage to biological molecules is the initial process in phototoxic responses. It is now recognized that many phototoxic compounds can photosensitize damage to more than one type of biological substrate. The in vitro light-initiated reactions of phototoxic compounds with DNA, soluble proteins and membrane components can be classified by their molecular mechanisms: (1) those in which an excited state of the phototoxic compound (or an unstable species derived from it) reacts directly with the biological substrate and (2) those in which a molecule derived from the phototoxic compound (a photoproduct or an activated oxygen species) reacts with the biological substrate. This paper describes the mechanisms by which chlorpromazine photosensitizes damage to membranes, protein and DNA and compares them to the mechanisms of photosensitization by psoralens, porphyrins, dyes, and other molecules.

Hypomania and mania after withdrawal of tricyclic antidepressants.

Seven patients who had been maintained on tricyclic antidepressants developed signs of hypomania or mania shortly (two-seven days) after drug withdrawal. Three patients responded promptly to treatment with neuroleptics. One patient receiving lithium and three others who received no further drug treatment experienced more gradual resolution of symptoms. Tricyclic withdrawal is accompanied by changes in the turnover rate of individual neurotransmitters as well as by shifts in the equilibrium between various transmitter systems. These events may be accompanied by alterations in mood. Although relapse to depression is more common, hypomania or mania may also occur.