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The authors measured steady-state protriptylive levels in 12 outpatients undergoing treatment for depression. The steady-state level of protriptyline was surprisingly high compared with levels obtained when other tricyclic antidepressants were prescribed. This finding probably accounts for the effectiveness of protriptyline at low doses and its frequent side effects.
The authors present five case reports illustrating that 10-20 mg of protriptyline in a single dose at bedtime can effectively control arousal dysfunction (sleep drunkenness and hypersomnia) and the narcolepsycataplexy syndrome without the apparent development of tolerance and without the side effects that are frequent complications of treatment with other agents. Although protriptyline was efficacious in controlling symptoms, it was found to have relatively poor REM sleep-suppressing properties.
Fourteen patients with an average of more than 60 episodes of upper airway obstruction during night sleep were treated with a nonsedating tricyclic antidepressant, protriptyline. Frequency and duration of recorded apneas decreased in 11 cases, and satisfactory control of sleep apnea was maintained with medical therapy alone in 8 of these 11 patients for 7 to 15 months. Potential adverse effects of protriptyline, particularly on the cardiovascular system, limit its use in this illness. These results indicate the possibility of pharmacologic reversal of sleep-induced incoordination of the upper airway.
A four-week comparison of protriptyline 10 mg three times a day and perphenazine 2 mg three times a day, alone and in combination, and a placebo in a group of nonpsychotic depressed outpatients showed no significant differences among any of the treatment groups after both two and four weeks, and a slight trend in favor of the placebo group. A significant positive correlation was observed between changes in hostility and changes in depression, contrary to many commonly held assumptions regarding the relationship between hostility and depression.
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.
The effects of protriptyline on sleep stage distribution and gas exchange have been assessed in eight patients with nocturnal hypoventilation secondary to restrictive chest wall disease. At a dose of 10-20 mg taken when they retired the total sleeping time was unaltered but the proportion of rapid eye movement (REM) sleep fell from 22% to 12% (p less than 0.05). The total time spent at an arterial oxygen saturation of less than 80% decreased (p less than 0.01) and the magnitude of the fall correlated with the reduction in REM sleep (r = 0.67, p less than 0.05). There was also a reduction in the maximum carbon dioxide tension reached during the night (p less than 0.01). The arterial oxygen tension measured diurnally increased (p less than 0.05) from a median of 8.0 kPa (60 mm Hg) to 9.0 kPa (67.5 mm Hg), but the carbon dioxide tension and base excess were unchanged. Anticholinergic side effects were experienced by most patients but did not limit treatment.
Protriptyline 20 mg daily reduced the total time spent in rapid eye movement sleep in an open study in four subjects with Duchenne muscular dystrophy. Sleep related hypoxaemia and episodes of desaturation were reduced. Anticholinergic side effects were prominent, however, in these patients, precluding its use for regular treatment.
The present paper deals with further studies on the interaction between clonidine and tricyclic antidepressants. The pronounced central hypotensive action of 1 mug clonidine/kg, administered into the left vertebral artery of chloralose-anaesthetized cats was readily reversed by protriptyline (300 mug/kg), infused via the same route shortly after the development of the maximum hypotensive effect of clonidine. In earlier studies it has been demonstrated that pretreatment with tricyclic antidepressants significantly diminishes the central hypotensive action of clonidine. This interaction has been presumed to occur at the level of central alpha-adrenoreceptors, where clonidine would be the agonist and tricyclic antidepressants the antagonist. The present findings suggest that a competitive antagonism at the central level, which can occur in either sense, may be involved.
A new metabolite of protriptyline formed by incubation of the drug in a rabbit liver microsomal system was identified as the hydroxylamine derivative by mass spectral and NMR analysis.
We studied the relationship between side effects, clinical outcome and the drug plasma levels in 28 female depressed patients treated with protriptyline. After 3 1/2 weeks treatment, patients with plasma levels within a median range (630 to 900 nmol/l) showed better responses to the drug than patients with plasma levels outside this range. There were no statistically signficant correlations between plasma levels and side effect scores or 'corrected' side effect scores (scores after subtracting pretreatment values) for the group at any time after starting the treatment. But we found positive correlations between plasma levels and 'corrected' side effect scores for the neurotic subgroup after 14 and 21 days of treatment. Other correlations between plasma levels and side effect scores were non-significant.
10,11-Dihydro-10,11-dihydroxyprotriptyline was identified in rat urine following administration of protriptyline 40 mg kg-1 i.p. Gas chromatographic-mass spectrometric characterization confirmed the structure of this stable metabolite, and its identity with a synthetic sample.
Two epoxide metabolites of 5-(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene (protriptyline) were identified in the urine of rats given 14-C-labeled drug. They were characterized by mass spectrometry, nuclear magnetic resonance spectrometry, and chemical reactivity as 10,11-dihydro-10,11-epoxy-5(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene (I) and 10,11-dihydro-10,11-epoxy-5(3-aminopropyl)-5H-dibenzo[a,d]cycloheptene (II). Over twice as much I as II was excreted and together the two metabolites accounted for approximately 40% of the urinary radioactivity.
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The pharmacological effects of three tricyclic antidepressant agents (desipramine, protriptyline and doxepin) are evaluated in rat isolated atria in relation to their accumulation and efflux kinetics. The pharmacological effects studed are: inhibition of 1-3H-noradrenaline uptake, potentiation of 1-noradrenaline chronotropic response, and changes in spontaneous atrial rate. All drugs inhibit noradrenaline uptake and potentiate noradrenaline chronotropic response (desipramine congruent to protriptyline greater than doxepin). Desipramine and protriptyline, at concentrations of 10(-7) -- 10(-6)M stimulate the spontaneous rate; higher concentrations (greater than 10(-6)M) depress it. Doxepin has only a negative chronotropic effect. When the drugs are removed from the incubation medium, the depressing effect starts to disappear immediately for doxepin and desipramine and after 20 min for protriptyline. On the contrary the stimulating effect persists after repeatedly washing the preparations. Desipramine, protriptyline and doxepin extensively accumulate in the myocardial tissue (desipramine larger than or equal to protriptyline greater than doxepin). In the efflux studies doxepin is washed out more rapidly than desipramine and protriptyline. Although the kinetics of uptake and efflux of the three compounds are not sufficient to interpret their different pharmacological activities in isolated atria, they give useful information on the persistance of the sympathomimetic effect and the rapid disappearing of the negative chronotropic effect after washing.