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At least 19 recordsLinked to original sources
PubMed1990

Antidepressant-like effects of trazodone on a behavioral screen are mediated by trazodone, not the metabolite m-chlorophenylpiperazine.

Trazodone is an atypical antidepressant drug (i.e. blocks neither monoamine uptake nor monoamine oxidase) which tests as an antidepressant drug on the differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule of reinforcement by increasing the reinforcement rate and decreasing the response rate. m-Chlorophenylpiperazine (m-CPP) is a 5-HT1B and 5-HT1C agonist, weak 5-HT2 antagonist, and trazodone metabolite. It has been suggested that formation of m-CPP is responsible for the antidepressant action of trazodone. Administration of m-CPP (1-10 mg/kg i.p.) 60, 30 or 10 min before the behavioral session did not mimic the reinforcement rate-increasing effects of trazodone (10-20 mg/kg i.p.) on rats performing under the DRL 72-s schedule of water reinforcement. Pretreatment with proadifen (50 mg/kg i.p.), an inhibitor of trazodone metabolism, caused a greater than 30-fold leftward shift in the dose-response curve for both the reinforcement rate and the response rate. These results suggest that the parent compound and not the trazodone metabolite m-CPP, mediates the antidepressant-like effects of trazodone on DRL 72-s behavior.

Animals↗
PubMed1988

Effects of a controlled-release formulation of trazodone on psychomotor and autonomic functions in healthy volunteers: comparison with trazodone (conventional formulation), amitriptyline and placebo.

Eight healthy male volunteers participated in four experimental sessions. In each session the subjects ingested a single dose of one of the following drugs: trazodone (controlled-release formulation), trazodone (conventional formulation), amitriptyline and placebo. Both trazodone and amitriptyline reduced subjectively rated alertness and increased digit cancellation time, and amitriptyline also reduced critical flicker fusion frequency. Both antidepressants reduced salivation, trazodone also caused miosis. There were no consistent differences between the effects of the two formulations of trazodone. The results of the psychological tests are indicative of the sedative properties of the antidepressants. It is likely that the reduction in salivation and pupil diameter by trazodone reflect alpha-adrenoceptor blockade, whereas the reduction in salivation by amitriptyline may be due to both cholinoceptor and alpha-adrenoceptor blockade.

Administration, Oral↗
PubMedDate not supplied

Effect of dosage and route of administration of trazodone on cerebral concentration of 1-m-chlorophenylpiperazine in rats. Kinetics of trazodone biotransformation in rats.

The levels of trazodone (TRZ) and its metabolite, 1-m-chlorophenylpiperazine (CPP) in the rat brain were tested after single and multiple administration of TRZ ip or po. After a single oral dose and after multiple ip or po administration of TRZ, the brain level of CPP exceeded markedly that of the parent compound. Some of pharmacokinetic parameters of TRZ and CPP were significantly changed after chronic treatment. As the biological effect of CPP is opposite to that of its parent compound, the high level of metabolite in the central nervous system may affect strongly the pharmacological activity of TRZ.

Animals↗
PubMedDate not supplied

Antidepressant properties of trazodone.

The chemistry, pharmacokinetics, biochemistry and pharmacology, clinical trials, adverse effects, FDA-approved indications, and availability and cost of trazodone hydrochloride, a triazolopyridine antidepressant, are reviewed. Trazodone is nearly completely absorbed after oral administration; although food delays absorption and reduces peak serum concentration, total area under the plasma concentration-time curve is not altered. Trazodone has biphasic elimination, with a redistribution half-life of about one hour and an elimination half-life of 10-12 hours. Trazodone is nearly completely metabolized hepatically by hydroxylation and oxidation to metabolites that are probably inactive. Trazodone is less potent but more selective than conventional tricyclic antidepressants; at low doses, trazodone acts as a serotonin antagonist, while at high doses it acts as a serotonin agonist. Trazodone has been compared with imipramine, amitriptyline, desipramine, and placebo in controlled clinical trials and found to be an effective antidepressant. Trazodone causes significantly fewer anticholinergic side effects than does imipramine. Trazodone has few cardiovascular side effects. In patients ingesting toxic amounts of trazodone, no deaths have been reported unless other drugs were present or ingested concomitantly. The usual adult daily dose of trazodone hydrochloride is 150-400 mg given in two divided doses. Trazodone is an effective antidepressant with a low incidence of serious adverse effects. It may be particularly useful in certain depressed patients who are intolerant of anticholinergic effects of other antidepressants, have cardiac conduction disturbances, or who do not respond to treatment with tricyclic antidepressants and in whom electroshock therapy is contraindicted.

Animals↗
PubMed1991

Pathophysiology of prolonged penile erection associated with trazodone use.

Treatment with the antidepressant trazodone has been associated with the occurrence of prolonged penile erection and priapism. To evaluate the effect of trazodone on erection we monitored the periodic physiological sleep-related erections in 6 healthy volunteers in a double-blind crossover study comparing the effect of trazodone, trimipramine (a tricyclic antidepressant) and placebo. In addition, to determine the effects of trazodone on the neurovascular control of penile smooth muscle we performed in vitro studies on corpus cavernosum tissue obtained from patients undergoing penile prosthesis implantation. Trazodone significantly increased the total interval of nocturnal erectile activity, while trimipramine had no effect. During the high dose treatment (nights 4 and 5) the average duration of erectile activity per night with placebo was 158 +/- 41 minutes (mean +/- standard deviation) for night 4 and 177 +/- 21 minutes for night 5. During trazodone treatment the erectile activity per night was significantly prolonged to 285 +/- 115 minutes during night 4 and 232 +/- 86 during night 5 (p less than 0.01). Analysis of the erectile activity in relation to the rapid eye movement sleep period during which erectile activity usually occurs revealed that the detumescence phase of erection, under sympathetic control, was significantly prolonged an average of 2.4 times by trazodone compared to placebo (p less than 0.05). In vitro, trazodone at concentrations comparable to those reached in plasma significantly impaired corporeal smooth muscle contractions elicited by electrical stimulation of adrenergic nerves and antagonized contractions induced by exogenous norepinephrine. We conclude that trazodone can enhance penile erection in man and propose a mechanism related to the alpha-adrenoceptor blocking properties of trazodone by interference with the sympathetic control of penile detumescence.

Adolescent↗
PubMed1992

Single dose pharmacokinetics of trazodone in healthy subjects.

Eight healthy subjects were administered trazodone-HCl orally (100 mg) with and without food and by infusion in a three way cross-over study. Unchanged trazodone was determined in serum and urine by high performance liquid chromatography after an alkaline extraction. Absorption of trazodone was irregular in fasting subjects and improved after food intake. Food intake significantly decreased the maximum serum concentrations of trazodone from 1.88 +/- 0.42 to 1.47 +/- 0.16 micrograms/ml, and increased the time for reaching maximum concentration from 1.3 +/- 0.8 hr to 2.0 +/- 1.5 hr. No differences were observed in the total amount of trazodone absorbed with or without food with bioavailability values of 65 +/- 6 and 63 +/- 4 per cent, respectively. The apparent volume of distribution and total body clearance for trazodone were estimated to 0.84 +/- 0.16 l/kg and 5.3 +/- 0.9 l/hr, respectively. The terminal elimination half-life of 7.3 +/- 0.8 hr showed no significant differences between the different ways of administration. Urinary excretion of unchanged trazodone during 26 hr was less than 0.13 per cent of the administered dose, suggesting a high degree of trazodone metabolism. Earlier statements of enterohepatic circulation of trazodone and pharmacokinetic differences between males and females were not confirmed by the present study. Due to the irregular absorption in fasting subjects, trazodone should preferably be administered after food.

Absorption↗
PubMed1989

[Effect of trazodone (KB-831) and its metabolites on brain monoamines in rat].

The effects of trazodone (KB-831) and its metabolites on the uptake, turnover and contents of monoamines in rats were studied in comparison with those of imipramine and mianserin. Trazodone exhibited a more potent inhibitory effect on the uptake of [3H] 5-hydroxytryptamine (5-HT) into brain synaptosomes than on the uptake of [3H]norepinephrine (NE). Trazodone at 10-30 mg/kg, p.o., also inhibited the p-chloramphetamine-induced depletion of 5-HT in rat brain, but not the 6-hydroxydopamine-induced NE depletion in rat heart. Trazodone was the most selective 5-HT uptake inhibitor among the drugs tested in vitro. Its metabolite, m-chlorophenyl-piperazine (m-CPP), inhibited 5-HT and NE uptake in vitro, but not in vivo. Trazodone (100 mg/kg) and imipramine (30-100 mg/kg) inhibited the depletion of NE induced by alpha-methyl-p-tyrosine, whereas mianserin (100 mg/kg) facilitated it. At 1 hr after a single administration of each drug, an increase in 5-HT content and a decrease in 5-hydroxyindole-3-acetic acid (5-HIAA) content were observed when 30 mg/kg trazodone was used. At 100 mg/kg, trazodone increased the levels of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and decreased the NE content. m-CPP (10-30 mg/kg) produced similar effects on monoamine contents to those of trazodone. Imipramine and mianserin had no effect on monoamine contents even at a dose of 100 mg/kg. After 3 weeks of successive administration, an increase in 5-HT and a decrease in 5-HIAA were induced by trazodone and m-CPP at 1 hr, but not at 17 hr, after the final administration. Imipramine decreased the contents of NE and 5-HIAA, and its effects lasted for 17 hr. These results suggest that trazodone is a selective 5-HT uptake inhibitor and that its neurochemical profile is different from those of imipramine and mianserin.

Animals↗
PubMed1983

Effects of acute and chronic trazodone administration on serum prolactin levels in adult female rats.

Trazodone was tested for its ability to elevate serum prolactin levels in mature female rats. When the drug was administered acutely to female rats at doses up to 80 mg/kg ip, it induced a clear rise in serum prolactin levels, with a minimum effective dose of 20 mg/kg; blood trazodone levels at these doses were between 1.6-2.4 micrograms/ml. However, trazodone could not be considered to be a potent stimulator of prolactin secretion, since the injection of haloperidol at 2 mg/kg elevated serum prolactin to values twice those seen in animals receiving the 80 mg/kg dose of trazodone. When trazodone was administered chronically in the diet for two or four weeks, at an average daily dose of 80 mg/kg, serum trazodone levels were found to be 100-200 ng/ml when measured at each stage of the estrous cycle. Serum prolactin levels in trazodone-treated animals, however, did not differ from those in control rats. Moreover, drug-treated animals showed normal proestrus surges in serum prolactin. The results of these studies thus indicate that acutely, at very high doses, trazodone probably can stimulate prolactin secretion modestly in female rats. However, when consumed chronically at 80 mg/kg/day, the drug has no effects on serum prolactin levels. Therefore, if trazodone stimulates prolactin secretion by altering neurotransmission across dopamine and/or serotonin synapses in brain, it is probably not potent in these actions, at least as concerns those dopamine and serotonin neurons that influence the secretion of prolactin.

Animals↗
PubMed1984

Interactions of trazodone with serotonin neurons and receptors.

Trazodone, 2-[3-[4-(m-chlorophenyl)-1-piperazinyl]propyl]-s- triazolo[4,3-a]pyridin-3(2H)one, was evaluated as an inhibitor of uptake into serotonin neurons in vivo in the brains of mice and rats by determining its ability to antagonize the depletion of brain serotonin by p-chloroamphetamine. In mice, trazodone was inactive under conditions in which many antidepressant drugs and other inhibitors of uptake are potent antagonists of the depletion of serotonin in brain induced by p-chloroamphetamine. Weak inhibition of uptake into serotonin-containing neurons in brain in vivo was demonstrated early after the injection of trazodone in rats, especially when the dose of p-chloroamphetamine was reduced to facilitate competitive inhibition of its effects. However, the effects of trazodone were short-lasting. Trazodone did not potentiate the elevation of serum corticosterone by L-5-hydroxytryptophan, in contrast to the effect of fluoxetine, a potent and selective inhibitor of the uptake of serotonin. Instead, trazodone antagonized a response mediated by a serotonin receptor, i.e. elevation of serum corticosterone by a serotonin agonist, quipazine, in rats. Trazodone also antagonized the serotonin-induced contraction of the rat jugular vein in vitro (a response mediated by 5-HT2 receptors), the pA2 being 8.79. These findings agree with previous reports that trazodone is a potent antagonist of serotonergic function. These data, together with earlier evidence, suggest it is unlikely that the inhibition of uptake of serotonin contributes to the clinical antidepressant effects of trazodone.

5-Hydroxytryptophan↗
PubMed1985

The role of trazodone metabolism in its inhibitory action on avoidance response.

To assess the role of trazodone metabolism in its depressant action on conditioned avoidance response we investigated whether in the mouse brain 3-chlorophenylpiperazine (CPP) is formed from trazodone, whether trazodone metabolism is affected by a drug metabolism inhibitor, proadifen, and how trazodone, CPP and their combinations act on avoidance responses in proadifen-pretreated mice. It was found that CPP is formed from trazodone in mice, that proadifen inhibits trazodone metabolism, and that the moderate and transient inhibitory effect of trazodone on avoidance responses is dramatically potentiated and prolonged in proadifen-pretreated mice. This effect, and inhibition of unconditioned escape response observed in mice receiving lower doses of trazodone after proadifen pretreatment, were counteracted by CPP. The results indicate that the inhibitory action of trazodone on avoidance response is caused by the parent compound, and that it is brief and moderate because of the rapid metabolism of the drug with formation of CPP which counteracts the depressant effect of the parent compound.

Animals↗
PubMed1990

A drug utilization review of prescribing patterns for trazodone versus amitriptyline.

The second-generation antidepressant trazodone has been thought by some clinicians to exert a less robust antidepressant effect than do tricyclic agents. This impression differs from the findings of numerous published clinical trials. In an effort to determine whether this discrepancy may be due to possible inappropriate dosing or use of trazodone for different patient subtypes, a retrospective chart review of 138 depressed inpatients treated with amitriptyline and of 42 depressed inpatients treated with trazodone was performed to compare their respective prescribing patterns. While these two groups did not differ with regard to most demographic variables, results revealed that patient prescribed trazodone were older (trazodone, mean +/- SD age = 54.5 +/- 8.8 years versus amitriptyline, 43.2 +/- 12.9 years; p less than .001), more often had a recurrent depressive disorder (trazodone = 57.1%, amitriptyline = 39.1%, p less than .06), and more frequently had a history of unresponsiveness to other antidepressants (trazodone = 47.6%, amitriptyline = 11.6%; p less than .001). In addition, initially prescribed daily doses of trazodone were below the recommended starting dose of 150 mg/day (mean +/- SD starting dose = 113.7 +/- 42.1 mg/day), while starting daily doses for amitriptyline (mean +/- SD = 69.8 +/- 20.1 mg/day) were judged to be more adequate relative to the recommended daily dose of 75 mg/day. Final trazodone dosage (mean +/- SD final dose = 217.9 +/- 87.5 mg/day) could be judged to have been far short of optimal levels of 250 to 350 mg/day and of up to 600 mg/day for inpatients and 400 mg/day for outpatient.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Post-mortem toxico-kinetics of trazodone.

Trazodone is a structurally unique bicyclic anti-depressant, said to be significantly less toxic than other anti-depressants following an acute overdose. We studied the tissue distribution and post-mortem redistribution of trazodone in two fatalities, one of which allowed comparison with trimipramine, a typical tricyclic anti-depressant. Case 1, a 53-year-old female weighing 72 kg, had femoral vein concentrations of trimipramine 5.5 micrograms/ml, trazodone 14.4 micrograms/ml and alcohol 107 mg%. Case 2, a 48-year-old female of 70 kg, had a femoral vein trazodone of 15.5 micrograms/ml and alcohol 34 mg%, with no other drugs detected. For case 1 and case 2 respectively, trazodone tissue concentrations were: skeletal muscle 7.3 and 9.0 micrograms/g; left and right lungs 13.3, 12.9 and 35.3, 40.1; myocardium, 30.9 and 28.9; kidneys 34.7 and 39.6; liver 73.7 and 82.4; fat 18.5 and 16.5; brain 48.6 and 20.9. For case 1 and 2, respectively, blood trazodone concentrations in 10 initial autopsy samples ranged from 13.7-17.3 and 14.4-16.9 micrograms/ml. Twenty-four and forty-eight hours later the respective ranges were 12.8-18.0 and 12.4-19.9 for case 1, 12.5-20.1 and 12.7-27.0 for case 2. By contrast, for trimipramine, blood concentrations at 0 time, 24 h and 48 hours ranged from 5.5-11.4, 5.2-14.3, and 4.2-18.2, respectively. We conclude that trazodone shows little preferential concentration in solid organs and consequently has relatively stable post-mortem blood concentrations with little drug redistribution artefact. Both the clinical pharmacokinetics and post-mortem toxicokinetics of trazodone differ significantly from the tricyclic anti-depressants.

Female↗
PubMed1989

Experimental examination of trazodone.

To establish the differential indication of trazodone and to find the predictors of its efficacy, we conducted a study in which 45 patients with major depressive disorder and 75 patients with acute schizophrenia were randomly assigned under double-blind conditions to either 400 mg trazodone daily, 150 mg amitriptyline daily, 20 mg haloperidol daily, or placebo daily. At the beginning of the investigations, numerous variables (basic data, MMPI, AMDP, HAM-A, HAM-D) were documented and evaluated on days 3, 7, 14, and 21. In our study, trazodone proved to be as effective an antidepressant drug as amitriptyline. In group comparison, no antipsychotic action of trazodone in schizophrenic patients could be proved. Yet the trazodone treatment was clearly of less risk than the amitriptyline treatment. Under trazodone, provocation of schizophrenic symptoms, which occurred numerously under amitriptyline, was found only in one patient out of 17 schizophrenics. Related to anamnesis and characteristics of the schizophrenic patient, a predictor-variable concerning the antipsychotic effect was not found. It can be assured, however, that patients with depressive symptoms (regarding the entity classification) respond to trazodone. After only 7 days of trazodone treatment, a relatively reliable decision can be established as to whether a therapeutical success can be expected if treatment is continued.

Adult↗
PubMed1984

The role of trazodone in the treatment of depressed cardiac patients.

The novel antidepressant trazodone is hypothesized to be less cardiotoxic than the tri-tetracyclic antidepressants. Recently, however, 2 patients with preexisting ventricular irritability showed an increased number of ventricular premature beats and of repetitive forms after starting on trazodone. Data are presented here from four studies on the cardiovascular safety of trazodone. Conclusions are: (1) Trazodone has little effect on cardiac conduction. (2) Trazodone does not worsen supraventricular arrhythmias. (3) Trazodone produces less postural hypotension than most other antidepressants and it tends to lower heart rate. (4) Lower doses of trazodone (100-300 mg) are better tolerated and more effective in major depressives simultaneously debilitated by significant cardiovascular disease. (5) It is possible that the so-called 'trazodone aggravation' of ventricular irritability is a statistical artifact--although further research is needed to verify this conclusion, and in the meantime the drug should be used with caution in such patients.

Aged↗
PubMed1983

Long-term therapy for depression with trazodone.

Trazodone and imipramine were compared in a two-center double-blind study of moderately to severely depressed outpatients. Results for 44 patients who have completed the 12-month comparison showed superior efficacy of trazodone at endpoint on all efficacy measures. Significant differences were also seen on individual Hamilton Depression Rating Scale items, with lower anxiety scores at 5 evaluation points for the trazodone group. Clinical Global Impressions ratings also favored trazodone treatment. Anticholinergic effects and tremor were significantly more frequent in imipramine-treated patients, whereas drowsiness was more frequent with trazodone. No significant changes were seen in blood pressure or ophthalmologic exams; 2 trazodone patients and 1 imipramine patient developed slight ECG changes during therapy; these may have been age-related. Continued clinical benefit has been seen in 12 patients who have received open-label trazodone for additional periods of up to 3 years. These findings show trazodone to be clearly effective in long-term treatment of moderate to severe depression; the drug may be of particular benefit when atropine side effects pose serious problems, as in the elderly and patients with cardiovascular disorders.

Ambulatory Care↗
PubMed1989

Quantitative analysis of trazodone hydrochloride in tablets by an ion-selective electrode.

A simple assay procedure for the quantitation of trazodone hydrochloride in tablets, without prior separation, has been developed using a trazodone-selective electrode. The electrode was based on a trazodone:tetrakis(p-chlorophenyl)borate ion-pair complex, dioctyl phthalate, and polyvinyl chloride matrix that were mounted on a PTFE membrane. The electrode showed a near-Nernstian response in the range of 10(-2) to 5 x 10(-6) M trazodone over the pH range of 2.5 to 5.0, with a cationic slope of 58 mV/concentration decade. The durability of the electrode and the reproducibility of the performance among the electrodes were sufficient. The electrode was used for the determination of the pKa value of trazodone. The selectivity of the electrode to a number of interferences was investigated. Many inorganic cations (alkali and alkaline earth metals) and pharmaceutical excipients did not interfere, but some organic ammonium compounds interfered according to their extractability. Determination of 10 to 3000 micrograms/mL of trazodone hydrochloride in aqueous solution showed an average recovery of 100.6% (mean standard deviation 0.4%) by direct potentiometry. This assay was applied to determine trazodone hydrochloride in tablets and the results compared favorably with those obtained by high-performance liquid chromatography.

Chromatography, High Pressure Liquid↗