Pharmacodynamics
Trazodone, being a triazolopyridine derivative, has a predominantly antidepressant effect, with some sedative and anxiolytic effects. Trazodone has no effect on MAO, which distinguishes it from MAO inhibitors and tricyclic antidepressants.
Quickly affects mental (affective tension, irritability, fear, insomnia) and somatic symptoms of anxiety (palpitations, headache, muscle pain, frequent urination, sweating, hyperventilation).
Trazodone is effective for sleep disorders in patients with depression, increases the depth and duration of sleep, and restores its physiological structure and quality.
Trazodone stabilizes the emotional state, improves mood, reduces pathological craving for alcohol in patients suffering from chronic alcoholism during the period of alcohol withdrawal syndrome, also in remission. For withdrawal symptoms in patients suffering from dependence on benzodiazepine derivatives, trazodone is effective in the treatment of anxiety, depression and sleep disorders. During remission, benzodiazepines can be completely replaced by trazodone.
The drug is not addictive.
Helps restore libido and potency, both in patients with depression and in people who do not suffer from depression.
The mechanism of action of trazodone is associated with the high affinity of the drug for certain subtypes of serotonin receptors, with which trazodone enters into an antagonistic or agonistic interaction depending on the subtype, as well as with the specific ability to cause inhibition of serotonin reuptake.
The neutral uptake of norepinephrine and dopamine has little effect.
The drug does not affect body weight.
Depression and sleep
Depression (D) has many faces in its clinical manifestations, and along with affective, motor, autonomic, obligate, dyssomnia disorders are present, which makes the problem of sleep disorders one of the most pressing in this disease. The term “dyssomnic” reflects the diversity of these disorders, including both insomnic (85–90%) and hypersomnic (10–15%) manifestations. Statistics on the prevalence of sleep-wake cycle disorders in D ranges from 83% to 100%, which is determined by various methodological possibilities for their assessment; in polysomnographic studies this is always 100%.
This obligatory pattern of sleep-wake cycle disorders in D is based on common neurochemical processes. A special place in this regard is occupied by serotonin, disturbances in the mediation of which, on the one hand, play a crucial role in the genesis of D, and on the other, are of great importance in the organization of delta sleep and in the initiation of the rapid eye movement (REM) phase. This also applies to other biogenic amines, in particular norepinephrine and dopamine, the deficiency of which is important both in the development of depression and in the organization of the sleep-wake cycle. The state of the melatonergic system, which determines both the chronobiology of sleep and chronobiological disorders in D., is also important.
To date, there is no complete understanding of the characteristic features of sleep disorders in various forms of depression, although their great phenomenological diversity has long been pointed out. Sleep changes in endogenous depression are characterized by a reduction in delta sleep, a shortening of the latent period of the rapid eye movement (REM) phase, an increase in the density of rapid eye movements (REM) - one of the main phenomena characterizing FBS, and frequent awakenings. In psychogenic depression, the predominance of sleep disturbances with compensatory prolongation of morning sleep in the structure of insomnia is indicated, while in endogenous depression, frequent nighttime and final early awakenings are more often recorded. Patients D show a decrease in the depth of sleep, an increase in motor activity and frequent awakenings, a pronounced reduction in the 4th stage of sleep, against the background of which there is often an increase in the superficial (1st and 2nd) stages of the slow-wave sleep (SMS) phase. The number of transitions from stage to stage increases, which indicates instability in the functioning of the cerebral mechanisms for maintaining sleep stages. In addition, a characteristic feature was an increase in the number of awakenings in the last third of the night.
The phenomenon of “alpha-delta sleep” described in patients D indicates a significant change in the organization of the deepest stages of FMS. It is a combination of delta waves and high-amplitude alpha rhythm (lower in frequency by 1-2 vibrations than in wakefulness) and takes up to 1/5 of the total sleep time. In this case, the depth of sleep turns out to be greater than in stage 2, which is determined by a higher awakening threshold. It is believed that alpha activity in delta sleep is a reflection of the activity of activating cerebral systems, which do not allow somnogenic systems to fully perform their functions. Disruption of the regular distribution of delta activity, as well as a decrease in the amplitude of the delta rhythm and its power, indicate a relationship between the mechanisms of FMS and depression. The special relationship between D and delta sleep is also indicated by the fact that when leaving D, delta sleep is one of the first to be restored. Subsequently obtained facts showed, however, that delta sleep disturbances in depression are more typical for men and are not specific only to depression. Significant fluctuations in the duration of stage 4 sleep associated with age have been established, in particular its significant reduction in the period of maturity and especially in older people.
In depression, changes in the FBS are observed. According to various data, in patients with depression there is a significant variation in the duration of FBS - from 14% to 31%. The most important indicator reflecting the amount of need for FBS is its latent period (LP). The phenomenon of LA contraction in depression has long attracted the attention of researchers. A reduction in FBS latency was regarded by the authors as a sign of increased activity of the devices generating this phase of sleep, and was associated with an increased need for REM sleep. It has been shown that the more pronounced the depression, the more REM movements are collected into “packs”, between which there are long periods without any oculomotor activity. However, according to other data, there is simply an increase in REM density in the first sleep cycles. There are reports that the reduction of the FBS latency is not to the same extent characteristic of different types of depression - a short latency is characteristic only of all primary depressions and is absent in secondary ones. However, it is not determined in any way by other sleep parameters and does not depend on age and the effect of medications. Perhaps these data indicate desynchronization of circadian ri and their shift to an earlier time of day. It is also possible that the characteristic changes in sleep themselves play a role in the pathogenesis of D. Some authors emphasize the connection between the nature and severity of dreams with quantitative and qualitative changes in FBS in patients with D. However, it is quite possible that a decrease in FBS LP is secondary to to insufficient duration of delta sleep in the first sleep cycle, as mentioned earlier.
Since the discovery by Kupfer and Foster of the association of depression with a reduction in the interval between falling asleep and the first episode of FBS in comparison with healthy controls (
.), the relationship between mental disorders and sleep disorders is the subject of intense scientific research. In recent years, as a result of a large-scale meta-analysis, the following conclusions have been formulated. D is usually accompanied by a number of sleep disturbances in comparison with healthy control subjects: 1) an increase in sleep onset latency; 2)increasing the percentage share of FBS; 3) an increase in the density of the BDG; 4) deterioration in sleep continuity; 5) a decrease in the percentage of delta sleep and 6) a reduction in the latent period of FBS. Although the influence of age, gender, and severity of the depressive episode on sleep disturbances remains to be clarified, distinguishing depressed patients from healthy individuals based on sleep indicators does not present great difficulties. However, as shown in the aforementioned meta-analysis, none of the established sleep disorders can reliably differentiate depression from other mental disorders, such as panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, schizophrenia, severe dementia or borderline personality disorder. Moreover, in polysomnography indicators it is not possible to identify clear differences between the subtypes of depression (primary, endogenous, atypical, etc.). Perhaps the most compelling differences concern the differentiation between psychotic and nonpsychotic depression. A few studies have attempted to take the opposite approach, i.e. group mental disorders or their subtypes based on biological markers, but the results do not support qualitative differences and common specific subtypes; only quantitative differences have been identified that support the concept of the “depressive spectrum.”
Several theories have been formulated to explain changes in sleep in untreated patients with major depressive disorder (MDD), the effects of medications on the sleep of such patients, and the effects of sleep manipulations, including total sleep deprivation or sleep deprivation.
There are a number of issues that are only partially resolved:
Are sleep disorders signs of a biological predisposition?
Do they reflect a depressive disorder and will they disappear after the clinical manifestations of a depressive episode are reduced?
Can effective antidepressants correct sleep disturbances found in untreated patients with MDD?
Can we assume that those sleep disorders that can be corrected in this way are primarily associated with depression?
Do drugs affect depression through sleep disturbances, or are the observed effects merely secondary effects?
Is it possible to predict in advance the effectiveness of this therapy 2 weeks after starting it?
Do they reflect the consequences of previous episodes?
Is it necessary to use sleeping pills or is it sufficient to use antidepressants to treat sleep disorders in patients with D?
The situation with neurotransmitters is no less complicated. For example, serotonin (5-hydroxytryptamine (5-HT)) is a major therapeutic target for depression and is important in sleep disorders. It would seem that selective serotonergic drugs can help clarify the relationship between these phenomena. However, the presence of several types of receptors (5-HT1A-D, 5-HT2A-C, 5-HT3 and 5-HT4), each of which has its own agonists and antagonists, not to mention their potential interactions with gamma-aminobutyric acid (GABA) ), norepinephrine (NA) or dopamine (DA), significantly complicates any scheme. Today, sleep research is an important part of the development of new psychotropic drugs, and almost every new drug is carefully studied for its effect on sleep.
Persistent insomnia is associated with a multiple-fold increased risk of developing MDD within 1–3 years, as well as an increased risk of recurrent depressive episode. Mood disorders have a high prevalence but often go unrecognized in people with chronic sleep disorders. Accordingly, today the development of optimal therapy for insomnia is becoming one of the most important health problems in industrialized countries. Because psychotropic medications can improve or impair sleep onset and sleep continuity, there is a need to consider insomnia in the development and selection of antidepressants. It is also known that antidepressants can provoke restless legs syndrome or periodic limb movements syndrome, which leads to worsening insomnia.
The effect of antidepressants on sleep
Monoamine oxidase inhibitors. Phenelzine, a monoamine oxidase inhibitor (MAOI), is able to almost completely suppress FBS after several weeks of therapy in both healthy individuals and patients with MDD. Other MAOIs, such as nialamide, pargylene, and mebanazine, have similar effects on sleep. This suppression of FBS coincides with the onset of the antidepressant effect, suggesting a physiological link between the suppression of FBS and the antidepressant effect. In most cases, MAOIs do not have a particularly pronounced effect on MBS, although these antidepressants are thought to reduce sleep efficiency.
The reversible MAOI moclobemide has polar effects: one study showed that its use increased sleep efficiency and shortened the latency period of FBS in patients with MDD; another study found almost completely the opposite results.
Tricyclic antidepressants . Tricyclic antidepressants (TCAs) differ from MAOIs in their ability to suppress FBS, since when using TCAs, suppression of FBS is observed immediately after the start of taking these drugs. Thus, clomipramine significantly suppresses FBS in control subjects. Imipramine and desipramine also have a significant suppressive effect on FBS, at least in healthy control subjects and animals. However, the effect of TCAs on FBS appears to be less consistent than the effect of MAOIs: long-term studies have documented normal and even elevated levels of FBS. One study in a group of patients with depression revealed an inhibitory effect of amitriptyline on FBS. After discontinuation of TCAs, the phenomenon of PBS rebound is often observed. It is interesting to note that not all TCAs have an inhibitory effect on FBS. For example, trimipramine, iprindole and viloxazine do not have a significant effect on FBS. As a group as a whole, TCAs increase the amount of delta sleep, with the exception of clomipramine. One study of clomipramine in a group of patients with MDD using spectral analysis showed a significant increase in delta waves corresponding to delta sleep. The use of desipramine in patients with MDD has been associated with difficulty falling asleep.
Tetracyclic antidepressants. Mianserin did not affect the duration of FBS in healthy control subjects and patients with MDD. Maprotiline suppresses FBS and increases the amount of stage 2 sleep in healthy control subjects. Both antidepressants can increase delta sleep rates.
Selective serotonin reuptake inhibitors . The selective serotonin reuptake inhibitor (SSRI) fluvoxamine suppresses FBS and increases latency in patients with MDD, but has no significant effect on delta sleep or delta waves as measured by spectral analysis. Paroxetine reduces total sleep time and reduces sleep efficiency in patients with MDD by decreasing FBS and increasing latency. In patients with MDD, the use of fluoxetine is accompanied by an increase in the frequency of awakenings, a decrease in sleep efficiency and a decrease in delta sleep, as well as an increase in the latency period and a reduction in FBS. Treatment of patients with MDD with sertraline is associated with an increase in sleep latency and a reduction in the duration of FBS. Citalopram persistently suppresses FBS, which is combined with the phenomenon of FBS rebound after drug withdrawal. According to spectral analysis, citalopram has no effect on delta waves. Trazodone at a dose of 100–150 mg/day suppresses FBS and increases delta sleep, and also improves subjective ratings of sleep quality, as shown in a group of middle-aged patients with insomnia. In high doses (400–600 mg/day), treatment with trazodone in patients with MDD is accompanied by an increase in total sleep time and delta sleep, but without significant changes in FBS and its latency. Nefazodone reduces arousals and increases sleep efficiency, and stabilizes or even increases FBS time in healthy subjects and patients with MDD; At the same time, a reduction in delta sleep was noted. SSRIs may cause periodic limb movement syndrome.
Serotonin and norepinephrine reuptake inhibitors. The serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine increases wake time and stages 1, 2, and 3 sleep in healthy subjects. There is a pronounced suppression of FBS and an increase in its latent period.
The noradrenergic and specific serotonergic antidepressant (NASSA) mirtazapine improves sleep in healthy subjects. Mirtazapine reduces the time it takes to fall asleep and increases the depth of sleep. There is also an increase in the latent period of FBS and a reduction in night awakenings. In patients with MDD, the use of mirtazapine improves sleep efficiency and increases total sleep time, while no effect on FBS was detected.
Other antidepressants . A study in young healthy subjects found no evidence of an effect of tianeptine at therapeutic doses (37.5 mg/day) on electroencephalographic (EEG) sleep parameters. Tianeptine has been shown to suppress FBS in healthy subjects and patients with comorbid depression and alcoholism. The same study showed improvement in sleep with tianeptine, as assessed by the Leeds Sleep Questionnaire.
Melatonin and melatonergic antidepressants . Almost all studies have identified certain hypnotic effects of melatonin and, first of all, acceleration of falling asleep. Regarding the antidepressant capabilities of melatonin, there are directly opposite points of view - from complete denial to confident confirmation. Without going into controversy, we emphasize that this new knowledge contributed to the creation of an absolutely new antidepressant in ideology and neurochemistry - agomelatine, which is an agonist of cerebral melatonin receptors of the 1st and 2nd subtypes (primarily in the suprachiasmatic nucleus) and an antagonist of 5-HT2C serotonin receptors. The uniqueness of this antidepressant lies in the fact that its hypnotic effect is not associated with the effect of sedation and occurs already on the 14th day. Of course, like any new pharmacological product, it requires further research, but theoretically its combined antidepressant and hypnotic effects seem to be very significant.
Possibility of using polysomnography to predict the effectiveness of antidepressants
By now, the significance of several such predictors can be debated.
- A short latency period of FBS before the start of therapy (baseline characteristic) correlates with a positive effect.
- For future responders, spectral analysis of electroencephalography (EEG) is characterized by high power of delta waves and low power of alpha, beta and theta waves throughout the night before the start of therapy.
- High REM density before therapy is associated with a poor prognosis, so it is important how quickly REM activity is suppressed during the initial period of therapy. Suppression of REM in the first two nights after starting TCAs has been shown to be associated with a high therapeutic effect. These data have not been confirmed in studies of SSRIs.
Despite their clear value, such prognostic strategies are rarely used in clinical practice.
Conclusion
A number of arguments have been put forward to support the hypothesis of a close connection between sleep dysregulation and the basic factors of depressive disorders:
- almost all patients suffer from sleep disorders (insomnia or hypersomnia);
- patients with chronic insomnia as a monosymptom are characterized by an increased risk of manifestation or relapse of depression;
- For the most part, pharmacological drugs effective for depression affect sleep, usually correcting the initial sleep disturbances in patients;
- Sleep deprivation is an effective therapy that provides relief from depressive symptoms in 50% of cases, although this effect is short-lived.
Most antidepressants suppress FBS quite quickly (TCAs, SSRIs, SNRIs and HASSA) or approximately 2 weeks (MAOIs) after initiation of therapy. However, there are a number of exceptions (trimipramine, iprindole, tianeptine, viloxazine, nefazodone). Sleep depth may increase (agomelatine, trazodone, nefazodone, mirtazapine), remain unchanged (most MAOIs, fluvoxamine), or decrease (clomipramine, desipramine, phenelzine, fluoxetine, paroxetine, sertraline, venlafaxine). The effects of long-term use of antidepressants are, in principle, poorly studied, although a tendency towards a gradual reduction of the initial effects has been found.
Here are some theories that help explain some facts.
The first theory is based on Borbely's general model of sleep regulation, in which the "S" process represents the delta wave EEG of sleep corresponding to deep sleep (roughly corresponding to stages 3 and 4 in hypnograms for visual assessment). One hypothesis is that depression leads to a decrease in slow wave sleep (SWS) or delta wave spectral power, which in turn frees up space for REM and stimulates a more rapid onset of REM at night with increased REM and decreased latency. One approach to confirm this hypothesis involves measuring the sleep EEG spectral power response in response to antidepressant therapy. A study using spectral analysis was performed in which a comparative assessment of the effects of trazodone and citalopram in patients with MDD was carried out. The aim of the study was to look for parallels between potential changes and timing of clinical improvement. This study shows that delta waves do not change significantly during the first 5 weeks of therapy, and the timing of changes in other waveforms does not correlate with clinical changes in patients' condition. Moreover, antidepressants varied significantly in their effect on sleep continuity, ranging from worse to better. Accordingly, the role of MVS restoration remains unclear.
The second theory is FBS pressure. It has been shown that almost all drugs that cause a pronounced and persistent reduction in the time of FBS and are characterized by the phenomenon of rebound of FBS after their withdrawal are effective means of treating endogenous depression. Antidepressant therapy, as well as sleep deprivation (partial, FBS-specific or complete), electroconvulsive therapy or psychotherapy act in parallel with the improvement or through the correction of pathological sleep disorders in patients with depression. It has been established that during depression, LP decreases and, regardless of the mechanism underlying this phenomenon, it must be increased; the percentage of FBS, on the contrary, increases with depression, so it should be reduced. However, it is obvious that the general rule for an effective antidepressant—reduction of FBS and increase in LP—has many exceptions. Therefore, it can be assumed that either more than one mechanism is involved and only some antidepressants are consistent with this rule, or changes in sleep parameters during antidepressant therapy are only indirectly related to their effectiveness against depression.
Although it is likely that sleep and its underlying neurophysiological mechanisms are closely related to the mechanisms of depression, these disorders do not appear to be identical, and we cannot argue that successful treatment of depression necessarily requires correction of sleep disturbances. At the same time, sleep cannot be considered as simply a concomitant phenomenon; this is contradicted by the frequent association of depression with sleep disturbances, changes in sleep structure, and modifications in sleep parameters during antidepressant therapy. However, sleep disturbances may not be a necessary component in the development of depression.
Thus, disturbances of the sleep-wake cycle in depression are diverse and include insomnia and hypersomnia. The “purer” the depression, the more likely it is to identify fairly characteristic changes in the structure of night sleep. Of great interest are not only the antidepressant effects, but also some non-pharmacological techniques that act on the depressive radical - sleep deprivation and phototherapy, which have proven to be quite effective and safe. The discovery of the commonality of some biochemical mechanisms of depression, sleep disorders and circadian rhythms further increases interest in this problem, especially since this opens up the possibility of new integrated approaches to the treatment of sleep disorders in depression.
Ya. I. Levin , Doctor of Medical Sciences, Professor of MMA named after. I. M. Sechenova, Moscow
Pharmacokinetics
Absorption of the drug from the gastrointestinal tract after oral administration is high. Taking trazodone during or immediately after a meal slows the rate of absorption, reduces Cmax of the drug in blood plasma and increases Tmax. Tmax of the drug is achieved 1/2–2 hours after oral administration.
The drug penetrates histohematic barriers, as well as into tissues and fluids (bile, saliva, breast milk).
Plasma protein binding is 89–95%.
Trazodone is metabolized in the liver, the active metabolite is 1-m-chlorophenylpiperazine. T1/2 in the first phase is 3-6 hours, in the second phase - 5-9 hours. The majority of the metabolized drug is excreted through the kidneys, in the urine (about 75%) and is completely completed 98 hours after taking the drug, excreted in the bile about 20%.
In vitro studies on human microsomes have shown that trazodone is primarily metabolized by cytochrome P450 CYP3A4.
Indications for the drug Trittico
anxiety-depressive states of endogenous nature (including involutional depression);
psychogenic depression (including reactive and neurotic depression);
anxiety-depressive states against the background of organic diseases of the central nervous system (dementia, Alzheimer's disease, cerebral atherosclerosis);
depressive states with prolonged pain syndrome;
alcoholic depression;
benzodiazepine dependence;
libido and potency disorders (including erectile dysfunction in depressive conditions).
Contraindications
hypersensitivity to the drug;
pregnancy period;
lactation period;
children under 6 years of age.
The drug should be prescribed with caution to patients with AV block, myocardial infarction (early recovery period), arterial hypertension (dose adjustment of antihypertensive drugs may be required), ventricular arrhythmia, a history of priapism, renal and/or liver failure. Patients under the age of 18 years, due to the possibility of developing the risk of suicidal behavior (suicidal plans, aggressiveness, tendency to contradict, anger).
Side effects
From the side of the central nervous system: increased fatigue, drowsiness, agitation, headache, dizziness, weakness, myalgia, incoordination, paresthesia, disorientation, tremor.
From the cardiovascular system and hematopoietic system: decreased blood pressure, orthostatic hypotension caused by adrenolytic action (especially in persons with vasomotor lability), arrhythmia, conduction disturbances, bradycardia; leukopenia and neutropenia (usually minor)..
From the gastrointestinal tract: dryness and bitterness in the mouth, nausea, vomiting, diarrhea, loss of appetite.
Other: allergic reactions, eye irritation, priapism (you should immediately stop taking the drug and consult a doctor).
Trittico in Dubna
Cases of suicidal ideation and suicidal behavior have been reported during trazodone therapy or in the early period after completion of therapy. The following symptoms, some of which have also been reported in cases of untreated depression, have been reported in patients taking trazodone. Organ System Class (MedDRA): Frequency unknown (frequency cannot be determined from available data) Blood and lymphatic system disorders: Agranulocytosis, thrombocytopenia, eosinophilia, leukopenia, anemia Immune system disorders: Allergic reactions Endocrine system disorders: Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) Metabolic and nutritional disorders: Hyponatremia, weight loss, anorexia, increased appetite Mental disorders: Suicidal thoughts or behavior, confusion, insomnia, disorientation, mania, anxiety, nervousness, agitation ( very rarely worsening to delirium attacks), delirium, aggressive reaction, hallucinations, nightmares, decreased libido, withdrawal syndrome Nervous system disorders: Serotonin syndrome, convulsions, neuroleptic malignant syndrome, dizziness, vertigo, headache, drowsiness, anxiety, decreased vigilance, tremor, visual impairment, memory impairment, myoclonic seizures, severe aphasia, paresthesia, dystonia, change in taste Cardiac disorders: Cardiac arrhythmia (including polymorphic ventricular tachycardia), palpitations, premature ventricular contraction, two consecutive sets of premature ventricular contractions, ventricular tachycardia, bradycardia, tachycardia, prolongation of the QT interval Vascular disorders: Orthostatic hypotension, arterial hypertension, syncope Disorders of the respiratory system, chest and mediastinal organs: Nasal congestion, shortness of breath Gastrointestinal disorders: Nausea, vomiting, dry mouth, constipation, diarrhea, dyspepsia, abdominal pain, gastroenteritis, increased salivation, paralytic ileus Liver and biliary disorders: Liver dysfunction (including jaundice and liver cell damage), intrahepatic cholestasis Skin and subcutaneous disorders tissues: Skin rash, itching, hyperhidrosis Musculoskeletal and connective tissue disorders: Pain in the limbs, back pain, myalgia, arthralgia Renal and urinary tract disorders: Urinary disorders Genital and breast disorders: Priapism6 General disorders and disorders at the injection site: Weakness, swelling, flu-like symptoms, fatigue, chest pain, fever Laboratory and instrumental findings: Elevated levels of liver enzymes
Interaction
Trazodone may enhance the effect of some antihypertensive drugs and usually requires a dose reduction.
Simultaneous administration with drugs that depress the central nervous system (including clonidine, methyldopa) enhances the effect of the latter.
Antihistamines and drugs with anticholinergic activity enhance the anticholinergic effect of trazodone.
Trazodone enhances and prolongs the sedative and anticholinergic effects of tricyclic antidepressants, haloperidol, loxapine, maprotiline, phenothiazine, pimozidane and thioxanthine.
When tricyclic antidepressants and trazodone are prescribed simultaneously, cardiovascular side effects may occur.
MAO inhibitors increase the risk of side effects.
When used together, it increases the concentration of digoxin and phenytoin in the blood plasma.
In vitro drug metabolism studies indicate the potential for pharmacological interaction of trazodone with cytochrome P450 CYP3A4 inhibitors such as ketoconazole, ritonavir, indinavir and fluoxetine. Inhibitors of CYP3A4 may lead to significant increases in plasma concentrations of trazodone, thereby increasing the likelihood of adverse events. Therefore, when used in combination with potent CYP3A4 inhibitors, the dose of trazodone should be reduced.
When trazodone is taken in combination with carbamazepine, the plasma concentration of trazodone is reduced. Therefore, patients taking trazodone and carbamazepine concomitantly should be closely monitored.
Trittico 150 mg 20 pcs. tablets aziende chimiche riunite angelini france
pharmachologic effect
Antidepressant.
Composition and release form Trittiko 150 mg 20 pcs. tablets aziende chimiche riunite angelini france
Tablets - 1 tablet:
- Active ingredient: trazodone hydrochloride 150.0 mg;
- Excipients: sucrose 84.0 mg; carnauba wax 24.0 mg; povidone 24.0 mg; magnesium stearate 6.0 mg.
10 tablets in a PVC/aluminum foil blister.
2 or 6 blisters along with instructions for use in a cardboard box.
Description of the dosage form
Biconvex tablets, white or white with a yellowish tint, oval in color with two parallel lines on both sides.
Characteristic
Triazolopyridine derivative.
Directions for use and doses
Tablets should be taken orally 30 minutes before meals or 2 to 4 hours after meals. The tablets should be taken whole, without chewing, and with plenty of water.
Initial dose of the drug: 100 mg, taken once before bed after meals. On the 4th day you can increase the dose to 150 mg. Further increases in the dose in order to achieve the optimal therapeutic effect should be made by 50 mg/day every 3-4 days until the optimal dose is reached. A daily dose of more than 150 mg should be divided into 2 doses, with the smaller dose taken after lunch and the main dose before bed.
The maximum daily dose for outpatients is 450 mg.
Maximum daily dose for inpatients. 600 mg.
For elderly and debilitated patients, the initial dose is up to 100 mg/day in divided doses or once before bedtime. It can be increased under medical supervision, depending on the effectiveness and tolerability of the drug. A dose exceeding 300 mg/day is usually not required.
Pharmacodynamics
Pharmacodynamics: trazodone inhibits neuronal reuptake of serotonin, is an antagonist of 5-HT2A/2c-serotonin receptors and an α1-adrenergic receptor blocker and has an antidepressant effect.
Pharmacokinetics
Absorption of trazodone from the gastrointestinal tract after oral administration is high. Taking trazodone during or immediately after a meal slows the rate of absorption, reduces the maximum plasma concentration of trazodone, and increases the time to reach maximum concentration (TCmax).
TCmax is achieved 1/2-2 hours after oral administration.
Trazodone penetrates through histohematic barriers into tissues and fluids (bile, saliva, breast milk).
Communication with plasma proteins is 89 - 95%.
Trazodone is metabolized in the liver, the active metabolite is 1-m-chlorophenylpiperazine. The half-life is 3-6 hours, in the second phase 5-9 hours. Elimination of most of the metabolized trazodone is carried out by the kidneys with urine - about 75%, and is completely completed 98 hours after administration; About 20% is administered with bile. In vitro studies on human microsomes have shown that trazodone is primarily metabolized by the cytochrome P450 isoenzyme (CYP3A4 isoenzyme).
Indications for use Trittico 150 mg 20 pcs. tablets aziende chimiche riunite angelini france
Depression with or without anxiety.
Contraindications
- Hypersensitivity to the active substance or any excipient;
- pregnancy period;
- lactation period;
- alcohol intoxication and intoxication with sleeping pills;
- The safety of trazodone for children under 18 years of age has not been established, therefore the use of the drug in children and adolescents is not recommended;
- sucrase/isomaltase deficiency, fructose intolerance, glucose-galactose malabsorption, since the drug contains sucrose.
With caution: the drug should be prescribed with caution to patients with AV block, myocardial infarction (early recovery period), arterial hypertension (dose adjustment of antihypertensive drugs may be required), ventricular arrhythmia, a history of priapism, and renal and/or liver failure.
Application of Trittico 150 mg 20 pcs. tablets aziende chimiche riunite angelini france during pregnancy and breastfeeding
The drug is not recommended for use by pregnant women. The drug is not recommended for use during breastfeeding.
special instructions
Suicide/suicidal ideation or worsening clinical symptoms: Depressive conditions have an increased risk of suicidal ideation, self-harm, or suicide. The risk may last until significant remission occurs. Since improvement may not occur for the first few weeks of treatment or more, patients should be closely monitored until such improvement occurs. It is common clinical experience that the risk of suicide may increase in the early stages of recovery. It is known that patients with a history of suicidal events, or patients who exhibit a significant degree of suicidal ideation even before treatment, have a higher risk of suicidal ideation or suicide attempts, and should be closely monitored during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants used in adults with mental disorders showed an increased risk of suicidal behavior in patients under 24 years of age when taking antidepressants compared with placebo. Careful monitoring of patients, especially those at high risk, should accompany drug therapy, especially in its early stages and after dose changes. Patients (and their caregivers) should be warned to monitor for any clinical deterioration, suicidal behavior or thoughts, or unusual changes in behavior, and to immediately seek professional advice if such symptoms occur.
Since the drug has some adrenergic blocking activity, bradycardia and a decrease in blood pressure may develop. Therefore, caution should be exercised when prescribing the drug to patients with a tendency to prolong the QT interval, atrioventricular block of varying severity, and patients with a recent myocardial infarction. When treated with trazodone in patients with bipolar disorder, depressive episodes can range from manic depression to manic psychosis. In these cases, it is necessary to interrupt treatment.
If you have epilepsy, use trazodone with caution, in particular avoiding sudden increases or decreases in dose. With simultaneous use of trazodone with drugs with serotonergic activity (tricyclic antidepressants, selective serotonin reuptake inhibitors, norepinephrine and serotonin reuptake inhibitors and monoamine oxidase inhibitors) and antipsychotics, serotonin syndrome may occur. When trazodone is used simultaneously with drugs containing St. John's wort, side effects may be more frequent.
When using trazodone, agranulocytosis may develop, so it is recommended to conduct peripheral blood tests, especially if there is a sore throat when swallowing and fever.
Trazodone is effective for sleep disorders in patients with depression, increases the depth and duration of sleep, and restores its physiological structure and quality. The use of the drug does not affect body weight.
The drug is not addictive.
Impact on the ability to drive vehicles and operate machinery
During the period of use of the drug Tritgiko, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.
Overdose
Symptoms: drowsiness, dizziness, nausea, vomiting. In more severe cases, coma, tachycardia, hypotension, hyponatremia, seizures and respiratory failure. Impaired function of the cardiovascular system (prolongation of the QT interval, bradycardia). After an overdose, symptoms may take 24 hours or more to appear.
Treatment: There is no specific antidote for trazodone. In cases of overdose, gastric lavage and administration of activated charcoal are necessary within 1 hour after taking the overdose. Symptomatic and supportive treatment is carried out.
Side effects Trittico 150 mg 20 pcs. tablets aziende chimiche riunite angelini france
Trittico may cause side effects, although not all patients experience them.
From the blood and lymphatic system: agranulocytosis, thrombocytopenia, eosinophilia, leukopenia and anemia.
From the immune system: allergic reactions.
From the endocrine system: syndrome of inappropriate secretion of antidiuretic hormone (SNA ADH).
Mental disorders: suicidal thoughts or behavior, confusion, mania, phobias, emotional instability, delirium, hallucinations.
From the nervous system: epileptic seizures, dizziness, headache, insomnia or drowsiness, amnesia, tremor, convulsions, paresthesia, impaired taste.
From the cardiovascular system: palpitations, tachycardia, bradycardia, ventricular extrasystoles, ventricular paroxysmal tachycardia, prolongation of the QT interval, increased blood pressure (BP), decreased blood pressure, fainting.
From the gastrointestinal tract: nausea, vomiting, dry mouth, dyspepsia; abdominal pain, diarrhea, increased salivation, paralytic ileus.
From the skin and subcutaneous tissues: itching, erythematous rash, sweating.
Musculoskeletal and connective tissue disorders: myalgia, arthralgia.
From the kidneys and urinary tract: urinary disorders.
On the part of the genital organs and breast: priapism (patients who experience this side effect should immediately stop taking the drug and consult a doctor).
Other: increased fatigue, weakness, increased body temperature, flu-like syndrome.
Drug interactions
Trazodone may enhance the effect of some antihypertensive drugs and usually requires a dose reduction.
Simultaneous use with drugs that depress the central nervous system (including clonidine, methyldopa) enhances the effect of the latter.
H1-histamine receptor blockers and drugs with m-anticholinergic activity enhance the m-anticholinergic effect of trazodone.
Trazodone enhances and prolongs the sedative and m-anticholinergic effects of tricyclic antidepressants, haloperidol, loxapine, maprotiline, phenothiazine, pimozidan and thioxanthine.
With the simultaneous use of tricyclic antidepressants and trazodone, cardiovascular side effects may occur.
MAO inhibitors increase the risk of side effects.
When used together, it increases the concentration of digoxin and phenytoin in the blood plasma.
In vitro drug metabolism studies indicate the possibility of pharmacological interaction of trazodone with inhibitors of the cytochrome P450 isoenzyme (CYP3A4 isoenzyme), such as ketoconazole, ritonavir, indinavir and fluoxetine. Inhibitors of the CYP3A4 isoenzyme may lead to a significant increase in plasma concentrations of trazodone, thereby increasing the likelihood of adverse events. Therefore, when taken in combination with potent inhibitors of the CYP3A4 isoenzyme, the dose of trazodone should be reduced. When trazodone is taken in combination with carbamazepine, the plasma concentration of trazodone is reduced. Therefore, patients taking trazodone and carbamazepine concomitantly should be closely monitored.
Directions for use and doses
Orally, 30 minutes before or 2–4 hours after meals. The tablets should be taken whole, without chewing and with plenty of water.
The initial dose is 50–100 mg, once before bedtime. On the 4th day it is possible to increase the dose to 150 mg. Further increases in dosage should be made by 50 mg/day every 3–4 days until the optimal dose is reached. A daily dose of more than 150 mg should be divided into 2 doses, with the smaller dose taken after lunch and the main dose before bed.
The maximum daily dose for outpatients is 450 mg, for inpatients - 600 mg.
Children 6–18 years old: initial daily dose of 1.5–2 mg/kg/day, divided into several doses. If necessary, the dose is gradually (with an interval of 3-4 days) increased to 6 mg/kg/day.
Elderly and debilitated patients: initial dose up to 100 mg/day in several doses or once before bedtime. If necessary, the dose can be increased (usually no more than 300 mg/day).
Treatment of libido disorders: recommended daily dose of 50 mg.
Treatment of erectile dysfunction: monotherapy - recommended daily dose - 150-200 mg, combination therapy - 50 mg.
Treatment of benzodiazepine dependence: The recommended treatment regimen is based on a gradual, sometimes over several months, reduction of the benzodiazepine dose. Each time, reducing the benzodiazepine dose by 1/4 or 1/2 tablet, 50 mg of trazodone is added at the same time. This ratio is left unchanged for 3 weeks, then a further gradual reduction in the dose of benzodiazepines is started until their complete withdrawal. After this, reduce the daily dose of trazodone by 50 mg every 3 weeks.
special instructions
Since the drug has some adrenolytic activity, bradycardia and a decrease in blood pressure may develop. Therefore, caution should be exercised when prescribing the drug to patients with cardiac conduction disorders, AV block of varying severity, or recent myocardial infarction. When using trazodone, a slight decrease in the number of leukocytes is possible, which does not require specific treatment, except in cases of severe leukopenia. Therefore, it is recommended to conduct peripheral blood tests, especially if there is a sore throat when swallowing and fever.
The drug does not have an anticholinergic effect, so it can be prescribed to elderly patients suffering from prostatic hypertrophy, angle-closure glaucoma, and cognitive impairment.
If you experience prolonged and inadequate erections, you should consult a doctor.
There have been no relevant studies on the effectiveness of the drug in pediatrics, so the drug should be used with caution in persons under 18 years of age. Doses for children under 6 years of age have not been established.
During treatment you should refrain from drinking alcohol.
Influence on the ability to drive vehicles and machinery. Since the drug has anxiolytic and sedative activity, a decrease in attention and reaction speed is possible. During treatment, you should refrain from engaging in potentially hazardous activities that require concentration and rapid psychomotor reactions.
Trittico
Use during pregnancy and breastfeeding
The drug is contraindicated for use during pregnancy and lactation (breastfeeding).
Use for liver dysfunction
The drug should be prescribed with caution to patients with liver failure.
Use for renal impairment
The drug should be prescribed with caution to patients with renal failure.
Use in children
The use of the drug in children and adolescents under 18 years of age is contraindicated (the safety of trazodone for children has not been established).
Use in elderly patients
For elderly and debilitated patients, the initial dose is up to 100 mg/day in fractional doses or 1 time/day before bedtime. The dose may be increased under medical supervision, depending on the effectiveness and tolerability of the drug. Usually no dose exceeding 300 mg/day is required.
special instructions
People with depression have an increased risk of suicidal thoughts, self-harm, or suicide. The risk may last until significant remission occurs. Since improvement may not occur for the first few weeks of treatment or more, patients should be closely monitored until such improvement occurs. It is common clinical experience that the risk of suicide may increase in the early stages of recovery. It is known that patients with a history of suicidal events, or patients who exhibit a significant degree of suicidal ideation even before treatment, have a higher risk of suicidal ideation or suicide attempts, and should be closely monitored during treatment. The results of a meta-analysis of placebo-controlled clinical trials of antidepressants used in adults with mental disorders showed an increased risk of suicidal behavior in patients under the age of 24 years while taking antidepressants compared with placebo. Careful monitoring of patients, especially those at high risk, should accompany drug therapy, especially in its early stages and after dose changes. Patients (and their caregivers) should be warned to monitor for any clinical deterioration, suicidal behavior or thoughts, or unusual changes in behavior, and to immediately seek professional advice if such symptoms occur.
Since the drug has some adrenergic blocking activity, bradycardia and a decrease in blood pressure may develop. Therefore, caution should be exercised when prescribing the drug to patients with a tendency to prolong the QT interval, AV block of varying severity, and patients with a recent myocardial infarction.
When treated with trazodone in patients with bipolar disorder, depressive episodes can range from manic-depressive to manic psychosis. In these cases, it is necessary to interrupt treatment.
If you have epilepsy, use trazodone with caution, in particular avoiding sudden increases or decreases in dose.
With simultaneous use of trazodone with drugs that have serotonergic activity (tricyclic antidepressants, selective serotonin reuptake inhibitors, norepinephrine and serotonin reuptake inhibitors and MAO inhibitors) and antipsychotics, serotonin syndrome may occur.
When trazodone is used simultaneously with drugs containing St. John's wort, side effects may be more frequent.
When using trazodone, agranulocytosis may develop, so it is recommended to conduct peripheral blood tests, especially if there is a sore throat when swallowing and fever.
Trazodone is effective for sleep disorders in patients with depression, increases the depth and duration of sleep, and restores its physiological structure and quality.
The use of the drug does not affect body weight.
The drug is not addictive.
Impact on the ability to drive vehicles and operate machinery
During the period of use of the drug, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.
