Trazodone
Encyclopedia
Trazodone is an antidepressant
of the serotonin antagonist and reuptake inhibitor
(SARI) class. It is a phenylpiperazine
compound. Trazodone also has anxiolytic
and hypnotic
effects. Trazodone has considerably less prominent anticholinergic
(dry mouth, constipation
, tachycardia
) and sexual side effect
s than most of the tricyclic antidepressant
s (TCAs).
in the 1960s by Angelini Research Laboratories as a second-generation antidepressant
. It was developed according to the mental pain hypothesis, which was postulated from studying patients and which proposes that major depression is associated with a decreased pain threshold. Trazodone was patented and marketed in many countries all over the world. It was approved by the Food and Drug Administration
(FDA) at the end of 1981.
at all of the following receptor
s except 5-HT1A where it acts as a partial agonist
similarly to buspirone
and tandospirone
but with greater intrinsic activity
in comparison:
It is an inhibitor
of the following transporters as well:
The affinities listed are the mean
s of selected values from the references included.
and depression. Trazodone's inhibitory effects on serotonin reuptake and 5-HT2C receptors are relatively weak (~15-fold lower than for 5-HT2A) and contribute only lightly to its overall effects. Hence, trazodone does not have similar properties to selective serotonin reuptake inhibitor
s (SSRIs) and is not particularly associated with increased appetite
and weight gain
, unlike other 5-HT2C antagonists like mirtazapine
. Moderate 5-HT1A partial agonism (6-fold lower than 5-HT2A) is likely to contribute to trazodone's antidepressant and anxiolytic actions to some extent as well.
Trazodone's potent α1-adrenergic blockade (~3-fold lower relative to 5-HT2A) may cause some side effect
s like orthostatic hypotension
and sedation
. Conversely, along with 5-HT2A antagonism, it may underlie trazodone's efficacy as a hypnotic
. This seems possible as trazodone's antihistamine
activity is relatively weak and probably clinically insignificant; hence, it cannot explain trazodone's sleep-inducing/enhancing effects. Notably, trazodone lacks any affinity for muscarinic acetylcholine receptor
s and therefore does not produce anticholinergic
side effects.
mCPP, a non-selective
serotonin receptor agonist
and serotonin releasing agent
is a common active metabolite
of trazodone, nefazodone
, etoperidone
, and mepiprazole
, and it has been suggested that it may play a role in trazodone's therapeutic benefits. However, scientific research has not supported this hypothesis, and mCPP may actually antagonize trazodone's efficacy as well as produce additional side effects.
, which may contribute to the side effect profile of trazodone. mCPP has been shown to activate numerous serotonin receptors, including 5-HT2C. Due to the short half-life of trazodone, if a dose is taken at night, mCPP would be present in the body during the following day, causing symptoms such as anorexia
(behavioral symptoms), anxiety
, hypolocomotion, headache, and depression
. Approximately 70–75% of 14C-labelled trazodone was found to be excreted in the urine within 72 hours. Trazodone is highly protein-bound.
As a consequence of the production of mCPP as a metabolite, patients administered Trazodone may test positive on Ecstasy EMIT
II urine tests for the presence of MDMA.
, a liver enzyme. Inhibition of this enzyme by various other substances may delay its degradation, leading to high blood levels of trazodone. CYP3A4 may be inhibited by many other medications, herbs, and foods, and as such, trazodone may interact
with these substances. One drug-food interaction is grapefruit juice
. Drinking grapefruit juice is discouraged in patients taking trazodone. One glass of grapefruit juice occasionally is not likely to have this effect on most people, but drinking large amounts, or drinking it regularly is proven to affect trazodone's clearance.
The possibility of suicide
in depressed patients remains during treatment and until significant remission occurs. The number of tablets prescribed at any one time should take into account this possibility, and patients with suicidal ideation
should never have access to large quantities of trazodone.
Trazodone has been reported to cause seizures in a small number of patients who took it concurrently with other anti seizure medications.
While trazodone is not a true member of the SSRI class of antidepressants, it does still share many properties of the SSRIs, especially the possibility of discontinuation syndrome
if the medication is stopped too quickly. Care must therefore be taken when coming off the medication, usually by a gradual process of tapering down the dose over a period of time.
A person who abruptly stops taking trazodone, even in doses as low as 25 mg (common for use as a sleep aid for people with anxiety disorders), may experience adverse mental reactions such as emotional instability, depressed mood, and suicidal thoughts. Although such warnings may be included in printed materials supplied with the drug, physicians prescribing trazodone, particularly those who are not psychiatrists, might not give oral warnings.
, likely due to its antagonism at α-adrenergic receptors. Priapism is a potentially harmful medical condition in which the erect penis does not return to its flaccid state (despite the absence of both physical and psychological stimulation) within four hours. In approximately 33% of the cases reported, surgical intervention was required and, in a portion of these cases, permanent impairment of erectile function or impotence resulted.
In women, a similar condition of persistent arousal can be caused and is called persistent genital arousal disorder.
have been observed, possibly due to the formation of reactive metabolites.
Elevated prolactin
concentrations have been observed in patients taking trazodone.
It has been concluded that Trazodone impairs motor healing in brain-injured rats.
Increased serum digoxin
and phenytoin
levels have been reported to occur in patients receiving trazodone concurrently with either of those two drugs. Little is known about the interaction between trazodone and general anesthetics; therefore, prior to elective surgery, trazodone should be discontinued for as long as clinically feasible.
Because it is not known whether an interaction will occur between trazodone and monoamine oxidase inhibitor
s (MAOI's), administration of trazodone should be initiated very cautiously with gradual increase in dosage as required, if an MAOI is given concomitantly or has been discontinued shortly before medication with trazodone is instituted.
Because of the absence of experience, concurrent administration of electroconvulsive therapy
should be avoided.
may be useful in facilitating elimination of the drug.
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
of the serotonin antagonist and reuptake inhibitor
Serotonin antagonist and reuptake inhibitor
Serotonin antagonist and reuptake inhibitors are a class of drugs used mainly as antidepressants, but also as anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also...
(SARI) class. It is a phenylpiperazine
Phenylpiperazine
1-Phenylpiperazine is a simple chemical compound featuring a phenyl group bound to a piperazine ring. The suffix '-piprazole' is sometimes used in the names of drugs to indicate they belong to this class....
compound. Trazodone also has anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
and hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
effects. Trazodone has considerably less prominent anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
(dry mouth, constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
) and sexual side effect
Sexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
s than most of the tricyclic antidepressant
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s (TCAs).
History
Trazodone was originally discovered and developed in ItalyItaly
Italy , officially the Italian Republic languages]] under the European Charter for Regional or Minority Languages. In each of these, Italy's official name is as follows:;;;;;;;;), is a unitary parliamentary republic in South-Central Europe. To the north it borders France, Switzerland, Austria and...
in the 1960s by Angelini Research Laboratories as a second-generation antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
. It was developed according to the mental pain hypothesis, which was postulated from studying patients and which proposes that major depression is associated with a decreased pain threshold. Trazodone was patented and marketed in many countries all over the world. It was approved by the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) at the end of 1981.
Indications
- Unipolar depression, with or without anxiety
- Bipolar depression, in some circumstances
- InsomniaInsomniaInsomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
(in some countries, this is an off-label useOff-label useOff-label use is the practice of prescribing pharmaceuticals for an unapproved indication or in an unapproved age group, unapproved dose or unapproved form of administration...
) - Control of nightmares or other sleep disturbances
Off-label and investigational uses
- FibromyalgiaFibromyalgiaFibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
- Panic disorderPanic disorderPanic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
- Diabetic neuropathyDiabetic neuropathyDiabetic neuropathies are neuropathic disorders that are associated with diabetes mellitus. These conditions are thought to result from diabetic microvascular injury involving small blood vessels that supply nerves in addition to macrovascular conditions that can culminate in diabetic neuropathy...
- Bulimia nervosaBulimia nervosaBulimia nervosa is an eating disorder characterized by binge eating and purging or consuming a large amount of food in a short amount of time, followed by an attempt to rid oneself of the food consumed, usually by purging and/or by laxative, diuretics or excessive exercise. Bulimia nervosa is...
- Obsessive-compulsive disorderObsessive-compulsive disorderObsessive–compulsive disorder is an anxiety disorder characterized by intrusive thoughts that produce uneasiness, apprehension, fear, or worry, by repetitive behaviors aimed at reducing the associated anxiety, or by a combination of such obsessions and compulsions...
(OCD) - Alcohol withdrawal
- SchizophreniaSchizophreniaSchizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
and other psychosisPsychosisPsychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"... - Complex Regional Pain SyndromeComplex regional pain syndromeComplex regional pain syndrome is a chronic progressive disease characterized by severe pain, swelling and changes in the skin. It often affects an arm or a leg and may spread to another part of the body.Though treatment is often unsatisfactory, early multimodal therapy can cause dramatic...
Binding profile
Trazodone behaves as an antagonistReceptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
at all of the following receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s except 5-HT1A where it acts as a partial agonist
Partial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
similarly to buspirone
Buspirone
Buspirone is an anxiolytic psychoactive drug of the azapirone chemical class, and is primarily used to treat generalized anxiety disorder Bristol-Myers Squibb gained FDA approval of buspirone in 1986 for treatment of GAD...
and tandospirone
Tandospirone
Tandospirone , also known as metanopirone, is an anxiolytic and antidepressant used in China and Japan, where it is marketed by Dainippon Sumitomo Pharma...
but with greater intrinsic activity
Intrinsic activity
Intrinsic activity or efficacy refers to the relative ability of a drug-receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind to its molecular target, and the EC50, which is a measure of the...
in comparison:
- 5-HT1A receptor5-HT1A receptorThe 5-HT1A receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gi/Go and mediates inhibitory neurotransmission...
(Kd = 78 nM) - 5-HT2A receptor5-HT2A receptorThe mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...
(Ki = 13 nM) - 5-HT2C receptor5-HT2C receptorThe 5-HT2C receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gq/G11 and mediates excitatory neurotransmission. HTR2C denotes the human gene encoding for the receptor, that in humans is located at the...
(Ki = 192 nM)
- α1-adrenergic receptorAlpha-1 adrenergic receptorThe alpha-1 adrenergic receptor is a G protein-coupled receptor associated with the Gq heterotrimeric G-protein. It consists of three highly homologous subtypes, including α1A-, α1B-, and α1D-adrenergic...
(Kd = 39 nM) - α2-adrenergic receptorAlpha-2 adrenergic receptorThe alpha-2 adrenergic receptor is a G protein-coupled receptor associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some species other than humans express a fourth α2D-adrenergic receptor as well...
(Kd = 405 nM) - H1 receptorH1 receptorThe H1 receptor is a histamine receptor belonging to the family of Rhodopsin like G-protein-coupled receptors. This receptor, which is activated by the biogenic amine histamine, is expressed throughout the body, to be specific, in smooth muscles, on vascular endothelial cells, in the heart, and in...
(Kd = 725 nM)
It is an inhibitor
Reuptake inhibitor
A reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
of the following transporters as well:
- SERTSerotonin transporterThe serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
(Kd = 160 nM)
The affinities listed are the mean
Arithmetic mean
In mathematics and statistics, the arithmetic mean, often referred to as simply the mean or average when the context is clear, is a method to derive the central tendency of a sample space...
s of selected values from the references included.
Clinical effects
Trazodone acts predominantly as a 5-HT2A receptor antagonist to mediate its therapeutic benefits against anxietyAnxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
and depression. Trazodone's inhibitory effects on serotonin reuptake and 5-HT2C receptors are relatively weak (~15-fold lower than for 5-HT2A) and contribute only lightly to its overall effects. Hence, trazodone does not have similar properties to selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
s (SSRIs) and is not particularly associated with increased appetite
Appetite
The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...
and weight gain
Weight gain
Weight gain is an increase in body weight. This can be either an increase in muscle mass, fat deposits, or excess fluids such as water.-Description:...
, unlike other 5-HT2C antagonists like mirtazapine
Mirtazapine
Mirtazapine is a tetracyclic antidepressant used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications...
. Moderate 5-HT1A partial agonism (6-fold lower than 5-HT2A) is likely to contribute to trazodone's antidepressant and anxiolytic actions to some extent as well.
Trazodone's potent α1-adrenergic blockade (~3-fold lower relative to 5-HT2A) may cause some side effect
Side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequences of the use of a drug.Occasionally, drugs are...
s like orthostatic hypotension
Orthostatic hypotension
Orthostatic hypotension, also known as postural hypotension, orthostasis, and colloquially as head rush or dizzy spell, is a form of hypotension in which a person's blood pressure suddenly falls when the person stands up or stretches. The decrease is typically greater than 20/10 mm Hg, and may be...
and sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
. Conversely, along with 5-HT2A antagonism, it may underlie trazodone's efficacy as a hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
. This seems possible as trazodone's antihistamine
Antihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
activity is relatively weak and probably clinically insignificant; hence, it cannot explain trazodone's sleep-inducing/enhancing effects. Notably, trazodone lacks any affinity for muscarinic acetylcholine receptor
Muscarinic acetylcholine receptor
Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
s and therefore does not produce anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
side effects.
mCPP, a non-selective
Binding selectivity
Binding selectivity refers to the differing affinities with which different ligands bind to a substrate forming a complex. A selectivity coefficient is the equilibrium constant for the reaction of displacement by one ligand of another ligand in a complex with the substrate...
serotonin receptor agonist
Serotonin receptor agonist
A serotonin receptor agonist is a compound that activates serotonin receptors, mimicking the effect of the neurotransmitter serotonin. There are various serotonin receptors and ligands.-5-HT1A receptor:...
and serotonin releasing agent
Serotonin releasing agent
A serotonin releasing agent is a type of drug which induces the release of serotonin from the pre-synaptic neuron into the synapse...
is a common active metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
of trazodone, nefazodone
Nefazodone
Nefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
, etoperidone
Etoperidone
Etoperidone , also known as clopradone and thozalinone, is an antidepressant of the phenylpiperazine class which was introduced in Europe in 1977...
, and mepiprazole
Mepiprazole
Mepiprazole is a minor tranquilizer with a phenylpiperazine structure used in Spain for the treatment of anxiety neuroses. It acts as a 5-HT2A and α1-adrenergic receptor antagonist, and has also been shown to inhibit the reuptake and induce the release of serotonin, dopamine, and norepinephrine to...
, and it has been suggested that it may play a role in trazodone's therapeutic benefits. However, scientific research has not supported this hypothesis, and mCPP may actually antagonize trazodone's efficacy as well as produce additional side effects.
Pharmacokinetics
Trazodone is well absorbed after oral administration with mean peak blood levels obtained at approximately 1 hour after ingestion. Absorption is somewhat delayed and enhanced by food. The mean blood elimination half-life is biphasic: the first phase's half-life is 3–6 hours, and the following phase's half-life is 5–9 hours. The drug is extensively metabolized with 3 or 4 major metabolites having been identified in the human body, particularly mCPP1-(3-Chlorophenyl)piperazine
meta-Chlorophenylpiperazine is a psychoactive drug of the phenylpiperazine class. It was initially developed in the late-1970s and used in scientific research before being sold as a designer drug in the mid-2000s...
, which may contribute to the side effect profile of trazodone. mCPP has been shown to activate numerous serotonin receptors, including 5-HT2C. Due to the short half-life of trazodone, if a dose is taken at night, mCPP would be present in the body during the following day, causing symptoms such as anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
(behavioral symptoms), anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, hypolocomotion, headache, and depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
. Approximately 70–75% of 14C-labelled trazodone was found to be excreted in the urine within 72 hours. Trazodone is highly protein-bound.
As a consequence of the production of mCPP as a metabolite, patients administered Trazodone may test positive on Ecstasy EMIT
Emit
Emit may refer to: melisa*Emit, North Carolina, an unincorporated community*Em:t Records, a British record label that specializes in ambient music...
II urine tests for the presence of MDMA.
Warnings
- If the patient has a known hypersensitivityHypersensitivityHypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
to trazodone - If the patient is under eighteen years of age and combines with other antidepressant medications it may increase the possibility of suicidal thoughts or actions.
Precautions
Trazodone is metabolised by CYP3A4CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
, a liver enzyme. Inhibition of this enzyme by various other substances may delay its degradation, leading to high blood levels of trazodone. CYP3A4 may be inhibited by many other medications, herbs, and foods, and as such, trazodone may interact
Drug interaction
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...
with these substances. One drug-food interaction is grapefruit juice
Grapefruit juice
Grapefruit juice is the fruit juice from grapefruits. It is rich in Vitamin C and ranges from sweet-tart to very sour. It is considered by some cultures to be a mystical tonic which promotes health and vigor. Certain civilizations have had holy men who live on Grapefruit juice alone...
. Drinking grapefruit juice is discouraged in patients taking trazodone. One glass of grapefruit juice occasionally is not likely to have this effect on most people, but drinking large amounts, or drinking it regularly is proven to affect trazodone's clearance.
The possibility of suicide
Suicide
Suicide is the act of intentionally causing one's own death. Suicide is often committed out of despair or attributed to some underlying mental disorder, such as depression, bipolar disorder, schizophrenia, alcoholism, or drug abuse...
in depressed patients remains during treatment and until significant remission occurs. The number of tablets prescribed at any one time should take into account this possibility, and patients with suicidal ideation
Suicidal ideation
Suicidal ideation is a common medical term for thoughts about suicide, which may be as detailed as a formulated plan, without the suicidal act itself. Although most people who undergo suicidal ideation do not commit suicide, some go on to make suicide attempts...
should never have access to large quantities of trazodone.
Trazodone has been reported to cause seizures in a small number of patients who took it concurrently with other anti seizure medications.
While trazodone is not a true member of the SSRI class of antidepressants, it does still share many properties of the SSRIs, especially the possibility of discontinuation syndrome
SSRI discontinuation syndrome
SSRI discontinuation syndrome, also known as SSRI withdrawal syndrome or SSRI cessation syndrome, is a syndrome that can occur following the interruption, dose reduction, or discontinuation of SSRI or SNRI antidepressant medications...
if the medication is stopped too quickly. Care must therefore be taken when coming off the medication, usually by a gradual process of tapering down the dose over a period of time.
A person who abruptly stops taking trazodone, even in doses as low as 25 mg (common for use as a sleep aid for people with anxiety disorders), may experience adverse mental reactions such as emotional instability, depressed mood, and suicidal thoughts. Although such warnings may be included in printed materials supplied with the drug, physicians prescribing trazodone, particularly those who are not psychiatrists, might not give oral warnings.
Pregnancy and lactation
- PregnancyPregnancyPregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
: Sufficient data in humans is lacking. Use should be justified by the severity of the condition to be treated. - LactationLactationLactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, however it predates mammals. In humans the process of feeding milk is called breastfeeding or nursing...
: Sufficient data in humans is also lacking. Additionally, trazodone may be found in the maternal milk in significant concentrations. Women should not breastfeed while taking trazodone.
Side effects
Adverse reactions reported include the following:- Headache or heaviness in head
- Nausea, vomiting, or bad taste in mouth
- Dry mouth
- Stomach pain
- Diarrhea
- Constipation
- Changes in appetite or weight
- Weakness or tiredness
- Nervousness
- Decreased ability to concentrate or remember things
- Confusion
- Nightmares
- Muscle pain
- Sweating
- Blurred vision
- Tired, red, or itchy eyes
- Ringing in ears
Serious side effects
"Some side effects can be serious. If you experience any of the following symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately:"
"IMPORTANT WARNING: ... You should know that your mental health may change in unexpected ways when you take trazodone or other antidepressants even if you are an adult over age 24. You may become suicidal, especially at the beginning of your treatment and any time that your dose is increased or decreased. You, your family, or your caregiver should call your doctor right away if you experience any of the following symptoms: new or worsening depression; thinking about harming or killing yourself, or planning or trying to do so; extreme worry; agitation; panic attacks; difficulty falling asleep or staying asleep; aggressive behavior; irritability; acting without thinking; severe restlessness; and frenzied abnormal excitement."
- Chest pain
- Fast, pounding, or irregular heartbeat
- Shortness of breath
- Fever, sore throat, chills, or other signs of infection
- Hives
- Skin rash
- Itching
- Difficulty breathing or swallowing
- Swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
- Hoarseness
- Decreased coordination
- Uncontrollable shaking of a part of the body
- Numbness, burning, or tingling in the arms, legs, hands, or feet
- Dizziness or lightheadedness
- Fainting
- Painful erection that lasts longer than normal
Cardiac arrhythmia
Recent clinical studies in patients with pre-existing cardiac disease indicate that trazodone may be arrhythmogenic in some patients in that population. Arrhythmia identified include isolated PVC's, ventricular couplets, and in two patients short episodes (three to four beats) of ventricular tachycardia. There have also been several post-marketing reports of arrhythmia in trazodone-treated patients who have pre-existing cardiac disease and in some patients who did not have pre-existing cardiac disease. Until the results of prospective studies are available, patients with pre-existing cardiac disease should be closely monitored, particularly for cardiac arrhythmias. Trazodone is not recommended for use during the initial recovery phase of myocardial infarction.Priapism
Trazodone has been associated with the occurrence of priapismPriapism
Priapism is a potentially harmful and painful medical condition in which the erect penis or clitoris does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours. There are two types of priapism: low-flow and high-flow. Low-flow...
, likely due to its antagonism at α-adrenergic receptors. Priapism is a potentially harmful medical condition in which the erect penis does not return to its flaccid state (despite the absence of both physical and psychological stimulation) within four hours. In approximately 33% of the cases reported, surgical intervention was required and, in a portion of these cases, permanent impairment of erectile function or impotence resulted.
In women, a similar condition of persistent arousal can be caused and is called persistent genital arousal disorder.
Other
Rare cases of idiosyncratic hepatotoxicityHepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
have been observed, possibly due to the formation of reactive metabolites.
Elevated prolactin
Prolactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...
concentrations have been observed in patients taking trazodone.
It has been concluded that Trazodone impairs motor healing in brain-injured rats.
Occupational hazards
Since trazodone may impair the mental and/or physical abilities required for performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned not to engage in such activities while impaired.Laboratory tests
It is recommended that white blood cell and differential counts should be performed in patients who develop sore throat, fever, or other signs of infection or blood dyscrasia and trazodone should be discontinued if the white blood cell or absolute neutrophil count falls below normal.Drug interactions
Trazodone may enhance the effects of alcohol, barbiturates, and other CNS depressants; patients should be cautioned accordingly as trazodone with the combination of another CNS depressant, can result in extreme tiredness and dizziness.Increased serum digoxin
Digoxin
Digoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
and phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
levels have been reported to occur in patients receiving trazodone concurrently with either of those two drugs. Little is known about the interaction between trazodone and general anesthetics; therefore, prior to elective surgery, trazodone should be discontinued for as long as clinically feasible.
Because it is not known whether an interaction will occur between trazodone and monoamine oxidase inhibitor
Monoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
s (MAOI's), administration of trazodone should be initiated very cautiously with gradual increase in dosage as required, if an MAOI is given concomitantly or has been discontinued shortly before medication with trazodone is instituted.
Because of the absence of experience, concurrent administration of electroconvulsive therapy
Electroconvulsive therapy
Electroconvulsive therapy , formerly known as electroshock, is a psychiatric treatment in which seizures are electrically induced in anesthetized patients for therapeutic effect. Its mode of action is unknown...
should be avoided.
Dosage
Trazodone adult and geriatric recommended starting dose is 150 mg once daily, it may be increased by 50 mg every three to four days. The dose may be increased slowly to a maximum of 400 mg daily for outpatients and to 600 mg daily in hospitalized patients. Pediatric initial dose should be 25 – 50 mg and may be increased up to 150 mg if necessary. Adult dosage for sedation and sleep aid is 25 – 50 mg. It is recommended that Trazodone be given in a divided dose. If necessary just a single dose, in the evening, may be given.Symptoms
Overdose of trazodone may cause an increase in incidence or severity of any of the reported adverse reactions, e.g. excessive sedation. Death by deliberate or accidental overdosage has been reported. However, trazodone is often used instead of tricyclic antidepressants because it is very difficult to overdose on. Depressed patients are therefore unlikely to successfully commit suicide with trazodone.Treatment
There is no specific antidote for trazodone. Management of overdosage should, therefore, be symptomatic and supportive. Any person suspected of having taken an overdosage should be evaluated at a hospital as soon as possible. Activated charcoal, gastric lavage, and forced diuresisForced diuresis
Forced diuresis may enhance the excretion of certain drugs in urine and is used to treat drug overdose or poisoning of these drugs and hemorrhagic cystitis.-Diuretics:...
may be useful in facilitating elimination of the drug.
Synthesis
- Palazzo, G.; Silvestrini, B.; 1968, .
- B. Silvestrini, G. Palazzo,