Tricyclic antidepressants

Tricyclic Antidepressants (TCAs)

Tricyclic antidepressants

Developed in the 1950s, tricyclic antidepressants, or TCAs, have a strong history of anxiety and depression treatment. The name “tricyclic” comes from the atomic structure of these medications, which consists of three molecular ring shapes.

TCAs were first developed when scientists began working on a series of compounds to improve antihistamines, sedatives, analgesics, and anti-Parkinson’s drugs. Imipramine, the first tricyclic antidepressant developed in the late ‘50s, showed positive effects when it was first tested on a group of participants diagnosed with depressive psychosis.

Modifications to TCA formulas led to the discovery of selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs).  

Commonly Prescribed TCAs

Until 1988, TCAs were commonly prescribed by physicians. However, with the discovery of many SSRIs, TCAs lost their significance due to a harsher profile of side effects. Today, many TCAs are used when other prescription antidepressant medications fail to produce positive treatment results. The TCAs most commonly prescribed today include:

Conditions Treated with TCAs

TCAs may be used in the treatment of a variety of conditions including, but not limited to:

Norpramin (desipramine), Aventyl (nortriptyline), Tofranil (imipramine), and Silenor (doxepin) are among the tricyclic drugs approved to treat depression. Research shows that newer antidepressant medications are no more effective at treating depression than the older tricyclics. However, tricyclics have much more pronounced and unpredictable side effects than many newer medications.

Tricyclic antidepressants have received new interest by some physicians for their potential to alleviate conditions involving chronic pain. For the treatment of a chronic condition, such as diabetic neuropathy, doctors usually prescribe a lower dose of these medications. Lower dosages help prevent many of the unwanted side effects of tricyclic antidepressants.

Mechanism of Action of TCAs

TCAs increase the quantity of neurotransmitters, such as serotonin and norepinephrine, in the central nervous system. They block specific serotonin (SERT or 5-HTT) and norepinephrine transporters (NET).

When affected, these transporters cannot play their part in the reuptake of neurotransmitters, which increases the concentration and ultimately has an effect on mood. Some TCAs bind with SERT and some bind with NET.

Clomipramine, for example, is a potent binder of SERT, but it is a weak binder of NET. Desipramine, on the other hand, is a strong binder of NET.

Additionally, it should be noted that antidepressant medications, when used for anxiety, depression, or other mental health issues, tend to be more effective when combined with some type of therapy.

Medication can help treat symptoms of mental health conditions, but pills do not address the underlying emotions, behaviors, and root causes of mental health issues.

If you are prescribed an antidepressant or other psychotropic medication, consider finding a qualified therapist to better understand and help treat your condition.

Side Effects and Adverse Drug Reactions

The potential side effects of these medications depend largely on which tricyclic antidepressant a person takes.

Drowsiness, dry mouth, and sexual problems are possible with any of these medications. Silenor, in particular, has been associated with a greater risk of weight gain.

Potentially severe side effects of these medications include low blood pressure and seizures. Other effects can include:

  • Anticholinergic effects: TCAs are notorious for causing anticholinergic effects (usually related to the parasympathetic nervous system) such as dry mouth, dry mucous membrane, mydriasis (dilation of the pupils), dilation of the urinary tract, hyperthermia, tachycardia, cycloplegia, and blurred vision. Constipation is also frequently reported.
  • Effects on the central nervous system: Confusion, delirium, irritability, loss of concentration, agitation, anger, anxiety, drowsiness, and insomnia are commonly reported side effects of TCAs. Suicidal ideation and worsening of depression may occur at the start of treatment with TCAs, and should be monitored carefully. Involuntary motor movements, dystonia, muscle breakdown, and seizures are minor effects that were reported by people using TCAs.
  • Effects on the cardiovascular system: Postural hypotension—the medical name for the dizzy or fuzzy feeling you get when standing up or stretching too quickly—is common. Alteration in electrocardiogram patterns (electrical activity of the heart), palpitation, arrhythmias, tachycardia, ventricular fibrillation, atrioventricular block, and bradycardia also occur. TCAs are not recommended for a person with a cardiac condition unless there is no other therapy available.
  • Liver effects: Asymptomatic increase in serum aminotransferase, changes in serum alkaline phosphatase concentration, obstructive type jaundice, and hepatitis have been reported when using TCAs. Hepatitis and jaundice can be treated with the discontinuation of medication. Monitoring of liver function tests is highly advised for people using this category of antidepressant.
  • Gastrointestinal effects: Constipation, dry mouth, anorexia, weight gain, increase in pancreatic enzymes, epigastric distress, abdominal cramps, and nausea are some common adverse effects of TCAs.
  • Possible effects on the urinary and reproductive systems: Impotence, delayed or premature ejaculation, testicular swelling, increased or decreased libido, breast engorgement, galactorrhea, and anorgasmia have been reported. Inappropriate secretion of antidiuretic hormone, irregular urinary frequency, and nocturia are also noted side effects of some TCAs.
  • TCAs and pregnancy: TCAs can be harmful to a developing fetus. Their use in pregnancy and for nursing mothers is not recommended animal studies.

Tricyclic Antidepressant Drug Interactions

It is important to discuss with your doctor any additional medications you are taking prior to starting treatment with a tricyclic drug. TCAs may have dangerous interactions with certain medications, drugs, or substances.

  • Monoamine oxidase inhibitors (MAOIs) combined with TCAs may produce tachycardia, hypertension, mania, confusion, and seizure.
  • Hypotensive agents (drugs used to treat blood pressure) such as clonidine cannot perform properly when combined with TCAs.
  • TCAs with central nervous system depressants such as alcohol, sedatives or hypnotics, and barbiturates may cause respiratory depression.
  • Antipsychotic agents should be avoided because they increase the blood concentration of TCAs.
  • Cimetidine (Tagamet), SSRIs, SNRIs, levodopa (Dopar), anticoagulants, thyroid agents, methylphenidate (Ritalin), cisapride (Propulsid), antidiabetic agents, anticholinergic agents, and sympathomimetics should be used with caution while taking a TCA.

FDA Recommendations

The FDA urges that the lowest dose should be used to start the treatment. Monitoring of the person in treatment is necessary and dose should be adjusted the results.

Withdrawal and TCAs

Withdrawal symptoms are possible when people suddenly stop taking tricyclic antidepressants or miss several doses. Nausea, headache, depression, anxiety, insomnia, and dizziness are common symptoms of withdrawal. Consult your doctor if you experience unwanted withdrawal symptoms.

References:

  1. National Library of Medicine – National Institutes of Health. (n.d.). Antidepressive Agents, Tricyclic. Retrieved from http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Tricyclic+Antidepressive+Agents
  2. Mayo Clinic. (n.d.). Depression (Major Depression). Retrieved from http://www.mayoclinic.com/health/antidepressants/MH00071
  3. WebMD. (n.d.). Tricyclic Antidepressants for Pain Treatment. Retrieved from http://www.webmd.com/pain-management/tricyclic-antidepressants-for-chronic-pain

Page content reviewed by James Pendleton, ND.

Source: https://www.goodtherapy.org/drugs/antidepressants-tricyclics.html

Review: selective serotonin reuptake inhibitors differ from tricyclic antidepressants in adverse events

Tricyclic antidepressants

To compare the efficacy, completion rates, and adverse event rates of selective serotonin reuptake inhibitors (SSRIs) with tricyclic antidepressants (TCAs) in treating depression.

Studies were identified by searching Medline, Embase, PsycINFO, International Pharmaceutical Abstracts, Pascal, Health Planning & Administration, Mental Health Abstracts, PharmacoEconomics & Outcomes News, and Current Contents databases (1980 to May 1996); scanning bibliographies of retrieved articles; hand searching journals; and consulting researchers.

Studies were selected if they were double blind, randomised controlled trials, used antidepressant treatment for 4–12 weeks, and reported numerical or graphical data. Studies were excluded if they reanalysed data from previous studies.

Data were extracted on efficacy, study completion, and adverse events.

162 randomised controlled trials were reviewed. SSRIs and TCAs were equally effective and the study completion rates did not differ. 7 adverse events increased and 3 decreased for SSRIs compared with TCAs (table⇓). There were no differences in palpitations, urinary disturbance, fatigue, tremor, hypotension, {blurred vision, anorexia, and sweating}*.

Selective serotonin reuptake inhibitors (SSRI) v tricyclic antidepressants (TCA)*

Serotonin selective reuptake inhibitors do not differ from tricyclic antidepressants in efficacy or completion rates, but have different adverse events: more nausea, diarrhoea, anxiety, agitation, insomnia, nervousness, and headache, and less dry mouth, constipation, and dizziness.

Choosing whether to use a tricyclic or SSRI as first line treatment of depression remains a controversial problem despite many trials and meta-analyses.

This detailed systematic review by the Canadian Coordinating Office for Health Technology Assessment (CCOHTA) examines the issue in more depth than most of its predecessors and reaches conclusions which agree with much (but not all) previous work. What is new is the exploration of dosage of tricyclics and side effects.

There has long been a consensus that tricyclics are only effective in doses >100 mg of amitriptyline or equivalent.1 Despite this consensus, there is considerable evidence that general practitioners treat depression with low dose tricyclics.

One strong argument in favour of SSRIs is the relative ease with which therapeutic doses may be attained. However, this review shows that even when standard SSRIs doses are compared with low dose tricyclics there is no difference in efficacy.

This is less surprising than it may seem; the evidence that high doses of tricyclics are required is flimsy and a handful of small trials.

SSRIs are pharmacologically “cleaner” and therefore, we are often told, have fewer side effects. This is the first systematic review to assess the frequency of side effects and unsurprisingly shows that patients on SSRIs report nausea and anxiety, whereas those on tricyclics complain of constipation and dry mouth.

SSRIs were associated with a greater total number of side effects than tricyclics: a finding which may have many interpretations but runs counter to most promotional literature.

Which drug is better tolerated? This question is usually answered by using the proxy measure of dropout rates from trials, and this review found similar dropout rates for both treatments except in adult outpatients who were more ly to drop out on tricyclics.

Whereas previous meta-analyses generally agreed with the conclusions of the CCOHTA's first report, their economic modelling will be more contentious.

To explore the cost of prescribing SSRIs v tricyclics, the CCOHTA examined 3 treatment protocols: (1) give tricyclics only; (2) give tricyclics first, then give an SSRI if the patient cannot tolerate it; and (3) start with an SSRI and then go onto a tricyclic. Most previous economic analyses decision modelling have favoured SSRIs.

This report suggests that using tricyclics alone is not cost effective, but starting tricyclics and moving to SSRIs if not tolerated (second option) is more cost effective than the third option.

There is much here to commend. The report used data derived from ran-domised trials wherever possible. The authors presented a more realistic therapeutic alternative to that used in many other economic models in this field. The main problem with the approach is that it is often multiple assumptions.

2 The authors partially overcame this by presenting a number of sensitivity analyses with different dropout rates and tricyclic doses, and the main findings are reasonably robust. However, they still had to cobble together results of other studies to estimate resource use on either treatment.

They also assumed that rates and costs of overdose, suicide, and road traffic accidents are similar on the 2 treatments—outcomes which are always difficult to model, but are probably rarer on SSRIs. Finally, costs are not constant between countries: what applies in one healthcare setting may not in another.

Whereas efficacy data are ly to be generalisable, cost effectiveness data are not.

Despite these caveats, these are important and useful reports. SSRIs have undoubted advantages, and as their price falls they may become first line treatment. For the time being, however, tricyclics remain the most cost effective first line treatment for depression.

To compare the efficacy, completion rates, and adverse event rates of selective serotonin reuptake inhibitors (SSRIs) with tricyclic antidepressants (TCAs) in treating depression.

Studies were identified by searching Medline, Embase, PsycINFO, International Pharmaceutical Abstracts, Pascal, Health Planning & Administration, Mental Health Abstracts, PharmacoEconomics & Outcomes News, and Current Contents databases (1980 to May 1996); scanning bibliographies of retrieved articles; hand searching journals; and consulting researchers.

Studies were selected if they were double blind, randomised controlled trials, used antidepressant treatment for 4–12 weeks, and reported numerical or graphical data. Studies were excluded if they reanalysed data from previous studies.

Data were extracted on efficacy, study completion, and adverse events.

162 randomised controlled trials were reviewed. SSRIs and TCAs were equally effective and the study completion rates did not differ. 7 adverse events increased and 3 decreased for SSRIs compared with TCAs (table⇓). There were no differences in palpitations, urinary disturbance, fatigue, tremor, hypotension, {blurred vision, anorexia, and sweating}*.

Selective serotonin reuptake inhibitors (SSRI) v tricyclic antidepressants (TCA)*

Serotonin selective reuptake inhibitors do not differ from tricyclic antidepressants in efficacy or completion rates, but have different adverse events: more nausea, diarrhoea, anxiety, agitation, insomnia, nervousness, and headache, and less dry mouth, constipation, and dizziness.

Choosing whether to use a tricyclic or SSRI as first line treatment of depression remains a controversial problem despite many trials and meta-analyses.

This detailed systematic review by the Canadian Coordinating Office for Health Technology Assessment (CCOHTA) examines the issue in more depth than most of its predecessors and reaches conclusions which agree with much (but not all) previous work. What is new is the exploration of dosage of tricyclics and side effects.

There has long been a consensus that tricyclics are only effective in doses >100 mg of amitriptyline or equivalent.1 Despite this consensus, there is considerable evidence that general practitioners treat depression with low dose tricyclics.

One strong argument in favour of SSRIs is the relative ease with which therapeutic doses may be attained. However, this review shows that even when standard SSRIs doses are compared with low dose tricyclics there is no difference in efficacy.

This is less surprising than it may seem; the evidence that high doses of tricyclics are required is flimsy and a handful of small trials.

SSRIs are pharmacologically “cleaner” and therefore, we are often told, have fewer side effects. This is the first systematic review to assess the frequency of side effects and unsurprisingly shows that patients on SSRIs report nausea and anxiety, whereas those on tricyclics complain of constipation and dry mouth.

SSRIs were associated with a greater total number of side effects than tricyclics: a finding which may have many interpretations but runs counter to most promotional literature.

Which drug is better tolerated? This question is usually answered by using the proxy measure of dropout rates from trials, and this review found similar dropout rates for both treatments except in adult outpatients who were more ly to drop out on tricyclics.

Whereas previous meta-analyses generally agreed with the conclusions of the CCOHTA's first report, their economic modelling will be more contentious.

To explore the cost of prescribing SSRIs v tricyclics, the CCOHTA examined 3 treatment protocols: (1) give tricyclics only; (2) give tricyclics first, then give an SSRI if the patient cannot tolerate it; and (3) start with an SSRI and then go onto a tricyclic. Most previous economic analyses decision modelling have favoured SSRIs.

This report suggests that using tricyclics alone is not cost effective, but starting tricyclics and moving to SSRIs if not tolerated (second option) is more cost effective than the third option.

There is much here to commend. The report used data derived from ran-domised trials wherever possible. The authors presented a more realistic therapeutic alternative to that used in many other economic models in this field. The main problem with the approach is that it is often multiple assumptions.

2 The authors partially overcame this by presenting a number of sensitivity analyses with different dropout rates and tricyclic doses, and the main findings are reasonably robust. However, they still had to cobble together results of other studies to estimate resource use on either treatment.

They also assumed that rates and costs of overdose, suicide, and road traffic accidents are similar on the 2 treatments—outcomes which are always difficult to model, but are probably rarer on SSRIs. Finally, costs are not constant between countries: what applies in one healthcare setting may not in another.

Whereas efficacy data are ly to be generalisable, cost effectiveness data are not.

Despite these caveats, these are important and useful reports. SSRIs have undoubted advantages, and as their price falls they may become first line treatment. For the time being, however, tricyclics remain the most cost effective first line treatment for depression.

Page 3

To compare the efficacy, completion rates, and adverse event rates of selective serotonin reuptake inhibitors (SSRIs) with tricyclic antidepressants (TCAs) in treating depression.

Studies were identified by searching Medline, Embase, PsycINFO, International Pharmaceutical Abstracts, Pascal, Health Planning & Administration, Mental Health Abstracts, PharmacoEconomics & Outcomes News, and Current Contents databases (1980 to May 1996); scanning bibliographies of retrieved articles; hand searching journals; and consulting researchers.

Studies were selected if they were double blind, randomised controlled trials, used antidepressant treatment for 4–12 weeks, and reported numerical or graphical data. Studies were excluded if they reanalysed data from previous studies.

Data were extracted on efficacy, study completion, and adverse events.

162 randomised controlled trials were reviewed. SSRIs and TCAs were equally effective and the study completion rates did not differ. 7 adverse events increased and 3 decreased for SSRIs compared with TCAs (table⇓). There were …

Source: https://ebmh.bmj.com/content/1/2/50

Tricyclic Antidepressants: List, Uses & Side Effects – Drugs.com

Tricyclic antidepressants

Tricyclic antidepressants (often abbreviated to TCAs) are a group of medicines that all have a similar structure and all work in a similar way. They may be used for the treatment of other conditions, not only depression.

Experts believe TCAs work by increasing levels of two neurotransmitters (these are chemicals that relay messages in the brain), norepinephrine and serotonin. Norepinephrine helps with attention and modulates emotional response.

Serotonin is often referred to as the “feel good hormone”. It carries messages between brain cells and contributes to well-being, good mood, and appetite, as well as helping to regulate the body’s sleep-wake cycle and internal clock.

TCAs may also block the actions of other neurotransmitters, such as acetylcholine and histamine.

Some TCAs affect these neurotransmitters more than others which explains why some TCAs work better for conditions other than depression or are more ly to cause side effects such as constipation, dry mouth, or sedation.

Antidepressants is the name given to all medicines that relieve the symptoms of depression. TCAs are just one of several classes of antidepressant.

Other types include norepinephrine and dopamine reuptake inhibitors (NDRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), serotonin antagonist and reuptake inhibitor (SARIs),  tetracyclic antidepressants (TeCAs), and the miscellaneous antidepressants.

What are tricyclic antidepressants used for?

Tricyclic antidepressants were among the first antidepressants developed. They have largely been superseded by newer antidepressants that have less side effects, although they may still suit certain people or be effective when other antidepressants have been ineffective.

In addition to depression, TCAs may also be used to treat a range of other conditions, for example:

Some reduction in symptoms may be noticed within one to two weeks; however, it may take six to eight weeks of treatment before the full effects are seen.

What are the differences between tricyclic antidepressants?

Although all TCAs are thought to act in the same way, with some slight variations in their effect on certain neurotransmitters, there are differences between individual TCAs with regards to how long they remain in the body, how they are metabolized, and their propensity for interactions with other medications, and their side effects.  For example, amitriptyline, doxepin, imipramine and trimipramine are more ly to cause sedation than nortriptyline and desipramine.

Amitriptyline, doxepin, and imipramine have been associated with more weight gain than some other TCAs; nortriptyline and desipramine may be better tolerated.

Some TCAs, such as amoxapine, are often listed as a TCA, but are in fact tetracyclic antidepressants.

Are tricyclic antidepressants safe?

When taken at the recommended dosage, tricyclic antidepressants are considered safe. However, they have been associated with a few severe side effects, some potentially fatal, such as:

  • An increase in suicidal thoughts and behaviors, particularly in children and young adults under the age of 25 years. This is most ly to occur when starting therapy
  • Serotonin syndrome – this is caused by excessive levels of serotonin in the body and is more ly to occur with higher dosages of SSRIs or when SSRIs are administered with other medications that also release serotonin. Symptoms include agitation, confusion, sweating, tremors, and a rapid heart rate
  • The precipitation of a manic episode in people with undiagnosed bipolar disorder
  • An increased risk of seizures in people with a history of seizures
  • An increased risk of arrhythmias, heart attacks, stroke, and other cardiovascular effects, particularly in people with pre-existing heart disease
  • The triggering of an angle closure attack in people with angle-closure glaucoma.

TCAs may also not be suitable for people with hyperthyroidism or receiving thyroid medications, or in those who use alcohol excessively.

What are the side effects of tricyclic antidepressants?

Some of the more commonly reported side effects with tricyclic antidepressants include:

  • A drop-in blood pressure when moving from a sitting to standing position
  • Blurred vision
  • Constipation
  • Disorientation or confusion
  • Drowsiness
  • Dry mouth
  • Excessive sweating
  • Increased or irregular heart beat
  • Sexual dysfunction (such as reduced desire or erectile dysfunction)
  • Tremor
  • Urine retention
  • Weight loss or weight gain.

For a complete list of side effects, please refer to the individual drug monographs.

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Source: https://www.drugs.com/drug-class/tricyclic-antidepressants.html

Tricyclic Antidepressants (TCAs): Uses, Side Effects, and More

Tricyclic antidepressants

Tricyclic antidepressants, also known now as cyclic antidepressants or TCAs, were introduced in the late 1950s. They were one of the first antidepressants, and they’re still considered effective for treating depression.

These drugs are a good choice for some people whose depression is resistant to other drugs. Although cyclic antidepressants can be effective, some people find their side effects difficult to tolerate.

That’s why these drugs are not often used as a first treatment.

The different cyclic antidepressants that are currently available include:

  • amitriptyline
  • amoxapine
  • desipramine (Norpramin)
  • doxepin
  • imipramine (Tofranil)
  • maprotiline
  • nortriptyline (Pamelor)
  • protriptyline (Vivactil)
  • trimipramine (Surmontil)

Some doctors may also prescribe the cyclic drug clomipramine (Anafranil) for treatment of depression in an off-label use.

Clinicians usually only prescribe tricyclic antidepressants after other drugs have failed to relieve depression. Tricyclic antidepressants help keep more serotonin and norepinephrine available to your brain. These chemicals are made naturally by your body and are thought to affect your mood. By keeping more of them available to your brain, tricyclic antidepressants help elevate your mood.

Some tricyclic antidepressants are also used to treat other conditions, mostly in off-label uses. These conditions include obsessive compulsive disorder (OCD) and chronic bedwetting. In lower doses, cyclic antidepressants are used to prevent migraines and to treat chronic pain. They are also sometimes used to help people with panic disorder.

Tricyclic antidepressants treat depression, but they have other effects on your body as well. They can affect automatic muscle movement for certain functions of the body, including secretions and digestion.

They also block the effects of histamine, a chemical found throughout your body. Blocking histamine can cause effects such as drowsiness, blurred vision, dry mouth, constipation, and glaucoma.

These may help explain some of the more troublesome side effects associated with these drugs.

Tricyclic antidepressants are more ly to cause constipation, weight gain, and sedation than other antidepressants. However, different drugs have different effects. If you have a troublesome side effect on one tricyclic antidepressant, tell your doctor. Switching to another cyclic antidepressant may help.

Possible side effects of tricyclic antidepressants include:

  • dry mouth
  • dry eyes
  • blurred vision
  • dizziness
  • fatigue
  • headache
  • disorientation
  • seizure (especially with maprotiline)
  • drowsiness
  • constipation
  • urinary retention
  • sexual dysfunction
  • low blood pressure
  • weight gain (especially with amitriptyline, imipramine, and doxepin)
  • nausea

People who drink alcohol frequently should avoid tricyclic antidepressants. Alcohol lessens the antidepressant action of these drugs. It also increases their sedating effects.

Tricyclic antidepressants can cause harmful side effects if you take them with certain medications, including epinephrine (Epi-Pen) and cimetidine (Tagamet).

Tricyclic antidepressants can increase the effects of epinephrine on your heart. This can lead to high blood pressure and problems with your heart rhythm.

Cimetidine can increase levels of tricyclic antidepressant in your body, making side effects more ly.

Other drugs and substances can also interact with tricyclic antidepressants. It’s important for you to tell your doctor about all drugs and substances you use. Your doctor can help you avoid any interactions.

These drugs can make some conditions worse. People with the following conditions should avoid tricyclic antidepressants:

  • angle-closure glaucoma
  • enlarged prostate
  • urinary retention
  • heart problems
  • thyroid problems

Tricyclic antidepressants also affect blood sugar levels, so people with diabetes who take these drugs may need to check their blood sugar level more frequently.

Pregnant women or women who are breastfeeding should talk to a doctor before using tricyclic antidepressants. The doctor will help weigh any possible risks to the mother or baby against the benefit of using these drugs.

Tricyclic antidepressants are effective, but they aren’t for everyone. They ly won’t be the first antidepressant your doctor has you try. This is mostly due to their potential for side effects.

If you are prescribed these drugs, talk with your doctor about any side effects you have. You should tell your doctor if you feel you can’t tolerate the side effects before changing your dosage or stopping treatment with these drugs. Abruptly stopping tricyclic antidepressant treatment can cause:

  • nausea
  • headache
  • dizziness
  • lethargy
  • flu- symptoms

Your doctor will taper your dosage over time to avoid these effects.

Source: https://www.healthline.com/health/depression/tricyclic-antidepressants-tcas

When Is the Right Time to Use a Tricyclic Antidepressant?

Tricyclic antidepressants

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Tricyclic antidepressants (TCAs) are drugs used to treat depression, bipolar disorder, and other conditions such as chronic pain and insomnia. While newer classes of antidepressant have far fewer side effects, TCAs still have their place in the treatment of these and other disorders.

First introduced in the 1950s, tricyclic antidepressants are so-named because their molecular structure is composed of three rings of atoms.

Broadly speaking, depression is caused by a chemical imbalance in the brain which results in abnormal communications between nerve cells (neurons). The chemicals that deliver these messages are called neurotransmitters. These chemical messages are relayed from one neuron to the next and, depending on the type of neurotransmitter involved, can influence how you feel and react.

Tricyclic antidepressants work by preventing the reabsorption of neurotransmitters called serotonin and norepinephrine. The body needs both of these to function normally. If there is too much of either, you may end up experiencing anxiety. If there is not enough, depression may ensue.

Because TCAs prevent the routine reabsorption (reuptake) of these neurotransmitters, there will be more freely circulating in the synaptic cleft between neurons in the brain. If you have depression, the restoration of the serotonin and norepinephrine levels can lead to an improvement in your symptoms.

Tricyclic antidepressants are used primarily to treat mood disorders but also have their place in the treatment of anxiety disorders, personality disorders, and neurological disorders. They are often used when other drugs are unable to provide relief.

Mood disorders often treated with TCAs include:

Anxiety disorders sometimes treated with TCAs include:

Neurological disorders sometimes treated with tricyclic TCAs include:

TCAs may also be used to treat insomnia, irritable bowel syndrome (IBS), interstitial cystitis, nocturnal enuresis (bedwetting), narcolepsy, and chronic hiccups.

With tricyclic antidepressants, other antidepressants, it will usually take between six to eight weeks before you feel any substantial improvement in your depression symptoms.

Some of the more commonly prescribed TCAs include:

  • Anafranil (clomipramine)
  • Ascendin (amoxapine)
  • Elavil (amitriptyline)
  • Norpramin (desipramine)
  • Pamelor (nortriptyline)
  • Sinequan (doxepin)
  • Surmontil (trimipramine)
  • Tofranil (imipramine)
  • Vivactil (protriptyline)

While different TCAs have slightly different mechanisms of action, they share similar side effects. Many of these are associated with the effect the drugs have on the smooth muscles of the internal organs.

Common side effects include:

  • Anxiety
  • Blurred vision
  • Constipation
  • Dizziness
  • Drowsiness
  • Increased appetite
  • Muscle twitches
  • Nausea and vomiting
  • Rapid or irregular heart rate
  • Sexual dysfunction
  • Sweating
  • Weakness
  • Weight gain

These side effects may be reduced if treatment is started with lower dosages and then gradually increased. While not strictly addictive per se, the long-term use of TCAs may lead to drug dependence.

TCAs are also a significant cause of fatal drug overdoses in the United States. Initial symptoms may include dry mouth, blurred vision, urinary retention, constipation, dizziness, vomiting, and hallucinations. If left untreated, an overdose may result in delirium, seizures, coma, cardiac arrest, and death.

Some of the side effects of tricyclic antidepressants may be intensified if taken with other drugs. In other cases, it can affect the bioavailability (concentration) of the drug in the bloodstream. As such, you should always advise your doctor about any substances you may be taking, including over-the-counter medications, herbal remedies, and recreational drugs.

Certain drugs are contraindicated for use with tricyclic antidepressants, including:

  • Alcohol blocks the action of TCAs and should be avoided.
  • Anticholinergic drugs used to treat urinary incontinence and COPD can cause intestinal paralysis if co-administered with a TCA.
  • Clonidine, used to treat hypertension, can trigger a dangerous rise in blood pressure if used with a TCA.
  • Epinephrine used to treat severe allergic reactions can also trigger severe high blood pressure if used with a TCA.
  • Monoamine oxidase (MAO) inhibitors, also used as antidepressants, can cause high fever, convulsions, and even death is coadministered with a TCA.
  • Tagamet (cimetidine), used to reduce stomach acid, may increase the concentration of the TCA in your blood, further intensifying the drug side effects.

Tricyclic antidepressants can be effective in treating depression but may not work as well in some people as others. In some cases, the drug side effects may become intolerable and interfere with your very quality of life.

If you are suffering serious side effects, call your doctor immediately but do not stop treatment until your doctor tells you to. Stopping abruptly can cause symptoms of withdrawal, including nausea, fever, chills, headache, dizziness, lethargy, and vomiting.

Your doctor may be able to lower your dosage to where treatment is tolerable. If not, he or she would need to gradually taper the dose until you are able to safely stop.

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Verywell Mind uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.

  1. Slomski, Anita. Somber Questions. Protomag.com. Massachusetts General Hospital. Spring 2012.

  2. Anxiety and Depression Association of America. Medication. Updated July 2019.

  3. National Center for Biotechnology Information. Depression: How effective are antidepressants? Updated Jan 12, 2017.

  4. Hawton K, Bergen H, Simkin S, et al. Toxicity of antidepressants: rates of suicide relative to prescribing and non-fatal overdose. Br J Psychiatry. 2010;196(5):354-8. doi:10.1192%2jp.bp.109.070219

  5. U.S. Food and Drug Administration. Pamelor Label. Updated 2007.

Additional Reading

  • Aarts, N.: Noordam, R.; Hofman, A.; Tiemeier, J.; Stricker, B.; and L. Visser. Self-Reported Indications for Antidepressant Use in a Population-Based Cohort of Middle-Aged and Elderly.Int J Pharmacol. 2016;38(5):1311-7. DOI: 10.1007/s11096-016-0371-9.

Source: https://www.verywellmind.com/tricyclic-antidepressants-379652

Tricyclic antidepressants: Video, Anatomy & Definition

Tricyclic antidepressants

Tricyclic antidepressants, or TCAs, are mainly used to treat major depressive disorder.

This disorder causes a persistent feeling of sadness and loss of interest in everyday activities.

Even though the exact cause of depression is still unknown, there's some evidence that suggests it’s related to low levels of neurotransmitters serotonin, norepinephrine, and dopamine.

Tricyclic antidepressants work by increasing the levels of serotonin and norepinephrine to alleviate the symptoms of depression.

Alright, now within the brain, there are many different types of neurons, but we’re just going to focus on two: serotonergic neurons which produce serotonin, and noradrenergic neurons which produces norepinephrine.

Each of these neurons synthesizes and stores their neurotransmitters in small vesicles.

So, when an action potential reaches the presynaptic membrane, these vesicles fuse with the membrane, releasing neurotransmitters into the synaptic cleft.

Once released, serotonin or 5-HT binds to 5-HT2 receptors on the postsynaptic membrane, thereby increasing neural stimulation and regulating mood, feeding, and reproductive behavior.

On the other hand, norepinephrine binds to norepinephrine receptors on the postsynaptic membrane, boosting alertness.

As long as there’s a high enough concentration of neurotransmitters in the synaptic cleft, the postsynaptic neurons will continue to fire.

Now, serotonergic neurons, on their presynaptic membrane, have serotonin transporters or SERT, while noradrenergic neurons have norepinephrine transporters or NET.

These membrane proteins transport the serotonin and norepinephrine in the synaptic cleft back into presynaptic neurons.

This leads to decreased neurotransmitter concentration within the synaptic cleft, causing the postsynaptic neurons to stop firing.

So, in conditions such as major depressive disorder, tricyclic antidepressants can be used to increase the levels of serotonin and norepinephrine.

Tricyclic antidepressants are subdivided into 2 main groups: tertiary TCAs, which include amitriptyline, imipramine, and clomipramine; and secondary TCAs, which include desipramine and nortriptyline.

Tertiary TCAs are also known as non-selective tricyclic antidepressants and they inhibit both serotonin transporters and norepinephrine transporters, while secondary TCAs, which are also known as selective tricyclic antidepressants, inhibit only norepinephrine transporters.

This way, tricyclic antidepressants are increasing levels of serotonin and norepinephrine or just norepinephrine within the synaptic cleft, thus increasing the activity of postsynaptic neurons.

It's important to note that these medications are slow-acting because it takes time for serotonin and norepinephrine to accumulate within the synaptic cleft. Because of this, it usually takes 2-4 weeks before improvements can be seen.

Even though they’re very effective in the treatment of depression, tricyclic antidepressants are not considered as the first line therapy due to their severe side effects.

They’re typically reserved for when there is no response to other antidepressants, such as selective serotonin reuptake inhibitors, or SSRIs.

Other indications for TCAs include phobic disorders, chronic neuropathic pain, peripheral neuropathy, and as migraine prophylaxis.

Now, for medication specific indications, clomipramine can be used in the treatment of obsessive-compulsive disorder, or OCD, while imipramine is used in the treatment of nocturnal enuresis, which is involuntary urination while asleep.

Besides serotonin and norepinephrine transporters, TCAs also block histamine H1 receptors, causing sedation; alpha 1 receptors, causing orthostatic hypotension; and muscarinic receptors, causing atropine- side effects.

Atropine- side effects occur more commonly with tertiary TCAs and they include dry mouth, tachycardia, urinary retention, confusion, and hallucinations.

TCAs can also cause serotonin syndrome, which is a life-threatening condition caused by serotonin accumulation and over stimulation of the nervous system.

This syndrome is characterized by skin flushing, hyperthermia, agitation, muscle rigidity, seizure, and coma.

Source: https://www.osmosis.org/learn/Tricyclic_antidepressants

CPIC® Guideline for Tricyclic Antidepressants and CYP2D6 and CYP2C19

Tricyclic antidepressants

October 2019: CYP2D6 genotype to phenotype translation changes: Up until August 2019, there were a few inconsistencies in the translation of CYP2D6 genotype to phenotype across guidelines (i.e.

CPIC and DPWG) and between clinical genetic testing laboratories. CPIC recently conducted a modified-Delphi project to obtain consensus among a panel of international CYP2D6 experts for a uniform system for translating CYP2D6 genotype to phenotype (more information).

Modifications to CPIC’s prior system include downgrading the value assigned to the CYP2D6*10 allele for activity score calculation from 0.5 to 0.

25 and changing the phenotype assignment for an activity score of 1 from normal metabolizer to intermediate metabolizer  (table of all previous and new phenotype groupings).

As a result, the following changes have been made in the CYP2D6 allele functionality table and the CYP2D6 genotype to phenotype table:

  • Diplotypes giving rise to activity scores of 1 changed from CYP2D6 normal metabolizer to CYP2D6 intermediate metabolizer assignments.
    • Impact on the recommendations in this guideline: The recommendation for CYP2D6 IM (reduce starting dose by 25%) should be considered for CYP2D6 AS of 1 (strength of recommendation: optional). The authors of this guideline are in the process of updating this guideline to reflect this change and evaluate new evidence since the publication of this guideline.
  • All activity scores for diplotypes containing a CYP2D6*10 allele have been updated accordingly (activity scores changed to reflect the lower activity value of 0.25 for CYP2D6*10). See table of all previous and new phenotype groupings.
    • Impact on the recommendations in this guideline: Prior to the consensus projects, the combination of a duplicated normal function allele with a CYP2D6*10 allele resulted in an activity score of 2.5 which translates to an ultrarapid metabolizer. The lower value of 0.25 for CYP2D6*10 results in an activity score of 2.25 for these allele combinations, which the new consensus project, now translates to a normal metabolizer.

Tables and figure provided in the main manuscript of the guideline:

Table 1. Assignment of ly phenotypes diplotypes
Table 2. Dosing recommendations for tricyclic antidepressants CYP2D6 phenotype
Table 3.

Dosing recommendations for the tertiary amines amitriptyline, clomipramine, doxepin, imipramine, and trimipramine CYP2C19 phenotype

Table 4. Dosing recommendations for amitriptyline both CYP2D6 and CYP2C19 phenotypes
Figure 1.

Major metabolic pathway of the tertiary amine amitriptyline and the secondary amine nortriptyline

Tables and figures provided in the guideline publication supplement or referenced in the guidelinea:

aSome of the tables included in the guideline may have been updated on-line, particularly to reflect newly described or newly characterized alleles. These include the gene-specific information tables (https://www.pharmgkb.

org/page/pgxGeneRef) that support CPIC guidelines by providing information regarding star (*) allele definitions, allele function, allele frequency by major ethnic groups, translations of diplotype to phenotype, and gene resource mappings.

bThese resources support the adoption of CPIC guidelines into the electronic health record with clinical decision support and provide information that clinical implementers find helpful.

Original guideline publication (May 2013):

This guideline has been endorsed by the American Society of Health-System Pharmacists (ASHP).

Source: https://cpicpgx.org/guidelines/guideline-for-tricyclic-antidepressants-and-cyp2d6-and-cyp2c19/

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