Tricyclic Antidepressants (TCAs) were developed in the 1950s as a way to treat depression with chemical compounds. These drugs are known for their specific chemical structure consisting of three rings of atoms, hence being referred to as “tri”-cyclic. Tricyclics were developed after researchers began exploring derivatives of the first typical antipsychotic medication Thorazine. Experimentation with derivatives lead to the development of the first TCA drug called “Imipramine.”
Initially the drug Imipramine was not intended to treat depressive symptoms, but it was found to induce mania. This lead researchers to believe that it may have some antidepressant effects. Upon testing Imipramine, it was found to yield a significant antidepressant response among depressed individuals. This lead to a trend of many companies developing tricyclic antidepressants with different three ring structures from Imipramine.
Tricyclic antidepressants became commonly prescribed for the treatment of major depression and were considered very effective at managing symptoms. Back when TCAs were approved, they were considered a first-line treatment option for depression. These days they are still used for depression, but are considered a second-line treatment to newer drugs like SSRIs/SNRIs and atypical antidepressants.
Many still consider them to be highly effective, but newer medications are typically favored by professionals and patients because they carry less side effects and are regarded as being safer. TCAs are usually prescribed as a second-line treatment option prior to trying Monoamine Oxidase Inhibitors (MAOIs).
Tricyclic Antidepressants List (TCAs)
Below are several lists of TCAs grouped by how they function. Although some TCAs tend to affect serotonin and norepinephrine equally, some affect one to a significantly greater extent. Additionally there are others that don’t affect either neurotransmitter to a significant extent; these are listed as “atypical” TCAs.
Balanced TCAs: Serotonin / Norepinephrine
Below is a list of TCAs that affect serotonin and norepinephrine to a similar extent. Although most affect one neurotransmitter slightly more than the other, differences are considered minimal.
Amitriptyline (Elavil): This is the most commonly used TCA on the market for treatment of major depression. It was created by Merck and approved by the FDA for medical use in 1961. This drug works primarily as a serotonin-norepinephrine reuptake inhibitor, favoring the serotonin reuptake inhibition slightly more than that of norepinephrine. There is even some evidence suggesting that this TCA may be more effective than SSRI antidepressants. It is on the World Health Organization’s List of Essential Medicines due to its efficacy as a TCA.
Amitriptylinoxide (Amioxid): This TCA drug hit European markets in the 1970s as a treatment for major depression. It produces similar effects to the drug Amitriptyline, which makes sense because it is a metabolite of Amitriptyline. It is considered to work more quickly with fewer side effects than Amitriptyline and is regarded as being equal in terms of efficacy. The way the drug works is nearly identical to Amitriptyline, except it affects the Alpha-1 receptors to a significantly lesser extent (60x less) and has among the weakest effects on acetylcholine receptors.
Butriptyline (Evadyne): This is a TCA that was introduced in Europe in 1974. It is very similar to Amitriptyline, but tends to have significantly less side effects and contraindications with other drugs (specifically those that are adrenergic). This drug acts as a potent antihistamine and anticholinergic, a modest agonist at the Alpha-1 receptor and 5-HT2 receptor. It affects serotonin to a very minor extent. Some believe that Butriptyline may act as a prodrug of Amitriptyline, with more favorable results.
Dosulepin (Prothiaden): This is a TCA that is used primarily in Australia, New Zealand, and South Africa for treating depression. In some cases it is used in European countries and South Asia. It was formerly recognized as “Dothiepin” in the United States. Although this drug has a higher affinity for serotonin transporters compared to norepinephrine, it still has a significant effect on both. It also carries anticholinergic and antihistamine properties and blocks the Alpha-1 receptor.
Doxepin (Sinequan): This TCA is utilized throughout the world for the treatment of major depression, anxiety disorders, and insomnia. It is also considered a drug that can be used to treat hives and extensive itchiness. Doxepin prevents reuptake of norepinephrine to a slightly greater extent than serotonin, but affects both significantly.
Melitracen (Trausabun): This is an antidepressant within the TCA class that is utilized throughout Europe and Japan for the treatment of major depression and anxiety disorders. It also is popular in the form of “Deanxit” which is a drug that combines Melitracen and Flupentixol. The way this drug works hasn’t been thoroughly researched, but some hypothesize that it may work similarly to the drugs Imipramine and Amitriptyline. In comparison to older TCAs, this drug is thought to work more quickly with more favorable side effects.
Nitroxazepine (Sintamil): This TCA was marketed in India to treat major depression in 1982. Like many other TCAs, it can also be used to treat childhood bedwetting. The properties of the drug suggest that it works by inhibiting the reuptake of serotonin and norepinephrine. Some suggest that it may generate similar responses to the drug Imipramine, but it may have less side effects (specifically those that are anticholinergic).
Noxiptiline (Agedal): This is a TCA that combines noxiptyline and dibenzoxine to treat depression. It was initially released in the 1970s throughout Europe and is thought to be among the most effective TCAs ever released. Some believe that it generates responses similar to that of Imipramine, but it functions mostly by preventing reuptake of serotonin and norepinephrine.
Propizepine (Vagran): This is a TCA that was released in France in the 1970s for the purpose of treating depression. There isn’t as much documentation released regarding the pharmacology of this drug compared to other TCAs. It is thought to affect norepinephrine and serotonin to a greater extent than other neurotransmitters.
Tricyclic Antidepressants: Serotonin
Below is a list of TCAs that increase serotonin to a significant extent compared to norepinephrine.
Clomipramine (Anafranil): This drug was developed in the 1960s and is derived from the first tricyclic antidepressant “imipramine.” It inhibits reuptake of serotonin to 200x the extent of its ability to prevent reuptake of norepinephrine. World In addition to inhibiting serotonin reuptake to a significant extent, it also acts as an antagonist at the H1-histamine receptor, the Alpha-1 adrenergic receptor, and various acetylcholine receptors. It should be noted that this medication is on the World Health Organization’s List of Essential Medicines.
Dimetacrine (Istonil): This TCA is utilized for the treatment of major depression throughout Europe. It was formerly used in Japan, but has since been discontinued from the market. It is thought to function very similar to the drug Imipramine, but is considered to have poorer efficacy. Additionally this drug is seldom used as a result of its affects on the liver.
Imipramine (Tofranil): This was the first TCA drug to be discovered and has been around since the 1950s. It is mainly utilized to treat major depression, but in some cases it is also prescribed to help treat nighttime bedwetting due to its ability to reduce delta brain waves during sleep. Although this drug has very strong serotonin reuptake inhibition properties, it has an effect on an array of other neurotransmitters including: norepinephrine (to a significant extent), dopamine (to a very minor degree at the D1 and D2 receptors), acetylcholine (an anticholinergic), epinephrine (antagonist), histamine (antagonist).
Imipraminoxide (Elepsin): This is a tricyclic antidepressant that was created in the 1960s and utilized throughout Europe to treat major depression. This drug is thought to work primarily by inhibiting reuptake of serotonin and norepinephrine. It also may affect epinephrine, histamine, and acetylcholine receptors as an antagonist. It is thought to have similar effects to the drug Imipramine due to the fact that it is a metabolite and is similar in structure. In comparison, this drug was found to work more quickly with more significant reductions in depression and less overall side effects than Imipramine.
Pipofezine (Azaphen): This TCA was approved to treat depression in the 1960s and is used in the country of Russia. It is documented as having significant effects on the reuptake inhibition of the neurotransmitter serotonin. This drug is thought to also have antihistamine properties due to many experiencing sedation as a side effect. Additionally it may carry anticholinergic and antiadrenergic effects.
Tricyclic Antidepressants: Norepinephrine
These are TCAs that affect norepinephrine to a significantly greater extent than serotonin. Many of these are thought to be more activating, which could also increase anxiety. These would be more ideal for individuals with lower levels of arousal.
Demexiptiline (Deparon): This is a TCA medication that has been used in France for treating major depression. It works mostly as a norepinephrine reuptake inhibitor similar to the more widely-documented drug Desipramine.
Desipramine (Norpramin): This drug primarily inhibits the reuptake of norepinephrine and to a lesser degree, serotonin. It is utilized to treat major depression, but has been found useful to treat neuropathic pain. Some suggest that this medication may be one of the more potent TCAs on the market, and due to the way it works, it may help some with ADHD symptoms. This drug is associated with increases in risk of breast cancer for women and is considered genotoxic. It contains an active metabolite of the drug Imipramine.
Dibenzepin (Noveril): This is a tricyclic antidepressant that is only available in European countries for the treatment of depression. It works primarily as a norepinephrine reuptake inhibitor, but also has significant antihistamine properties. It is regarded as being similar to the TCA Imipramine with less side effects and a similar degree of efficacy.
Lofepramine (Gamanil): This drug was introduced in 1983 as a TCA for major depression. It works mostly by preventing reuptake of norepinephrine to a significant extent and serotonin to a moderate degree. It is a relatively weak antagonist at acetylcholine receptors. It is considered less sedating and safer (for preventing overdose) than other TCAs.
Metapramine (Prodastene): This TCA was introduced to the country of France in the mid 1980s for individuals with major depression. The drug works primarily as a norepinephrine reuptake inhibitor without having an impact on serotonin and dopamine. It is thought to have slight effects as an NMDA receptor antagonist. This drug also has an impact as an analgesic, so some physicians may prescribe it to help treat pain. It does not carry anticholinergic properties like other TCAs.
Nortriptyline (Pamelor): This is a second-generation TCA utilized for major depression and sometimes childhood bedwetting. It primarily works by preventing reuptake of norepinephrine at a significantly greater rate than that of serotonin and histamine. Due to its stimulating properties, it is sometimes used to help treat chronic fatigue, neuropathic pain, and ADHD.
Protriptyline (Vivactil): This is a TCA that it used to treat major depression as well as ADHD. This drug works by significantly blocking the reuptake of norepinephrine and affects serotonin to a minor degree. It also has been documented as blocking activity of the neurotransmitter acetylcholine. This drug is known for its stimulating effects and tends to promote wakefulness, hence being used in some cases of narcolepsy.
Atypical Tricyclic Antidepressants
The atypical TCAs work differently than most and carry unique properties. Unlike other TCAs that focus primarily on norepinephrine, serotonin, or a combination of both, these may affect 5-HT2 receptors, dopamine, Sigma-1 receptors, and/or glutamate receptors.
Amineptine (Survector): This drug was developed in the 1960s and approved in 1978 to tread major depression in France. Due to its slightly euphoric stimulant effects, word had quickly spread about the drug. Many people began using it recreationally and abusing it. It is regarded as an atypical tricyclic antidepressant because it is one of the few that inhibits reuptake of dopamine and to a lesser degree, norepinephrine. Unfortunately the drug eventually was withdrawn from Europe in 1999 after surfacing reports of liver damage. The drug was never approved by the FDA in the United States.
Iprindole (Prondol): This TCA has been utilized throughout Europe since 1967 to treat depression. It works primarily as a 5-HT2 receptor antagonist, with minimal effects on serotonin and norepinephrine. Some sources suggest that it was among the first second generation antidepressants to hit the market due to the fact that it primarily affected 5-HT2 receptors. This drug is known to be better tolerated than most, but its efficacy is thought to be slightly poorer than other TCAs. Structurally this drug is considered unique from other TCAs.
Opipramol (Insidon): This is a TCA that is used throughout various European countries to primarily treat anxiety disorders as well as depression. Opipramol acts primarily as a Sigma-1 receptor agonist and to a lesser extent a Sigma-2 receptor agonist. It is unique among TCAs because it lacks reuptake inhibition properties. It is most commonly used to treat generalized anxiety disorders and insomnia due to its potent anxiolytic and tranquilizing effects. Compared to SSRIs and SNRIs, this drug is noted as having less side effects.
Quinupramine (Kinupril): This TCA is utilized throughout Europe for the treatment of depression. It acts primarily as an acetylcholine receptor antagonist as well as a histamine antagonist at the H1 receptor. It has been documented as affecting the 5-HT2 receptor as a modest antagonist. It does not promote significant serotonin, norepinephrine, or dopamine reuptake inhibition. Some hypothesize that it may have similar functioning to the drugs Imipramine, Desipramine, and Demexiptiline.
Tianeptine (Stablon): This is a TCA that was developed in the 1960s and is used primarily to treat major depression, but in some cases is prescribed to treat irritable bowel syndrome. Although this drug is classified as a TCA, it functions differently than most. It works by influencing both AMPA and NMDA glutamate receptor activity as well as BDNF (brain-derived neurotrophic factor). It is also believed to enhance the reuptake of serotonin. Researchers also have noted that it functions as an agonist at both the mu-opioid receptor and delta-opioid receptor. Some hypothesize that affecting the mu-opioid receptor could be contributing to the antidepressant effect of the drug. In comparison research, this drug has proven to have less side effects than Amitriptyline, Imipramine, and Prozac, with comparable efficacy.
Trimipramine (Surmontil): This is a TCA that is utilized to treat major depression as a 5-HT2 receptor antagonist and a H1 receptor antagonist. It is known for having very sedating effects and in some cases this drug is thought to work well for treating insomnia and anxiety. This is considered unique in the fact that it is the only medication that is thought to not affect sleep stages.
Tricyclic Antidepressants: Should They Be Used More Often?
There is some debate as to whether TCAs deserve to be classified as second-line treatments for depression. Some people believe that SSRIs, SNRIs, and newer atypical antidepressants are the safest, yield the least side effects, and are more effective than TCAs. However, many people do not respond to these classes of drugs, and for them the tricyclic class may be a perfect fit.
There is some evidence suggesting that the tricyclics may be better at treating individuals that have significant melancholic features associated with their depression. The TCA class is often only tested when a patient hasn’t experienced any improvement in depressive symptoms from newer classes of medications. Assuming a person can tolerate the initial side effects, TCAs can be highly effective as antidepressants.
In my opinion, these drugs should be considered more frequently, especially before various antidepressant augmentation strategies are pursued. I don’t really like the idea of a person being given an antipsychotic as an adjunct which is likely to yield significantly more unwanted side effects than a TCA. The side effect profile associated with TCAs is a bit more noteworthy than modern day SSRIs, but some individuals actually tolerate them better.
It should be mentioned that these drugs are also sometimes utilized for conditions other than depression including: ADHD, chronic pain, insomnia, and nocturnal enuresis. I am with the mainstream psychiatric opinion that newer antidepressants should be considered first-line treatment options ahead of TCAs. However, this class is different than newer medications and if used responsibly, should not be feared.
Most of these drugs act as SNRIs by preventing reuptake of both serotonin and norepinephrine, but many favor one neurotransmitter over the other. The nice thing about TCAs is that each drug tends to have slightly different properties. If a person believes their depression is caused by low norepinephrine, there are many TCAs that act as potent norepinephrine reuptake inhibitors.
On the other hand, there are TCAs that tend to significantly favor serotonin too. None of the TCA drugs have much of an effect on dopamine, but many also have significant antihistamine and anticholinergic properties. They also notably act as sodium and calcium channel blockers in the brain. This is still a very therapeutic class of antidepressant medication that cannot be ignored if first-line treatments are unsuccessful.
If you have experience with a TCA, feel free to share your thoughts in the comments section below. How do you think this drug class compares to SSRIs? A minority of people actually believe that they are a superior class of drugs to the newer medications on the market.