Tetracyclic antidepressants (TeCAs) are a class of antidepressants that are similar to tricyclic antidepressants, except they are composed of four atomic rings; hence the name “tetra”-cyclic. This class of drugs was developed in the 1970s and most hit the market decades after the first tricyclic antidepressants. These were essentially a spin-off of TCAs with one more atomic ring and were developed later.
Tetracyclic Antidepressants List (TeCAs)
Below is a list of various tetracyclic antidepressant drugs with a brief description of each. Some of these drugs ended up being used more to help manage symptoms of schizophrenia rather than treat depression. Others like Mazindol carried alternative properties resulting in appetite suppression.
This is an antidepressant in the tetracyclic class of drugs that was initially approved in 1992 for treatment of major depression in the United States. This drug has a variety of effects, but is thought to work mostly as a strong serotonin and norepinephrine reuptake inhibitor. It also has been documented as having some similar mechanisms of action as atypical antipsychotics. Amoxapine is considered faster-acting than most with most people experiencing depressive relief within a week or two of starting treatment.
Loxapine (Loxapac / Loxitane)
This is a tetracyclic antipsychotic drug that is most commonly utilized for the treatment of schizophrenia. The active metabolite of this drug is the TeCA drug Amoxapine and it is similar in composition to the drug Clozapine. It works primarily by acting as an antagonist at the H1 histamine receptor and has an affinity for the 5-HT2A receptor as well. It affects the D2 dopamine and 5-HT2C receptors to a lesser extent.
In some cases this drug is used as an inhalant to help treat feelings of agitation in adults with bipolar disorder and schizophrenia. In one study comparing four other antipsychotics, this drug was noted as the only one to aid in the brain developing new neural connections.
This is a tetracyclic antidepressant that became available in the early 1980s. It works primarily by acting as a reuptake inhibitor on norepinephrine, an antagonist on both the H1 histamine receptor and 5-HT7 receptor. It also has been found to act on the 5-HT2 and Alpha-1 receptor as a modest antagonist. It thought to yield insignificant effects on dopamine and serotonin (unless taken at high doses).
In addition to having antidepressant properties, this drug also acts as an anxiolytic and sedative. It is thought that due to its anxiolytic characteristics, this drug is better suited for depression with comorbid anxiety or agitation. When this drug first hit the market, it was touted as having a better side effect profile than other antidepressants. Later it was found to cause seizures, decrease white blood cell count, and cause adverse skin reactions more frequently than other antidepressants.
Mazindol (Mazanor / Sanorex)
This is a tetracyclic stimulant drug that was developed in the 1960s and is utilized primarily as an appetite suppressant among obese individuals. In most cases it is used over a short duration to help promote weight loss with a combination of a healthy diet, exercise, and behavioral changes. Due to the fact that this drug is not promoted as an FDA treatment for weight loss, it is not used in the United States for obesity. The only approved usage in the United States is to help manage muscular dystrophy.
The drug stimulates activity in the central nervous system similar to amphetamines. Mazindol has only been found helpful for short-term improvements in obesity, the drug tends to wear off within a month of administration. This drug is hypothesized to work by preventing the reuptake of norepinephrine, as well as dopamine and serotonin (to a lesser degree).
Mianserin (Lerivon / Norval / Tolvon)
This is a tetracyclic antidepressant drug that is commonly used in countries outside of the United States including the United Kingdom and Australia. It works primarily as an NaSSA (Noradrenergic and Specific Serotonergic Antidepressant) similar to the drug Remeron. Specifically, this drug acts as an antagonist at the H1 histamine receptor more than any other. It also works as an antagonist at the 5-HT2C, 5-HT2A, Alpha-2A, and 5-HT2B receptors.
In addition to having antidepressant properties, the drug also acts as an anxiolytic, sedative, and appetite boosting drug. It was considered less dangerous than most tricyclics (TCAs) in regards to overdose. The efficacy of this drug is comparable to that of many other TCAs including Amitriptyline and Doxepin as well as various SSRIs such as Paxil and Prozac.
There is also some evidence supporting the use of this drug as an antidepressant augmentation strategy. Mianserin has been found helpful in alleviating various negative symptoms and cognitive symptoms of schizophrenia and has proven to help treat psychosis in Parkinson’s disease. As a potent antihistamine, extensive use of this drug can lead to weight gain and feelings of lethargy.
Remeron was already discussed under the list of atypical antidepressants that was created. Just like Mianserin, this drug is classified as a tetracyclic antidepressant and functions as an NaSSA (Noradrenergic and Specific Serotonin Antidepressant). The drug works primarily as an antagonist at the H1 histamine receptor. It also has modest effects as an antagonist at the 5-HT1A receptor and the Alpha-2C / Alpha-2A receptors.
It was marketed in the United States since 1996 and is utilized to treat severe cases of depression. Other uses for this drug include: an anxiolytic, sedative, and appetite booster. This drug has been found to be very effective for depression. One meta-analysis in 2009 demonstrated that Remeron was more effective than all other antidepressants on the market.
Despite being more effective, the degree to which it was considered more effective wasn’t clinically significant. It should also be mentioned that the side effect profile associated with this drug is considered average compared to other drugs. In comparison to various TCAs, this drug has been found to be better tolerated with equal efficacy. This is a faster-acting antidepressant that can sometimes lead to symptom improvement within a week or two of administration. It is thought to have many similar side effects to drugs in the SSRI class.
This is a tetracyclic antidepressant (TeCA) released in 1989 that works similarly to the drug Remeron, as an NaSSA (Noradrenergic and Specific Serotonergic Antidepressant). It was initially approved in Japan and is thought to function primarily as a norepinephrine reuptake inhibitor, H1 histamine receptor antagonist, Alpha-2 receptor antagonist, and serotonin receptor antagonist. Although it is prescribed primarily for depression, there is some evidence suggesting that it may be helpful at reducing the negative symptoms of schizophrenia.
Other Tetracyclic Antidepressants (TeCAs)
Below are some other TeCA drugs that were developed, but never marketed.
This was a TeCA drug that was put through clinical trials for major depression in the 1980s. It worked as an Alpha-2 antagonist with some effects as an H1 histamine receptor antagonist and 5-HT2 receptor antagonist. Its Alpha-2 antagonism was thought to be up to ten times as potent as Mianserin. It didn’t really affect levels of the neurotransmitters serotonin and norepinephrine. It functioned as an NaSSA (Noradrenergic and Specific Serotonergic Antidepressant). This drug never ended up being marketed by pharmaceutical companies.
This was a TeCA drug that was developed in the 1970s that never hit the pharmaceutical markets. It functioned as an antidepressant as well as a weight loss drug, acting mostly as a norepinephrine reuptake inhibitor. In rodents the drug was thought to produce an “energy wasting” effect without signs of increased central nervous system stimulation. It also had some effects on the reuptake inhibition of dopamine and minimal effect on the H1 histamine receptor.
This is a TeCA drug that contains the S-enantiomer of Remeron and has a similar structure. Like Remeron, this drug acts heavily on the H1 histamine receptor, Alpha-2 receptor as well as the 5-HT2 receptor. It was initially in development for treating symptoms of menopause, primarily hot flashes and insomnia. The drug was going through clinical trials, but its development was abandoned by Merck for various reasons.
Oxaprotiline (C 49-802 BDA)
This TeCA drug functions as a norepinephrine reuptake inhibitor and is similar to the drug Maprotiline. It was primarily thought to have antidepressant properties by increasing norepinephrine, as well as acting on the H1 histamine receptor as a selective antagonist and to a lesser extent the Alpha-1 receptor. Despite being investigated, the drug never ended up becoming available for clinical use.
Tetracyclic Antidepressants (TeCAs): How do they compare to other classes?
This class of drugs was lesser explored and there weren’t as many drugs that actually made it to the market as other classes. The tricyclic antidepressant class seems to have more drugs that ended up being effective to treat depression than the tetracyclics. Really the only tetracyclic antidepressant that has proved itself as being highly effective for depression is Remeron.
Remeron has been extensively studied and is considered a very potent and effective treatment option by professionals. Although it is older, the drug tends to work very well for people who aren’t responding to other medications. Nearly all of the other drugs in the TeCA class tend to be problematic due to their sedating effects and affinity for the H1 histamine receptor. Some people may be interested in noting differences between tetracyclic drugs and tricyclics, but other then for historical purposes, there’s no reason to further investigate this class of drugs for depression.
Besides Remeron, most of these drugs aren’t even considered for treatment of depression in the United States. Although some TeCAs initially appeared to hold some promise, many never ended up being marketed, proving to be a waste of time and money. Are you intrigued by the tetracyclic class? Feel free to share your thoughts on TeCAs in the comments section below.