A new substance named Lu AF60097 may help reduce side effects from tricyclic antidepressants


About one in five Danes are affected by depression at some point in their lives. The severe depressions may be treated with the so-called ‘tricyclic antidepressants’, an antidepressant drug that is more effective than the drugs used for mild and moderate depressions.

But unfortunately, the tricyclic antidepressants also have a downside: significantly more and more serious side effects. So serious that many people stop taking the drug and thus receive no treatment for their depression.

Now, researchers from the Faculty of Health and Medical Sciences at the University of Copenhagen, in collaboration with Lundbeck A/S and the National Institutes of Health in Baltimore, have discovered a substance that may solve that problem.

‘We have discovered a substance, Lu AF60097, that works in a different way from the ones presently in use.

If the new substance works, it may help the existing drugs get rid of the serious side effects’, says Professor at the Department of Neuroscience at the Faculty of Health and Medical Sciences, Claus Juul Løland.

Therapeutic effect without side effects

Serotonin is a so-called neurotransmitter, a chemical substance found in the brain. In a person with severe depression, the level of serotonin is very low. Antidepressant drugs make adjustments to get a higher level of active serotonin.

‘The antidepressants we use today work by going in and binding to the same site as serotonin on the serotonin transporter (SERT). The antidepressants block the return transport of serotonin and thereby also the removal of the active serotonin.

But such blockage requires a relatively large dose of the antidepressant substance. And with the tricyclic antidepressants, that causes some serious side effects’, says Claus Juul Løland.

The side effects can be anything from life-threatening heart problems to severely dry mouth, visual disorders, development of mania, weight problems and digestive challenges.

The substance discovered by the researchers binds to another site on SERT: the ‘allosteric site’. When a substance binds to the allosteric site rather than the same site as serotonin, it is possible to regulate the function of the serotonin transporter instead of completely blocking it.

Serotonin is a so-called neurotransmitter, a chemical substance found in the brain. In a person with severe depression, the level of serotonin is very low. Antidepressant drugs make adjustments to get a higher level of active serotonin.

‘In this case, we have shown that when we bind this substance to the allosteric site while giving the tricyclic antidepressant, we can amplify the binding of the antidepressant substance.

Therefore, we can use a much smaller concentration of the antidepressant substance. It might cause fewer side effects, but have the same therapeutic effect’, says Claus Juul Løland.

From concept to drug

The researchers have, over a long period of time and in several rounds, screened a number of substances from Lundbeck’s drug library to find a substance that had a sufficiently strong link to the allosteric site to make it possible to study the pharmacological effect. With Lu AF60097, they finally succeeded.

But there is still a long way to go before the substance can be used as an actual drug. The researchers have shown that a substance that binds to the allosteric site can have this pronounced, pharmacological effect in cells and in rats. From here, it is up to the pharmaceutical companies to develop substances that may have the same effect in humans.

‘We have taken the first step. But perhaps also the biggest. We have shown that the concept works. If it also works in practice, hopefully in the future it can be used to treat people with severe depression’.

While antidepressants may be the drug of choice for depression, they also have FDA approval as treatments for other medical disorders. For example, antidepressants are useful in the treatment of obsessive-compulsive disorder, social phobia, panic disorder, generalized anxiety disorder (GAD), and post-traumatic stress disorder (PTSD).[1] 

Antidepressants also have non-FDA approved, off-label indications. For example, tricyclic antidepressants are prescribed for pain, insomnia, and migraine. Trazodone, a serotonin modulator, is used off-label for insomnia.[2]

Mechanism of Action

The different classes of antidepressants all work in slightly different ways and target certain neurotransmitters to modulate mood and behavior. All currently licensed antidepressants are believed to work by increasing the neurotransmitters serotonin or norepinephrine, or both, in the synapse. The mechanisms to increase these neurotransmitters vary, though antidepressant drugs target reuptake by the nerve terminals.[3] For example, selective serotonin reuptake inhibitors (SSRIs) work by inhibiting 5-HT reuptake by the presynaptic cleft in a synapse, thus increasing available serotonin levels.[4] Serotonin and norepinephrine reuptake inhibitors (SNRIs) block serotonin reuptake, like SSRIs, however, they also block norepinephrine reuptake in the synapse.[5]

Atypical antidepressants have different mechanisms of action. Bupropion, for example, works by inhibiting the reuptake of dopamine and norepinephrine at the presynaptic cleft.[6] Another atypical antidepressant, agomelatine, works by agonizing melatonin receptors MT1 and MT2 while antagonizing serotonergic 5-HT2C receptors, promoting dopamine and norepinephrine release.[7] Serotonin modulators, like nefazodone, may work by down-regulating postsynaptic serotonin 5-HT2A receptors.[6]

Tricyclic antidepressants, like amitriptyline, are thought to work by inhibiting the reuptake of serotonin and norepinephrine.[8]

Lastly, monoamine oxidase inhibitors (MAOIs), work by inhibiting the monoamine oxidase enzyme, which catabolizes serotonin, norepinephrine, and dopamine.[9] Another antidepressant drug that does not work by blocking reuptake is mirtazapine.

Mirtazapine works by blocking alpha-2 adrenergic receptors on the cell bodies and nerve terminals, promoting the release of norepinephrine into the synapse.

Furthermore, mirtazapine antagonizes 5-HT and 5-HT receptors, which has been shown to increase norepinephrine and dopamine in the cortical regions of the brain.[3]


Currently, commercially available antidepressants are available to be administered in the form of oral tablets, oral extended-release tablets, oral suspensions, topical creams, and transdermal patches. Studies are examining alternative administration routes, via inhalation, intranasal, sublingual, and rectal forms. These alternative routes are not yet commercially available for antidepressant therapy.[10]Go to:

Adverse Effects

Among the most prevalent side effects of antidepressants include sexual dysfunction, drowsiness, weight gain, insomnia, anxiety, dizziness, headache, dry mouth, blurred vision, nausea, rash, and tremor. Patients may also describe asthenia and malaise while on antidepressant therapy. Clinicians may note symptoms of hyperprolactinemia, syndrome of inappropriate antidiuretic hormone (SIADH), and hyponatremia in patients taking antidepressants.[11]Go to:


There are several scenarios where antidepressant use may be contraindicated. These scenarios vary between and within classes. Antidepressants should be used with caution in patients with known hypersensitivities or who are taking other psychotropic medications.

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), for example, should not be taken with other SSRIs, monoamine oxidase inhibitors, tricyclic antidepressants, and other psychotropics; this is due to the risk of serotonin syndrome, which can lead to severe neuromuscular and autonomic symptoms.[12]

Tricyclic antidepressants can provide another good example of relative contraindications in antidepressant therapy. Clinicians should be mindful when prescribing tricyclic antidepressants to individuals with cardiovascular disease.

Tricyclic antidepressants have been shown to cause orthostatic hypotension.

Additionally, in patients with preexisting bundle-branch disease, tricyclic antidepressants may lead to heart block.[13]

 Buproprion, an atypical antidepressant, has seizure disorder listed as a major contraindication. This contraindication applies to patients with an active seizure diagnosis or with a history of prior seizure activity.

Like other antidepressants, bupropion should not be used in patients taking monoamine oxidase inhibitors, or drugs that can lower the seizure threshold.[14]

University of Copenhagen


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