New medicine ups the ante on depression

Anton* was doing extremely well. One of those small crust of high earners who make up the business elite of South Africa, he was in a relationship and was an active and dedicated sportsman. Then he had to be hospitalised for an acute attack of pneumonia, and when he was released he fell into a deep clinical depression.

He wound up in psychiatrist Dr Rykie Liebenberg’s consulting rooms. Apart from psychotherapy, she prescribed a range of the available antidepressants—the selective serotonin reuptake inhibitors that have been the gold standard for treating depression in the past decade. But as so often happens with these drugs, “within a week, his libido had ­disappeared and he found that unacceptable. He was sleeping badly, very anxious, unable to function at work, and his mood remained very low.”

Liebenberg decided to put Anton on a new drug that had recently been given to her for “compassionate” cases—those people whose situations are so desperate that it seems kinder to get them started on a new drug as soon as p­ossible, even before it has been commercially launched.

Agomelatine—which, by the time you read this, will be available in South Africa under the brand name Valdoxane—has a completely different action to other antidepressants.

Whereas other antidepressants work by altering the levels of serotonin, dopamine or similar neurotransmitters, agomelatine targets the brain’s clock, a little mechanism called the suprachiasmatic nucleus of the anterior hypothalamus. The suprachiasmatic nucleus is a kind of master clock that orchestrates other clocks in the body and it is a key regulator of our circadian rhythm.

What is the circadian rhythm? The origin of the word provides a clue: circa in Latin means “around” and dies means “day”. So the circadian rhythm is a roughly 24-hour cycle of activity in living things, encompassing biochemistry, physiological processes and behaviour. In humans it is marked by the secretion of melatonin, which travellers will know as the substance that helps you adjust to jet lag, the changes in body temperature—your temperature is at its lowest at about 5am, two hours before waking—and the level of cortisol, one of the stress hormones. Your circadian rhythm is what tells you when to feel sleepy or to feel energetic, and when to feel mentally alert.

The suprachiasmatic nucleus responds to the input of light through the eye; humans need a daily cycle of dark and light to function effectively. It is the shift between light and dark and even between the different spectra of light during the day that triggers production of certain neurohormones and neuropeptides. Scientists tell us this is “non-visual photoreception”, which means even visually challenged people respond in a similar way, according to Joan E Roberts of Fordham University’s paper “Circadian Rhythm and Human Health”.

Natural rhythm is healthiest
Targeting the brain’s master clock seems intuitively right. After all, disturbance of the sleep-wake cycle is one of the most prominent symptoms of a major depressive disorder.

And we have known for a long time that people who do not get enough daylight during winter in the far north, for example, can suffer from a condition known as seasonal affective disorder, a form of depression that can be helped or prevented by exposure to ultraviolet light, even artificially created light.

We have also long known that jet lag, resulting from crossing time zones, can cause fatigue, insomnia, anxiety, irritability and even memory loss. It has been shown that shift workers who work by night and have to sleep in the day can suffer from the most devastating health impacts, increasing their risk of obesity, cancer and type-2 diabetes, as well as affecting their mood. Roberts points out in her paper that the human immune response follows a circadian cycle; when it is disrupted, there is a greater risk of infectious and auto-immune disease.

Sleep cycles are at the core of both our mental and physical health. “Sleep comes in cycles beginning with slow-wave sleep and ending with REM (rapid eye movement) or dream sleep. Each cycle of sleep induces a different neuroendocrine change, which affects all aspects of human physiology. Delta sleep is the deepest sleep and is restorative. During this cycle there is a decrease in stress-related hormones, lowering of blood pressure, heart and respiration rate and an increase in growth hormone. REM sleep is a state of brain activation that increases heart rate and blood pressure and induces irregular respiration,” said Roberts.

About 15% of our night-time sleep was that restorative delta sleep, said Roberts, as opposed to only 5% of daytime naps, which explained why people forced to sleep in the daytime might be more stressed than their night-sleeping peers.

The World Health Organisation has warned that, by about 2030, depression will be the single biggest burden on our societies, both in terms of costs to the healthcare system and social costs. As South African psychiatrist Dr Franco Colin put it, clinical depression “is an illness of the brain that is severely disruptive, a whole-body disease that penalises its sufferers” by raising their risk of physical problems such as disturbances of the heart’s rhythms. And you cannot just “pull yourself together”, he said. “How can you pull yourself together using the very area of the brain that is sick?”

It is tempting to speculate that the researchers who developed this new drug have stumbled on a greater truth: constant exposure to artificial light, which has extended our active lives and provided so much that is useful and enjoyable, may be taking its toll in disturbing our circadian rhythms and making us more susceptible to major depressive disorders, among other things.

Resetting the clock
Recognising that the brain’s time-keeping is in some way impaired, psychiatrists and psychotherapists already work with the circadian rhythm of patients suffering from depression, teaching them to get into a regular pattern.

Agomelatine provides a significant chemical boost that takes resetting the rhythm to another level entirely. The drug has a similar structure to melatonin and does similar work in the suprachiasmatic nucleus. It stimulates melatonin receptors in the nucleus and elsewhere, blocks serotonin receptors and encourages neurogenesis, the growth of brain cells. One of the effects of depression is to “prune” connections in the brain and neurogenesis helps to repair this damage. The suprachiasmatic nucleus responds by resetting abnormal rhythms.

The appealing thing about this new drug is that it has to be taken as you go to sleep, because it heads straight for the suprachiasmatic nucleus. It does its job, helping you to drop to healthy sleep and then leaves the body fast. Within one week, sleep quality and patterns have improved and mood has lifted—but not at the expense of side effects such as lost sexual desire. And tapering is not needed—the psychiatrist can start patients at an effective dose instead of working up to the right dose and if patients want to quit the drug they can just stop, instead of slowly reducing doses over weeks.

“It’s not a magic wand,” Liebenberg said. “You still have to look at all the other factors involved: diet, lifestyle, exercise, substance abuse, relationships and so on.” But it is revolutionary and exciting—and it advances the treatment of this terrible affliction in an important way.

*Name and circumstances were changed to protect privacy

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