A Closer Look At Antidepressants 

A Clinical Overview Of The Different Types Of Antidepressants In Ireland, Including Their Mechanism Of Action And Patient Selection.

OVERVIEW 

The first antidepressants were developed in the 1950s. There are now about 30 different kinds of antidepressants available and there are several main types: 

• Tricyclics. 
• MAOIs (monoamine oxidase inhibitors). 
• SSRIs (selective serotonin reuptake inhibitors). 
• SNRIs (serotonin and noradrenaline reuptake inhibitors). 
• NASSAs (noradrenaline and specific serotonergic antidepressants). 
• Serotonin modulator. 

HOW ANTIDEPRESSANTS WORK IN BRIEF 

Antidepressants increase the activity of neurotransmitters serotonin and noradrenaline in the brain. Melatonergic agonists increase the release of melatonin in the brain, which has a positive effect on mood and sleep. Agomelatine is the only drug in this class so far. 

WHAT ARE THEY USED FOR? 

Antidepressants should never be used for mild depression; ‘talking treatments’ such as Cognitive Behavioural Therapy should always be considered the first option in mild depression. Antidepressants should only be used for moderate-to-severe depression. Antidepressants are also used for the following conditions: 

• Severe anxiety and panic attacks. 
• Obsessive compulsive disorders. 
• Chronic pain. 
• Eating disorders. 
• Post-traumatic stress disorder. 

HOW WELL DO THEY WORK? 

After three months of treatment, it is estimated that 50-to-65 per cent of patients with depression show improvement when treated with antidepressants. This compares with 25-to-30 per cent of patients who are treated with a placebo. 

ARE NEWER ANTIDEPRESSANTS BETTER? 

Older tablets such as tricyclic antidepressants are just as effective as the newer ones (SSRIs), but the newer ones generally have less side-effects. Newer antidepressants are also less dangerous on overdose. However, older antidepressants still have some benefits. For example, because tricyclic antidepressants cause more drowsiness, they are sometimes prescribed to be taken at night in patients suffering from severe insomnia due to depression. 

SIDE-EFFECTS OF ANTIDEPRESSANTS 

The most common side-effects are as follows: 

Tricyclics 

Tricyclics commonly cause dry mouth, a slight tremor, fast heartbeat, constipation, sleepiness, and weight gain. These effects are reduced if a low dose is given to start, and the dose is then slowly increased. Other side-effects which are more common in older people include confusion, inability to pass urine, and postural hypotension. They should be avoided in patients with heart conditions, as they can cause irregular heartbeat. They can cause erectile dysfunction and delayed ejaculation in men. Tricyclic antidepressants are dangerous in overdose, as they can cause cardiac problems. This is especially true for amitriptyline, which should not be used for depression. Amitriptyline is generally only used for nerve pain nowadays. 

SSRIs 

SSRIs can cause nausea and anxiety initially; however, these side-effects often wear off after a few weeks. They can cause indigestion, but this can be avoided by taking with food. They can also cause sexual dysfunction, such as loss of libido. There have been rare reports of episodes of aggression. 

Most people only experience mild side-effects (if any). The side-effects usually wear off over a couple of weeks as the body gets used to the medication. The more serious ones — problems with urinating, memory problems, falls, confusion — are uncommon in healthy, younger, or middle-aged people. 

SNRIs 

The side-effects are very similar to the SSRIs, although venlafaxine should not be used with a serious heart problem. It can also increase blood pressure, so this should be monitored, especially initially. 

MAOIs 

MAOIs are rarely prescribed nowadays because of the higher risk of side-effects and interactions, so they are generally reserved for resistant depression (despite treatment with other antidepressants) under specialist supervision. This is because they can cause a hypertensive response (dangerously high blood pressure) if foods containing tyramine are eaten with them. Foods containing tyramine include mature cheese, pickled herring, broad bean pods, and yeast extracts, including brands like Bovril, Oxo and Marmite. Even stale or gone-off food can cause this reaction. Interactions are more common with MAOIs, including a higher risk of serotonin syndrome (SS) with other antidepressants (see more later). 

NASSAs 

Mirtazapine is the most common drug used in this group. The side-effects are very similar to SSRIs. It can cause drowsiness and weight gain, but it causes less sexual problems than SSRIs. 

Melatonergic agonists 

Side-effects include headache, migraine, and dizziness. They are considered to have less sexual side-effects and fewer withdrawal symptoms than other antidepressants. 

MORE ON THE NEWEST ANTIDEPRESSANT ON THE MARKET 

As vortioxetine is the newest antidepressant on the market, I am going to discuss it in a little more detail than other antidepressants. 

SEROTONIN MODULATOR 

Serotonin modulator is a relatively new class of antidepressant used to describe vortioxetine (Brintellix), which is the only drug in this class. How is works is not fully clear, but it is thought to act as a serotonin reuptake inhibitor (SRI), agonist of the 5-HT1A receptor, and antagonist of the 5-HT3 and 5-HT7 receptors. 

It is indicated for major depressive illness and is generally reserved for when other antidepressants are not successful; generally, where at least two other antidepressants were not successful. There was no convincing clinical effectiveness evidence to show that vortioxetine was more or less effective than other antidepressants, but it may have a better overall safety profile than other antidepressants. Nausea is a very common side-effect, with the following being other possible side-effects: Dizziness, serotonin syndrome, flushing, diarrhoea, constipation, vomiting, pruritis and night sweats. It is recommended that treatment with vortioxetine is continued for at least six months after symptoms improve. Vortioxetine does not have discontinuation or withdrawal symptoms, so it can be stopped without the need to reduce the dose slowly. 

RISK OF SEROTONIN SYNDROME (SS) WITH VORTIOXETINE 

According to the SPC from the manufacturer of vortioxetine, serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are two life-threatening conditions that can occur when vortioxetine is administered with other serotonergic-active substances, including opioids and triptans, medications that impair the metabolism of serotonin (ie, MAOIs), antipsychotics, and other dopamine antagonists. 

Prescribers and patients should be vigilant for the signs and symptoms of SS or NMS, especially when vortioxetine is prescribed with other drugs that increase the risk. 

SS symptoms include mental status changes (ie, agitation, hallucinations, coma), autonomic instability (ie, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (ie, hyperreflexia, incoordination) and/ or gastrointestinal symptoms (ie, nausea, vomiting, diarrhoea). NMS symptoms include fever, muscular rigidity, autonomic dysfunction (ie, Parkinson’s-type systems), and altered mental status. If symptoms of SS or NMS occur, vortioxetine should be discontinued by the prescriber immediately and the patient should get symptomatic treatment for these symptoms. 

While the SPC for vortioxetine severely warns of the risks of SS and NMS when administered with other serotonergic-active substances like antipsychotics, practice and studies over the last 10 years show that vortioxetine can be safely prescribed with antipsychotics like lithium, with minimal incidences of SS or NMS. While monitoring and caution are advised, vortioxetine can be given safely with most other serotonergic-active substances in most cases. 

Concomitant use with non-selective monoamine oxidase inhibitors (MAOIs) or selective MAO-A inhibitors is the exception, so vortioxetine is contraindicated with these due to high risk of SS. Avoid MAO inhibitors with vortioxetine. Examples to be avoided with vortioxetine include linezolid (antibiotic), moclobemide, phenelzine and tranylcypromine (three MAOI antidepressants), and rasagiline and selegiline (primarily used as an adjunct in advanced Parkinson’s). 

The safety of vortioxetine in combination with other antidepressants has not been fully studied, but concomitant use should be avoided whenever possible. SS would be a risk if given with other antidepressants. 

ARE ANTIDEPRESSANTS ADDICTIVE? 

Antidepressant drugs do not have addictive properties, unlike tranquillisers, alcohol, or nicotine. Therefore, the patient will not need to keep increasing the dose to get the same effect or they will not find themselves craving them when they stop taking them. 

However, up to a third of people who stop SSRIs and SNRIs have withdrawal symptoms, which can last between two weeks and two months. 

Withdrawal effects include gastrointestinal disturbance, headache, dizziness, sleep disturbance, fatigue, sweating, and sensations in the body like electric shocks. For most patients, any withdrawal effects are mild, but for a minority they can be severe. They seem to be most likely to happen with paroxetine and venlafaxine. Withdrawal effects can be minimised by reducing them slowly when going off them. 

Some patients indicate that after taking an SSRI for a few months, they experience difficulties managing after the SSRI is stopped, which gives them the feeling that they are addicted to it. However, most experts agree this is due to the depression returning because of discontinuation of the drug, rather than any addictive properties of SSRIs. The Committee of Safety of Medicines in the UK reviewed the evidence in 2004 and concluded: “There is no clear evidence that SSRIs and related antidepressants have a significant dependence liability or show development of a dependence syndrome according to internationally accepted criteria.” 

SUICIDAL FEELINGS WITH SSRIS IN YOUNGER PEOPLE 

There is some evidence of increased suicidal thoughts in young adults prescribed antidepressants, however this has not manifested itself in increased risk of actual suicidal acts. The National Institute for Health and Care Excellence (NICE) in the UK has stated that fluoxetine, an SSRI antidepressant, can be used in the under- 18s for moderate-to-severe depression and is considered the only antidepressant where the benefits outweigh the risk to under- 18s. It was noted by the Royal College of Psychiatrists in 2004 in relation to SSRI use in under-18s that “there is no clear evidence of an increased risk of self-harm and suicidal thoughts in adults of 18 years or over. Young adults are more likely to commit suicide than older adults, so a young adult should be particularly closely monitored if he or she takes an SSRI antidepressant.” The FDA (in the USA) comes to a similar conclusion in relation to SSRIs in younger adults. 

HOW LONG DO THEY NEED TO BE TAKEN FOR? 

Studies show that if antidepressants are stopped within eight or nine months, the symptoms of depression are more likely to come back. The current recommendation is that it is best to take antidepressants for at least six months after the patient starts to feel better. In patients who have had two or more attacks of depression, then treatment should be continued for at least two years. 

ANTIDEPRESSANTS DURING PREGNANCY 

The benefits of antidepressants sometimes outweigh the risks during pregnancy. Non-drug methods such as Cognitive Behavioural Therapy should be tried before drugs in pregnancy. If medication is needed, for example in cases of suicidal feelings, SSRIs are the most-commonly prescribed. Tricyclics are best avoided in pregnancy. 

ANTIDEPRESSANTS IN BREASTFEEDING MOTHERS 

A baby will get only a small amount of antidepressant from mother’s milk. Babies older than a few weeks have very effective kidneys and livers, so they can effectively metabolise and get rid of the small amounts of the antidepressant they may absorb in the same way as adults do, so the risk to the baby is minimal. 

IMPORTANT POINTS WHEN TAKING ANTIDEPRESSANTS 

• They should be taken every day, otherwise they will not work. 
• After commencing, it will take one-to-two weeks to start seeing the benefit on mood and can take up to six weeks for full effect. 
• With some of the older tricyclic drugs, it is best to start on a lower dose and work upwards over a few weeks. 
• The dose of SSRI antidepressant generally does not have to be increased slowly. The dose the patient starts with is usually the dose they carry on with. 
• It doesn’t help to increase the dose above the recommended levels. 
• Many patients are put off by the initial side-effects, such as nausea. 
• Initial side-effects of antidepressants such as nausea generally wear off in a few days. They should not be stopped unless the side-effects are very severe. 
• Perseverance is important — the commonest reason for antidepressants not working is stopping too soon and not giving them a chance to work. 
• The doctor should be informed about any major changes in mood, especially when the dose of antidepressant is changed. 
• Alcohol should be taken in moderation only, or avoided if possible. Alcohol is a known depressant so can make depression worse, but with antidepressants, alcohol increases risk of drowsiness and lethargy.