Antidepressants

Authors: Dr. David Healy, Dr. Joanna Le Noury, Dr. Dee Mangin

Last updated: 2016

What are antidepressants?

Antidepressants are psychiatric drugs that are licensed for the treatment of depression. Some are also licensed for other conditions such as anxiety, eating disorders and obsessive compulsive disorder (OCD).

Types of antidepressants include:

• Selective serotonin reuptake inhibitors (SSRIs)
• Serotonin-norepinephrine reuptake inhibitors (SNRIs)
• Tricyclic antidepressants (TCAs)
• Monoamine oxidase inhibitors (MAOIs)

Deciding to start an antidepressant

People are often unsure whether they should start an antidepressant. They are likely to hear very strong opinions on both sides of the argument.

Part of the problem lies in the changing views of depression brought about by the interaction between the development of antidepressants and the marketing strategies of drug companies. When first developed, these drugs were used to treat a condition called melancholia or endogenous depression, but the boundaries between this disorder and normal sadness have disappeared and many people now get antidepressants who shouldn’t.

Depending on the circumstances, antidepressants should not typically be used for situational and social problems, such as:

• bereavement
• exam stress
• financial difficulties
• relationship problems
• work-related stress

In these cases, the potential harm is likely to outweigh the benefit. The drug may initially feel like it is helping, for example by making you less emotional. However, the side effects may have a significant impact on your quality of life and you may have difficulty getting off treatment due to serious withdrawal problems. You may also be left with persisting side effects after stopping, some of which may be permanent.

If you are a woman of child-bearing years, you may be unable to get off treatment if you want to become pregnant. The risk of birth defects can persist for months or perhaps longer after stopping an antidepressant.

Antidepressants should only be considered where:

• the person is in crisis and other first line therapies have failed
• the problem is becoming more enduring and other first line therapies have failed

Antidepressants given short term can work for a problem that does not seem to be resolving spontaneously. But once recovery has come about, consideration should be given to stopping them and if the problem appears to come back, the possibility of a withdrawal syndrome should be kept in mind.

The benefits of antidepressants

What do antidepressants do?

They do not correct an abnormality. The antidepressants are a group of very different drugs that act in quite different ways. If one group doesn’t suit you, others may suit better.

Drugs that act on the serotonin system, like the SSRIs and SNRIs and some of the tricyclics, can reduce anxiety and produce an emotional numbing effect. The SSRIs and SNRIs have the strongest numbing effects.

Drugs that are active on the noradrenaline system like the MAOIs and some tricyclics are more energizing or stimulant.

Others act on receptors that can restore appetite and increase sleep.

Some of the tricyclics are the most potent antidepressants, and do a little of all of the above.

Do antidepressants work?

If the question is do SSRIs emotionally numb? – the answer would be yes. If tested for these effects, SSRIs are as easy to distinguish from placebo as alcohol is — and we don’t need trials for this. Trials are needed for the antidepressants because there are doubts as to how helpful effects like emotional numbing are in depression.

For most people, saying a treatment “works” suggests it saves lives, or enables people to return to work, or makes the chances of an illness returning in the future less likely.

As of 2016, the trials that had been done for antidepressants involving over 100,000 patients showed more deaths in those on antidepressants than on placebo.¹

There is no formal research showing that antidepressants get people back to work — no one has ever attempted to investigate this. Studies have looked at quality of life, but only 5% of the results have been published.

There is some evidence that antidepressants may make future episodes of depression more likely.

SSRIs and other newer antidepressants do not work for severe disorders. SSRIs are much more useful for some nervous states such as obsessive compulsive disorder than other antidepressant groups.

What overall impact will antidepressants have on how I function?

If you are severely depressed and given an older tricyclic antidepressant, it may dramatically shorten the episode, save your life, your marriage and get you back to work.

If you are suffering from mild to moderate depression, or from chronic (long-term) depression, the treatments are more likely to produce side effects rather than benefits. Any improvement on medication is more likely to be due to time or the placebo effect, and your problem is then ensuring you can get off treatment. If you can identify a very clear benefit such as reduced anxiety, there is a chance the antidepressant rather than placebo is making a difference.

If you are on a cocktail of drugs, you might ask your doctor the question how they would function on this cocktail and if the answer is not very well, the same is likely to apply to you.

Are the effects of antidepressants down to placebo?

Many publications state that 5 out of 10 people respond to antidepressants and 4 out 10 respond to placebo, giving the impression that the effects of antidepressants are all in the mind. They aren’t. What this data shows is that many of us get better without medication or therapy.

To give antidepressants indiscriminately on the basis of these clinical trials makes as much sense as giving alcohol would. Just as there is a right time and person for alcohol therapy, so also there is a right drug for someone who is nervous and a right time to give it — but it takes caution and wisdom to get it right.

Just as the hazards of alcohol deter us from using it as a treatment, the antidepressants come with side effects that are not in the mind — risks of getting hooked, birth defects, impaired sexual functioning, strokes, fractures, suicide and homicide, and in children stunted growth.

It may make sense to take these risks if there is a clear benefit from treatment. But what the trials show is that many doctors when they see a patient improve on treatment assume that the treatment has produced the benefit — without asking the patient whether they can detect anything useful the treatment is doing.

In contrast any side effects will be attributed to your illness rather than the pill.

How long do I have to be on treatment?

Half of those put on an antidepressant stop within a month — in part because of side effects.

There is no research that matches people with optimal time on treatment. When antidepressants produce a clear benefit, the original clinical view was that 3-4 months was adequate. Recent views linked to the pharmaceutical industry began at 6-12 months, then moved out to over a year and since then to indefinite treatment.

Treatment combinations

Patients who don’t respond to an antidepressant are sometimes prescribed additional medication such as a second antidepressant or an antipsychotic.

There is no strong evidence for the use of treatment combinations. Continuing to take a medication that isn’t working is generally inadvisable.

If you do not show a response to the addition of another drug within days, you should probably not remain on any combined treatment for long.

What are the risks?

The standard list of antidepressant side effects in the manufacturers information leaflets include nausea, vomiting, sedation, constipation, fainting, palpitations, sweating, tremulousness, headache, blurred vision, rashes, weight gain, along with depersonalization, derealization, confusion, mania, and psychosis.

The information leaflets that come with medications are written by drug companies. They need to be viewed with caution. They can vary dramatically in what they say about problems linked to a drug from country to country — with a drug having potentially lethal side effects in one country that don’t show in another.

Depending on the drug, antidepressants can also cause:

• Anxiety or agitation — severe in 20% of cases. (See akathisia)
• Dependence leading to significant withdrawal problems — up to 50%. For some it will be extremely difficult, if not impossible, to get off them.
• Birth defects ranging from heart defects through to autistic spectrum disorders, and increased rate of miscarriages.
• Alcoholism
• Sexual dysfunction in close to 100% of people who take them, and for some this may be permanent.
• They can trigger suicidality, aggression and violence in the early weeks of treatment, with any dose change and on withdrawal.
• For a small number of people there may be a toxic effect during the first week of treatment that leaves them significantly incapacitated for years afterwards.
• There may be subtle problems linked to increased bleeding times, or visual difficulties, or increased risks of bone fractures. All of these risks are increased if the antidepressant is combined with other pills, and can endure for years after stopping.

For more details, see Side Effects of Antidepressants.

Side effects may be misdiagnosed

Your doctor may misdiagnose some side effects as stemming from your condition. Suicidality, anxiety, change of personality, sexual dysfunction, insomnia — almost anything — can be portrayed as a feature of depression. It is important to recognize the differences, which can be difficult. These side effects ambush people, the way pre-menstrual tension does — often you only make the connection after the difficulty has cleared up. A trial of stopping treatment may be the only way to work out what is going on.

The same problem faces people with asthma whose drugs may cause respiratory side effects or people with bowel conditions like Crohns’ disease whose treatment may cause gut side effects. Even if you become convinced of a link, you may find your doctor difficult to persuade. Prescription drugs are always innocent and patients guilty. In contrast, street or over the counter drugs are always guilty.

How likely are listed side effects of antidepressants to happen?

No one knows. Companies say that if they have happened even once we have to list them. This implies they are rare. But in fact side effect data are not collected properly. The best example are the sexual side effects of SSRIs which companies listed as happening in less than 5% of cases when in fact they happen in close to 100% of cases.

What unacknowledged risks can reasonably be suspected?

On launch the antidepressants should have come with clear statements about the risks of dependence, withdrawal, birth defects and other difficulties. We simply do not know what chronic actions on systems like the serotonin system might trigger for good or bad.

Stopping

Depending on the antidepressant, up to 50% of people may have withdrawal difficulties. It may be possible to minimize problems by tapering the drug very slowly using a liquid formulation. But for some this doesn’t work – around 1 in 16 people are unable to stop even with tapering. Some of those say that withdrawal is more difficult than from opiates or alcohol.

This can be a particular problem for those who want to become pregnant, or those who find themselves unexpectedly pregnant.

SSRIs and SNRIs can blunt normal emotions such as anger. Stopping them can lead to a resurgence of these emotions in someone who is no longer used to dealing with them, posing significant problems.

For the people who are on antidepressants and find that they feel much worse when they come off and that things improve when they go back on treatment, the likelihood is that you are dependent on the antidepressant or that you have lost your ability to tolerate emotions.

For more information, see Stopping Antidepressants.

Long-term effects

Taking and stopping antidepressants is not the same as never taking them.

Antidepressants can leave you with altered physiology after stopping. There is no timescale for recovery – this may persist for years or indefinitely.

Problems may include:

• Altered bone densities
• Changes to blood clotting
• Emotional numbness
• Gastrointestinal problems
• Restlessness
• Sensory problems
• Sexual side effects
• Urinary difficulties
• Vision problems

While some long-term effects may develop on treatment and remain after stopping, other problems may only emerge when the drug is actually stopped, such as:

• Cognitive problems. Some people notice that they are no longer able to think as clearly. This may range from concentration and memory issues, through to a general sense of “brain fog”.
• Dysthymia – a persistent mild depression.
• Stress intolerance. You may develop an inability to deal with stress, or find that you become anxious in difficult situations.

Myths about antidepressants

1. There is a lowering of serotonin or a chemical imbalance in depression.

This idea had been discarded by the early 1970s but was resurrected with the marketing of the SSRIs — there is nothing to it other than good marketing.

There is almost certainly some physical disorder in severe depression (melancholia) — but no-one knows what it is.

Over 90% of the serotonin in the body is in the gut or cardiovascular system, which means that drugs acting on serotonin reuptake are likely to have potent effects throughout the body — impairing sexual function, remodeling bones, making hemorrhages more likely.

2. Depression causes birth defects.

This is completely untrue but is used to scare women who are pregnant into taking antidepressants against their better judgment. Antidepressants increase rates of birth defects, miscarriages, and development delay in children.

3. Antidepressants take several weeks to work.

This is completely untrue. Antidepressants produce benefits and side effects within hours or days of first taking them. It may take several weeks for a clinical syndrome to lift, but the emotional numbing that can make an SSRI helpful or the increased sleep and appetite and other effects that may make a tricyclic helpful may be present from the first hour or two.

The argument that the drug takes time to work is trotted out as part of the defense against claims that an antidepressant has triggered suicide or violence.

4. Antidepressants do not cause addiction.

Many antidepressants cause people to be hooked to them — it becomes impossible to stop because of how bad the person feels on stopping and the relief from restarting treatment. Some drugs are worse than others. Because companies have denied there is any problem, it is difficult to know which drugs are the worst offenders and how to manage the problem.

Companies and their experts refer to discontinuation syndromes — another term for withdrawal or being hooked — in an attempt to avoid the stigma of withdrawal. But even national regulators now concede it may be impossible to stop certain antidepressants.

5. Antidepressants should not be given to bipolar disorder patients.

The depression in manic-depressive disorder is identical to straightforward depression and the response of both depressions to the drugs is similar.

Some experts suggest the patients likely to become suicidal on antidepressants are bipolar patients who are misdiagnosed and should instead have been put on a mood stabilizer. They also suggest that antidepressants destabilize bipolar disorders and lead to a greater number of episodes. But mood stabilizers can also cause suicide, even in patients with no psychiatric condition, and no mood stabilizer has been shown to reduce the number of episodes that patients have.

Alternatives to medication

For mild to moderate depression, your doctor should be prepared to wait and monitor the situation — especially for younger patients.

For many nervous illnesses the answer may be:

• Time: Most people who are “depressed”, nervous or anxious, have a condition that clears up in 12-16 weeks whether treated or not.
• Lifestyle: Improvements to physical activity, diet, sleep hygiene and limiting alcohol or other substances.
• Problem solving: Tackling problems in relationships or at work.

There is more evidence that these factors produce benefits in mild to moderate depression or anxiety, than there is for either medication or talk therapy.

As the disorder becomes more severe, the evidence for the benefit of a tricyclic antidepressant gets stronger. If a condition becomes more enduring, the treatment options become more complex and may vary all the way from changing work or relationships to a full investigation of contributing physical factors.

Consideration should always be given to the role that current medications may have in stalling recovery — for every 9 people out of 10 who have the expected response to a drug, there will be 1 out of 10 who has just the opposite response. The only way to assess this is to stop treatment.

Publications and studies

What studies have been done on these drugs?

Almost all studies on the antidepressants have been carried out or commissioned by the pharmaceutical companies that produce them. There are a vanishingly small number of independent studies. No government agency or independent authority runs studies. It’s as if automobile makers or hoteliers did their own rating of their products.

What data underpin the use of these drugs?

The raw data from studies of the antidepressants is almost universally unavailable, even though no-one in these trials gave consent to their data being sequestered.

Has anyone access to all the data?

No one has seen or has had access to all the data, not even FDA. The data is lodged in company vaults — and even hidden within the vaults.

What publications are there on the use of these drugs?

There have been several thousand publications from over 1,000 clinical studies involving antidepressants.²

Of the publications most (50-90%) appear likely to have been ghostwritten — that is written by a professional writer on behalf of a pharmaceutical company and published under the name of eminent physicians who may not have read the text.

For the most commonly prescribed antidepressants, between 40-50% of studies undertaken remain completely unpublished.

In up to 30% of the publications that claim a drug works well independent experts reviewing the data from the underlying study have concluded that the drug did not work.³

While some studies remain unpublished, others give rise to multiple publications — the record appears to be 234 publications from four Zyprexa (olanzapine) studies, none of which contain a clear picture of the weight gain, raised lipid levels, or glucose levels or rates of suicide this drug can cause — in other words the benefits are published on multiple occasions but the problems are hidden.⁴

One reason there are few articles on the risks of antidepressants (or other on-patent treatments) lies in the concerns of medical journals that they will be sued by pharmaceutical companies. Another is a general bias against publishing even convincing case studies that outline the hazards of treatment.

How good are the studies?

Even if all studies were published by real authors, there would be a problem. Almost all the trials done only last a few weeks. They do not look at outcomes that matter to the people who take the pills such as whether I live or die, get back to work, or have a better quality of life. The rating scales used to decide if the drugs work in fact can show an improvement in your depression score even if all that is happening is that you are suffering from side effects.

The studies do not cover what happens to anyone on these drugs for more than a few weeks.

Do the people in the studies resemble me?

Many of the people in antidepressant trials were recruited by advert. A lot were volunteered by their doctor rather than volunteering themselves. None gave informed consent. Some didn’t exist.

If you are severely depressed — there were almost no people with severe depression. If you are being treated for another condition in addition to depression or anxiety, there were few people like you in the trials.

Are there any problems if my doctor keeps to recognized guidelines?

It is customary to think that independent guidelines are superior to guidelines linked to pharmaceutical companies. But in fact the guidelines tend to be identical and independent guidelines may be more dangerous by virtue of their apparent independence.

When the independent Cochrane Center reviewed the antidepressants, they concluded that Sertraline (Zoloft) was among the most effective and safest, but taking unpublished data into account it ranks among the least effective.

When the Cochrane Center first reviewed the use of antidepressants for children, they concluded these drugs were safe and effective, but when legal cases brought unpublished data to light it was clear they weren’t.

When the Cochrane Center first reviewed the evidence on Tamiflu they concluded it was beneficial but when unpublished data became available they had to revise their view.⁵

Commonly used antidepressants

Type	Generic Name	Brand Name
SSRI	Citalopram	Celexa, Cipramil
SSRI	Escitalopram	Lexapro, Cipralex
SSRI	Fluoxetine	Prozac
SSRI	Fluvoxamine	Luvox
SSRI	Paroxetine	Paxil, Seroxat
SSRI	Sertraline	Zoloft, Lustral
SNRI	Desvenlafaxine	Pristiq, Khedezla
SNRI	Duloxetine	Cymbalta
SNRI	Venlafaxine	Effexor, Efexor
TCA	Amitriptyline	Elavil, Endep
TCA	Clomipramine	Anafranil
TCA	Desipramine	Norpramin
TCA	Dosulepin	Prothiaden
TCA	Doxepin	Silenor
TCA	Imipramine	Tofranil
TCA	Lofepramine	Lomont
TCA	Nortriptyline	Pamelor, Aventyl
TCA	Trimipramine	Surmontil
MAOI	Moclobemide	Aurorix
MAOI	Phenelzine	Nardil
Other	Agomelatine	Valdoxan
Other	Bupropion	Wellbutrin, Zyban
Other	L-tryptophan	Optimax
Other	Maprotiline	Ludiomil
Other	Mirtazapine	Remeron, Zispin
Other	Reboxetine	Edronax
Other	Trazodone	Oleptro

Further reading

• Notes on Antidepressant Withdrawal to take to your Therapist
• Serotonin and Depression – The marketing of a myth (external link)
• Restoring Study 329 (external link)

Footnotes

1. Unpublished data — communication from FDA ↩︎
2. Healy D (2004). Let Them Eat Prozac. New York University Press, New York; Healy D (2012) Pharmageddon. University of California Press, Berkeley. ↩︎
3. Turner EH, Matthews AM et al (2008). Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 358, 252-260. ↩︎
4. Healy D (2012). Pharmageddon. U of California Press, Berkeley. ↩︎
5. Jefferson R, Doshi P et al (2011). Ensuring safe and effective drugs: who can do what it takes? BMJ 342, 148-151. ↩︎