Antidepressants & Anti-Anxiety Medications
Historically, the first clinically useful class of antidepressants become tricyclics, introduced in 1950s. Named for their three-ring chemical structure, they work by inhibiting norepinephrine, serotonin, and dopamine reuptake.
Given the pronounced adverse effects of the tricyclics (TCAs), substantial research work was launch in the early 1970s to design more selective antidepressant focussing on influencing brain serotonin levels.
In reality, most antidepressants are equally effective. However certain drugs may work better depending on the type of depression and concomitant diseases. While newer antidepressants are better tolerated, there’s still not much improvement with onset of action or efficacy -- the old tricyclic antidepressants are just as effective as the new SSRIs or SNRIs10.
Generally, after 3 months of treatment, the proportions of people with depression who will be much improved are: 50-65% if given an antidepressant compared with 25 – 30% if given an inactive “sugar” pill, or placebo. Antidepressants are effective, but some of their benefits are due to the placebo effect.
There is evidence the tricyclic antidepressants (TCAs) are more effective for melancholic or severe depression than SSRIs11.
Antidepressants with multiple neurotransmitter actions such as venlafaxine, mirtazapine, and duloxetine may have distinct advantages in terms of faster onset of action, higher rates of remission, and increased efficacy in relieving the physical symptoms of depression12, 13.
SSRIs affect fewer sites of action than TCAs, and as a result cause fewer types of adverse effects and have better safety than TCAs. A major advantage for the newer drugs is that they are not so dangerous in case of overdose.
Venlafaxine is more toxic than SSRIs in overdose, with a fatal toxic dose closer to that of the tricyclics. Doses of 900 mg or more are likely to cause moderate toxicity16.
Onset of action - time to see benefits
Antidepressants are not a quick fix and take time to work. All antidepressants, regardless of their type, have slow onset of action, usually three to five weeks. Although adverse reaction may occur as early as the first dose, significant therapeutic improvement is always delayed.
Mirtazapine has a more rapid onset of action than SSRIs. Escitalopram is a fast-acting antidepressant with a more quick onset of effect among SSRIs.
Antidepressants aren’t just for depression
Antidepressants are not just for the treatment of depression. These drugs may be useful in a range of other disorders:
Discontinuation syndrome (also known as withdrawal symptoms) occurs upon the abrupt discontinuation or a decrease in dosage of the antidepressant. Withdrawal symptoms include: irritability, agitation, anxiety, dizziness, flu-like symptoms, headache, nausea, insomnia, tingling sensations.
Antidepressant discontinuation syndrome is more likely with a long-term treatment and a medication with shorter half-life.
Most likely to cause withdrawal symptoms: Venlafaxine and paroxetine, both of which have short half-lives and wash out of the body most quickly.
Least likely to cause withdrawal symptoms: Fluoxetine is the least likely to cause any discontinuation symptoms because it has the longest elimination half-life (7–15 days) and remains in the body longer.
Withdrawal symptoms don't mean craving
Antidepressants are not technically addictive:
However, there is a debate about addiction. In spite of not having the symptoms of addiction, up to a third of people who stop SSRIs and SNRIs have withdrawal symptoms.
The Committee of Safety of Medicines in the UK reviewed the evidence in 2004 and concluded "There is no clear evidence that the SSRIs and related antidepressants have a significant dependence liability or show development of a dependence syndrome according to internationally accepted criteria."
Interaction with alcohol
Most antidepressants (SSRIs, SNRIs, bupropion, desipramine) are not “sedatives” and do not substantially add to the impairing effects of alcohol when consumed concomitantly.
However, most people with mood disorders (e.g., depression, anxiety) are vulnerable to alcohol's effect on mood stability.
Nearly all antidepressants have the potential to cause weight gain with both long-term and short-term use. Unexpected weight gain ranks among the main reasons why people stop taking medications. Unwanted extra pounds can seriously impact self-esteem.
There are several ways how antidepressants can lead to weight gain. They may increase the appetite, causing you to eat more, or slow down the metabolism. Antidepressants can also make you more sedentary through fatigue and tiredness. Some antidepressants (e.g. sertraline and amitriptyline) may cause strange food cravings.
SSRIs-induced weight change is related to alteration in serotonin 2C receptor activity, appetite increase, carbohydrate craving, or recovery from depression1,3. It is less likely to occur when SSRIs are used for less than 6 months. Paroxetine causes the greatest incidence of weight gain than the other SSRIs.
Tricyclic antidepressants (TCAs) are more likely to cause weight gain than Selective Serotonin Reuptake Inhibitors. Tricyclics appear to slow metabolism and promote carbohydrate cravings4. Because tertiary tricyclic antidepressants (e.g. amitriptyline, imipramine, and doxepin) are stronger histamine blockers than are tricyclics (e.g. desipramine and nortriptyline), the tertiary tricyclics are more likely to cause weight gain.
Mirtazapine has been associated with significant weight gain and may be placed between the SSRIs and the TCAs in terms of relative risk for gaining extra pounds. Mirtazapine contributes to weight gain through blockade of histamine H1 and serotonin 2C receptors. The problem may occur even during the first 4 weeks of treatment with mirtazapine5.
Most likely to cause weight gain: tricyclic antidepressants, monoamine oxidase inhibitors and mirtazapine. Among the SSRIs, paroxetine is the worst offender.
Less likely to cause weight gain (weight-neutral antidepressants): Bupropion is one of the most stimulating antidepressants. It is unlikely to cause weight gain, and sometimes may cause weight loss6.
Tricyclics appear to slow metabolism and may promote carbohydrate cravings. Tertiary tricyclic antidepressants such as amitriptyline, imipramine, and doxepin are more likely to cause weight gain than secondary tricyclics such as desipramine and nortriptyline.
Depression is often accompanied by the lack of sex drive. Rather ironically, virtually all antidepressants can worsen the sexual life.
In fact, sexual dysfunction is a common side effect of all classes of antidepressants, but remains highly unrecognized and underreported. Antidepressants produce a variety of sexual disturbances, including erectile dysfunction (impotence), delayed orgasm, anorgasmia, delayed ejaculation, and decreased libido .
Although some side effects get milder or disappear after several weeks of antidepressant treatment, sexual difficulties rarely go away with time. Antidepressants cause sexual problems in both men and women17. However, incidence of sexual dysfunction in men is higher than in women.
Suggested causes of sexual side effects include increased serotonin, decreased dopamine, blockade of cholinergic and alpha-1 adrenergic receptors, inhibition of nitric oxide activity, and elevation of prolactin levels7. Serotonin tends to diminish sexual function, while dopamine tends to enhance sexual function. So drugs that enhance serotonin or block dopamine tend to decrease sexual activity.
In most cases, once the offending medication is stopped, sexual functioning comes back to normal. But some people are faced with the persistent long-lasting symptoms called post-SSRI sexual dysfunction.
Most likely to cause sexual problems: paroxetine, and to a lesser degree fluoxetine, citalopram, sertraline9.
Least likely to cause sexual problems: The most "sex-friendly" antidepressant is thought to be bupropion8. It has stimulating properties. Mirtazapine and trazodone also are unlikely to affect sexual function.
Tricyclic antidepressants are highly cardiotoxic. According to the clinical data tricyclic antidepressants are associated with a 35% increased risk of cardiovascular disease (CVD).
Among the SSRIs citalopram has been reported to cause a dose-dependent prolongation of QT interval.
List of Antidepressants
Selective serotonin reuptake inhibitors (SSRIs)
Serotonin and norepinephrine reuptake inhibitors (SNRIs)
Norepinephrine and Dopamine Reuptake Inhibitors (NDRIs)
Noradrenergic and specific serotonergic antidepressants (NaSSAs)