Antidepressants

How do antidepressants work?  The basics of brain chemistry

The chemicals present in the brain that control its functions (perceptions, thoughts, emotions, motivations and behaviors) are called neurotransmitters,  so named because they exist in neural tissue in the brain and nervous system, and because they transmit information between individual nerve cells (called neurons).  There are a wide variety of these chemicals in the brain, and scientists are identifying more all the time.

Neurotransmitters play an important role in regulating brain functions such as mood, sleep, pain, appetite, sexual interest, pleasure and many more. Much like flipping a switch to turn a light “on” or “off,” neurotransmitters convey information between nerve cells to direct their behavior.

Three of the most important neurotransmitters are dopamine, serotonin and norepinephrine, which have been known to scientists for decades.  When the brain is functioning normally, these neurotransmitters work to provide the proper “on/off” signals between neurons.  But the presence of depression is an indication that the presumed balance has been disrupted.  One common example of this is when the amount of serotonin or norepinephrine present appears to be inadequate, so that their receptors are not adequately stimulated. The class of antidepressants used to address this, called “reuptake inhibitors,” work by decreasing this reuptake, allowing the neurotransmitter molecules to exert greater impact and hopefully restore a normal balance.

More recent theories suggest that the mechanism through which antidepressants work may be more complex (which could perhaps help to explain why they can take weeks to take effect), but slowing reuptake is a significant factor for many of the most commonly used antidepressants such as SSRIs.

How well do antidepressants work?

Antidepressants are typically prescribed when:

Depending upon the class of antidepressant, they typically take several weeks to show any benefit, and two to three months for the maximum benefit to accrue. It is unwise to make any changes to the treatment plan before first establishing that the medication has been taken in an adequate does and for an adequate duration to demonstrate its effectiveness.  This can only be determined in partnership with your prescribing healthcare provider.

To date, no antidepressant has been proven more effective than any other. Different types may be more or less effective with different individuals, and each may have a unique profile of side effects that can also vary by patient. We are learning that such side effects often are linked with an individual’s genetic makeup. That’s why, for many people, it may be necessary to try more than one type of antidepressant, or a combination of medications to arrive at the best course of treatment. Only about 40% of patients who are correctly diagnosed with major depressive disorder will respond to the first medication tried, but up to 70% will eventually respond if pharmacological strategies are tried and given adequate time to show results. This often requires different combinations of medications, the addition of augmenting agents, or changes in dosage.

When antidepressants don’t work, the reason can often be explained by factors such as receiving an incorrect diagnosis, being prescribed an inadequate dose of the medication, failing to adhere to treatment recommendations, or stopping the medication prematurely. It’s also important to note that antidepressants have also been shown to be more effective when used in combination with psychotherapy.

A future goal is to achieve personalized treatment, based on knowing enough about an individual’s genetics and other measurable characteristics of personal biology (referred to as biomarkers) to be able to predict in advance which treatment approach is most likely to be most effective, rather than determining a treatment plan through trial and error.

How long are antidepressants needed?

The length of time a patient may need to take antidepressants varies. Some patients require a lifelong course of medication to maintain wellness.
Several factors can impact the timeline, including:

It’s important not to stop taking an antidepressant before it is recommended by a healthcare provider, even if symptoms seem to have diminished or even disappeared.  The risk of relapse increases when these medications are discontinued prematurely or abruptly.  For more information about why and how to adhere to a treatment program, see Sticking with your plan, and Preventing Recurrence.

Types of antidepressants

Antidepressants are commonly divided into five classes:

Selective serotonin-reuptake inhibitors (SSRIs)

SSRIs work as described in the example cited earlier. SSRIs are among the most widely-prescribed antidepressants in the US. They are also effective in treating anxiety, panic, obsessive-compulsive disorder and the co-occurrence of these conditions.

It may take one to three months for an SSRI to reach its full effectiveness. During that time, it is possible that an individual’s feelings of depression or anxiety may temporarily worsen during the early stages of treatment. Frequent and careful monitoring is needed during the initial weeks of treatment, especially with adolescents. Although SSRIs generally provide relief with fewer side effects than other medications, a number of different side effects may appear when using SSRIs, and it is common to experience some, especially during the early stages of treatment.  Generally, patients adapt over time and these side effects become tolerable.

Side effects may include:

In addition to the above list of side effects, which do not necessarily warrant discontinuing the medication, there are several additional factors to consider.  These factors, called adverse events, are more rare, but also more serious, and may require immediate medical attention:

Tricyclic antidepressants (TCAs)

Tricyclic antidepressants (TCAs), so named because their molecular structure features three rings of atoms, is a class of medication first introduced in the 1950s for the treatment of depression as well as anxiety, obsessive-compulsive disorder, attention-deficit hyperactivity disorder, insomnia, depression with pain and other disorders.

When first introduced, TCAs were the first-line medication prescribed for depression, and they are still considered an effective approach.  However, in recent years doctors have increasingly relied upon newer medications, notably SSRIs, which are thought to have fewer side effects.

TCAs are sometimes used in patients suffering from treatment-resistant depression who may have tried SSRIs without success.  Like all antidepressants, TCAs are non-addictive.

Possible side effects from TCAs include:

dry mouth restlessness
dry nose dizziness
blurry vision changes in appetite and weight
constipation sweating
cognitive impairment sexual dysfunction
memory trouble muscle twitches
increased body temperature weakness
drowsiness nausea and vomiting
anxiety irregular heart rhythms
confusion  

 

These side effects often decrease over time, and patients may be able to better tolerate them as treatment continues. For elderly patients, constipation, urinary hesitancy, dizziness, fainting and falls are special concerns.

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

SNRIs are another class of antidepressants recently developed in response to the need for still more effective treatments with fewer, more manageable side effects.  Although SSRIs improved on the previous class of medications (TCAs) in reducing their most serious side effects, they may be slightly less effective than TCAs in treating patients with very severe symptoms and/or those with co-occurring conditions. 

Studies comparing SNRIs with older-generation TCAs indicate higher rates of remission, improved outcomes for individuals whose depression occurs along with pain or other physical symptoms, and more tolerable side effects.

SNRIs inhibit the uptake of both serotonin and norepinephrine. This dual action is believed to be preferable to blocking only one neurotransmitter or the other.

In addition to their effectiveness in treating serious depression, clinical studies point to the potential of SNRIs to help patients achieve remission.  Early studies of this new class of medications indicate that they may represent an important step forward in the prevention of recurrence – a major treatment goal.

Although when compared with other classes of antidepressants SNRIs appear to deliver greater effectiveness, greater likelihood of producing remission, and improvements in many of the painful physical symptoms experienced by some patients with depression, they, too, come with the risk of additional side effects, which are most common during the early stages of treatment.  The most frequently-reported side effects associated with SNRIs include:

Nausea Increased heart rate
Dizziness Sweating
Restlessness Dry mouth
Insomnia Headache
Fatigue Constipation

 

In some patients, treatment with certain SNRIs may also cause sustained increases in blood pressure. Regular blood pressure monitoring is recommended.

Monoamine oxidase inhibitors (MAOIs)

MAOIs are a unique class of medicines used to treat depression and related illnesses such as panic disorder, social anxiety or agoraphobia. Because of potentially significant interactions with various foods and other medications, MOIs are traditionally considered a last line of defense, used only after other classes of medications such as SSRIs, SNRIs or TCAs have failed to provide relief. 

MAOIs work by inhibiting the activity of enzymes called monoamine oxidase, which keep key neurotransmitters from being broken down or metabolized. 

Patients who have been prescribed MAOIs must avoid specific foods and other medications which can cause very serious interactions.  Foods and medications to avoid include:

In addition, MAOIs are NEVER to be combined with SSRIs, SNRIs or miscellaneous antidepressants.

A complete list of what to avoid will be provided by your healthcare provider if you are prescribed an MAOI. 

Possible side effects that patients may encounter when taking MAOIs include:

These side effects often decrease over time, and patients may be able to better tolerate them as treatment continues.

Miscellaneous Antidepressants

The treatment of depression in some patients may include other medications that do not fit within any of the classes described above.  Like SSRIs and SNRIs, these miscellaneous antidepressants may also act to increase the release of serotonin and/or norepinephrine by blocking key receptors.

Miscellaneous antidepressants may be helpful for patients who do not respond to other types of antidepressants. Each medication within the miscellaneous classification works in a slightly different way and is associated with a different list of potential side effects.  For example, one medication may yield a better result for patients who have experience sexual dysfunction when taking an SSRI.  Others have been employed successfully with elderly patients, and still others with patients whose depression is accompanied by anxiety or insomnia.