Long-Term Use of Antidepressants

Antidepressants are a type of medication that is primarily used as a treatment for major depressive disorder. Although they are useful for treating depression, they can also be used as a treatment for other mental health conditions such as:

Note that this is not an exhaustive list.

Likewise, antidepressants can also be prescribed as a treatment for medical conditions such as fibromyalgia, chronic fatigue, neuropathy (e.g., diabetic neuropathy), and premenstrual syndrome.

antidepressants tablets

Why do people take antidepressants?

Antidepressants are usually recommended for disorders where they are shown to be effective.

People who take antidepressants may be taking them to help with depressive symptoms such as feeling low or fatigued. They may also be taken to help people feel emotionally stable and to follow a normal daily routine without the interruption of symptoms they are experiencing.

Moreover, some antidepressants can help improve the quality of sleep and increase appetite and concentration. However, it is worth noting that some of the side effects of antidepressants could affect sleep or reduce appetite.

The type of condition and severity of symptoms being experienced can determine the type of antidepressant being taken and the dosage prescribed.

One of the first known cases of successful antidepressant use was in the 1950s. At this time, scientists initially used a medication called iproniazid to treat tuberculosis but discovered that patients experienced extreme euphoria and hyperactivity.

Since then, several types of antidepressants have become commonly used due to their ability to alter imbalances in the brain’s chemistry which causes disruptions in mood.

Antidepressants are often prescribed for mood disorders based on an individual’s symptoms and the function of each medication.

Anti-anxiety medications such as benzodiazepines can carry a risk of addiction, so they are not desirable to be taken long-term.

Also, antipsychotic medications, usually used to treat hallucinations and delusions experienced in psychosis but shown to also be helpful for mood disorders, can cause sedative effects, movement disorders, and increased blood sugar and cholesterol if taken long-term.

As many of the conditions which use antidepressants as a treatment are either chronic or the symptoms return once stopped taking the medication, some people may take antidepressants for years.

Only recently has research been looking into the long-term effects of using antidepressants to understand their impact long-term better.

How antidepressants work

Antidepressants work by acting on some part of neurotransmission, which is when neurotransmitters (chemical messengers) are released from the ends of the neurons via the presynaptic terminals.

They are then released into a gap between two neurons called the synaptic cleft to be taken up by the corresponding receptors of the postsynaptic neuron. This is how different chemicals travel around the brain and influence mood and behavior.

Three main neurotransmitters are influenced by antidepressants: serotonin, dopamine, and norepinephrine.

Serotonin is believed to play a role in mood regulation, feelings of happiness, rewards, appetite, and sleep. Dopamine plays a role in how pleasure is experienced, motivation, arousal, and decision-making.

Whilst norepinephrine is important for regulating cognition, motivation, alertness, and regulating heart rate, and blood pressure during times of stress.


There are several classifications of antidepressants, all of which affect neurotransmission in different ways.

Selective serotonin reuptake inhibitors (SSRIs)

SSRIs were developed in the 1980s and 1990s, and as the name suggests, they mainly affect the neurotransmitter serotonin rather than any other neurotransmitters.

They do not cause more serotonin to be produced by the brain but instead help the brain to use the serotonin levels in a more effective way.

SSRIs work by blocking the reuptake of serotonin into the presynaptic neuron.

SSRIs work by blocking the re-uptake of serotonin into the presynaptic neuron

Because of this, more serotonin will be circulating through the synaptic cleft, making it more likely that serotonin will reach the receptors of the postsynaptic neuron.

If this happens, it means more serotonin will work in the brain and should increase mood and feelings of happiness.

SSRIs are usually the most prescribed type of antidepressant due to them being more tolerable than other antidepressants and having fewer severe side effects.

Some of the side effects that could be experienced are headaches, nausea, drowsiness, sleep problems, and increased sweating.

Monoamine oxidase inhibitors (MAOIs)

MAOIs were one of the first classes of antidepressants developed in the 1950s. In the brain, monoamine oxidase is an enzyme present at the synapses (where neurons communicate with each other) which works to break down any neurotransmitters in the synapse that do not get taken up by receptors on the postsynaptic neuron.

MAOIs work to block this enzyme meaning there will be more neurotransmitters (serotonin, dopamine, and norepinephrine) circulating around the synapses, making it more likely that these neurotransmitters will reach the receptors of the next neuron, leading to an increase in mood.

These days, MAOIs are not typically prescribed as a first option since they are very strong and carry several strong side effects, such as nausea, insomnia, restlessness, and drowsiness.

Dietary restrictions must be followed if taking MAOIs as these can cause adverse reactions to certain foods such as strong cheeses, processed meats, alcohol, and soybeans.

Tricyclics (TCAs)

TCAs are recognized as another first generation of antidepressant medications along with MAOIs. TCAs were initially used in the 1960s to treat individuals who had schizophrenia.

During neurotransmission, when neurotransmitters reach the synaptic cleft and the possibility of being broken down by monoamine oxidase, any leftover neurotransmitter may be reabsorbed back into the presynaptic neuron which released it.

This means that these neurotransmitters are not influencing the brain. TCAs work in the brain by blocking the reuptake of the neurotransmitter serotonin and norepinephrine.

If they are prevented from being reabsorbed, this makes it more likely they will reach the postsynaptic neuron and influence mood.
As with MAOIs, TCAs are also very strong and are therefore not often prescribed in the first instance due to their side effects.

Some side effects may include weight gain, fatigue, dizziness, nausea, disorientation, irregular heart rate, and sexual dysfunction.

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

SNRIs were first introduced as an antidepressant in the mid-1990s. They work similarly to SSRIs in that they block the reuptake of serotonin from being reabsorbed back into the presynaptic neuron.

SNRI also blocks the reuptake of the neurotransmitter norepinephrine, meaning that more of these two chemicals will be in the synaptic cleft making it more likely these will reach the appropriate receptors on the postsynaptic neuron.

Some of the potential side effects of SNRIs are dizziness, nausea, muscle weakness, increased blood pressure, increased heart rate, and agitation.

Do antidepressants permanently alter brain chemistry?

As discussed, antidepressants are widely used to treat mood and anxiety disorders. However, the neuronal bases of both positive and negative effects of antidepressants, specifically SSRIs, remain poorly understood.

Researchers conducted a study of treating adult male mice with fluoxetine (a type of SSRI).

During treatment, the mice showed significant increases in day-to-day fluctuations of activity levels, often switching between hyper and hypoactivity within a few days.

As well as this, anxiety-related behaviors were observed up to 4 weeks after fluoxetine treatment stopped. When examining the brains of the mice, it was found that there was a reverse state of maturation of types of cells called granule cells in the hippocampus (an area associated with memory).

The researchers concluded that this dematuration of the hippocampus granule cells might be associated with the destabilized behaviors as a result of fluoxetine (Kobayashi, Ikeda, & Suzuki, 2011).

Other research has suggested that antidepressants can activate neuroplasticity in adult human brains. Neuroplasticity is the ability of the brain to form and reorganize synaptic connections. This has been observed in preliminary studies showing increased neuroplasticity in the visual cortex.

Whether the effects observed in these studies are permanent is unclear. Some believe it is unlikely that antidepressants cause any permanent changes to brain chemistry in the long term.

The evidence seems to indicate that these medications cause brain changes that only persist while the medication is being taken or in the weeks following withdrawal.

Long-term effects of antidepressants

Antidepressants can either be prescribed as a short-term treatment for those with acute symptoms or long-term for those who may experience worsened symptoms.

Many people who are known to have histories of recurrent depressive episodes may even require indefinite treatment with antidepressants. Increases in long-term antidepressant treatment of depression have continued to rise over the years, with prescribing guidelines being more geared towards long-term maintenance treatment.

An investigation of the patient’s perceived side effects of taking antidepressants over 1-2 years found that TCAs were associated with more side effects than others.

Some of the symptoms found with TCAs were dry mouth and constipation. The most frequently reported side effects for SSRIs, the most commonly prescribed antidepressants, were dry mouth, profuse sweating, sexual dysfunction, and weight gain (Bet et al., 2013).

Another study by Cartwright et al. (2016) investigated patients’ views and experiences of long-term antidepressant use over the period of taking the medications between 3-15 years.

The majority of patients reported that the antidepressants improved their depression, whereas around 30% reported moderate to severe depression being experienced while taking antidepressants.

The most common adverse effects reported by patients included withdrawal effects (73.5%), sexual problems (71.8%), and weight gain (65.3%). Reported adverse emotional effects also reported were feeling emotionally numb (64.5%) and addicted (43%).

While most of these patients were pleased with the benefits of antidepressants, many were concerned about the adverse effects. Plus, patients reported a need for more information regarding the long-term risks and support in discontinuing the medication.

As previously mentioned, antidepressants could have long-term effects on physical and mental health. Specifically, weight gain seems to be a common long-term risk, especially the medications that affect serotonin levels.

This could be because serotonin is associated with an increase in appetite. There is also a risk of higher blood sugar levels and diabetes with taking antidepressants long-term.

Although a relatively small risk, it appears that higher doses of certain antidepressants (specifically TCAs and SSRIs) can lead to a worsening of blood sugar control, possibly because some medications cause weight gain.
Another potential effect of long-term antidepressant use is that they may eventually stop working overtime.

It is not certain why some people develop a tolerance to antidepressants, but a theory is that the receptors in the brain become less sensitive to the medication.

Other potential factors for tolerance could be related to age, stress levels, alcohol or drug misuse, or the presence of another mental health condition.

Occasionally, some people may be resistant to treatments for depression. This is known as treatment-resistant depression (TRD) and can occur in about 10-30% of those with depression.

TRD is usually categorized as failing to respond to two or more treatment attempts. Causes for this could be a result of a misdiagnosis, metabolic disorder, or genetic factors.

How to manage long-term antidepressant use

Antidepressants, specifically SSRIs, which are considered the most tolerable and are, therefore, the most prescribed, are generally safe to take long-term.

The long-term effects discussed above may only occur for a small number of people, and the medication itself should disclose a list of possible side effects.

In order to manage or prevent any of the long-term negative effects from happening, there are some ways to help:

  • Check-in with your doctor regularly (at least twice a year) to assess whether the antidepressants are still working as they should or if the dose needs changing.
  • If wanting to stop taking the medication, only do so under the doctor’s guidance and gradually, over several months or longer. A slow withdrawal should minimize the withdrawal symptoms and make it easier to reverse the course of depression surges.
  • Combine the use of antidepressants with counseling or psychotherapy such as cognitive behavioral therapy (CBT). The use of psychotherapy can teach individuals the skills they need to manage feelings of anxiety or depression and should minimize the risk of a relapse.
  • Be vigilant about negative changes to identify early warning signs, such as difficulty sleeping. Noticing these changes early can allow adjustments to dosages to be made sooner.
  • If presenting with TRD, depending on the case, some people may be prescribed different antidepressants, include a second type of medication where appropriate, and undertake psychotherapy or electroconvulsive therapy (ECT).
  • If the medication appears to stop working, they may be advised by a doctor to either increase the dosage, change the type of medication, consider psychotherapy or make some lifestyle changes.
  • If weight gain or issues with blood sugar and diabetes are prevalent, individuals may be advised to undertake physical exercise or make dietary changes to account for the weight gain experienced by some antidepressants.

Do you need mental health help?


Contact the National Suicide Prevention Lifeline for support and assistance from a trained counselor. If you or a loved one are in immediate danger: https://suicidepreventionlifeline.org/



Contact the Samaritans for support and assistance from a trained counselor: https://www.samaritans.org/; email jo@samaritans.org .

Available 24 hours a day, 365 days a year (this number is FREE to call):


Rethink Mental Illness: rethink.org

0300 5000 927


Cartwright, C., Gibson, K., Read, J., Cowan, O., & Dehar, T. (2016). Long-term antidepressant use: patient perspectives of benefits and adverse effects. Patient preference and adherence, 10, 1401.

Kobayashi, K., Ikeda, Y., & Suzuki, H. (2011). Behavioral destabilization induced by the selective serotonin reuptake inhibitor fluoxetine. Molecular brain, 4(1), 1-11.

Bet, P. M., Hugtenburg, J. G., Penninx, B. W., & Hoogendijk, W. J. (2013). Side effects of antidepressants during long-term use in a naturalistic setting. European Neuropsychopharmacology, 23(11), 1443-1451.

Florence Yeung

BSc (Hons), Psychology, MSc, Clinical Mental Health Sciences

Psychological Wellbeing Practitioner

Florence Yeung is a Doctorate student in Clinical Psychology at the University of Hertfordshire, UK.

Olivia Guy-Evans

Associate Editor for Simply Psychology

BSc (Hons), Psychology, MSc, Psychology of Education

Olivia Guy-Evans is a writer and associate editor for Simply Psychology. She has previously worked in healthcare and educational sectors.

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