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Long-Term Use of Antidepressants

What are the risks?

By Olivia Guy-Evans, published June 16, 2021

by Saul Mcleod, PhD

antidepressants tablets

What are antidepressants?

Antidepressants are a type of medication that are 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:

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.

People who take antidepressants may be taking them to help with feeling down or exhausted. 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, antidepressants can help improve quality of sleep, increase appetite and concentration. The type of condition and severity of symptoms being experienced can determine the type of antidepressant being taken and the dosage prescribed.

Antidepressants could be taken alongside other therapies such as cognitive behavioral therapy (CBT) or counselling.

One of the first known cases of successful antidepressant use was in the 1950s. Scientists at this time were initially using a medication called iproniazid to treat tuberculosis but discovered that patients experienced feelings of 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 are causing disruptions in mood.

Antidepressants are usually prescribed for mood disorders over other types of medications, a reason being that other types of medication can have harmful side effects if taken long-term.

Anti-anxiety medications such as benzodiazepines can carry a risk of addiction so 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 better understand their impact long-term.

How antidepressants work

Antidepressants work by acting on some part of neurotransmission, which is when neurotransmitters (chemical messengers) which have travelled through a neuron, 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, in order to be taken up by the corresponding receptors of the postsynaptic neuron. This is how different chemical travel around the brain and have an influence on mood and behavior.

There are three main neurotransmitters that 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 re-uptake 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 neurotransmitter.

They do not cause more serotonin to be produced by the brain, but instead help the brain to use the serotonin levels it has more effectively. SSRIs work by blocking the re-uptake 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 around 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 be working 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 to 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.

There are also dietary restrictions which 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 recognised as the second generation of antidepressant medications after MAOIs. TCAs were initially used in the 1960s to treat individuals who had schizophrenia.

During neurotransmission, when neurotransmitters reach the synaptic cleft, as well as 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 works in the brain by blocking this 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 its side effects.

Some of the 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 in a similar way to SSRIs in that they block the re-uptake of serotonin from being reabsorbed back into the presynaptic neuron.

SNRI also block 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.

SNRIs are typically prescribed for short-term use, and some of the potential side effects 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 of 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 may be associated with the destabilised 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 reorganise synaptic connections. This has been observed in preliminary studies which showed increased neuroplasticity in the visual cortex.

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

Evidence seems to indicate that these medications cause brain changes which only persist whilst 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 experienced 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 antidepressants 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 compared to 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 patient’s 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 whilst 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%).

Whilst the majority 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 as well as support in discontinuing the medication.

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

This could be due to the fact that 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 of depression. This is known as treatment-resistant depression (TRD) and can occur for about 10-30% of those with depression.

TRD is usually categorised by failing to respond to two or more treatment attempts. Causes for this could be as 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:

  • Checking 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 doctor’s guidance and gradually, over several months or longer. A slow withdrawal should minimise the withdrawal symptoms and make it easier to reverse the course if depression surges.
  • Combine the use of antidepressants with counselling 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 minimise the risk of a relapse.
  • Be vigilant about any negative changes to identity any 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, undertake psychotherapy, or electroconvulsive therapy (ECT).
  • If the medication appears to stop working, it may be advised by a doctor to either increase the dosage, change the type of medication, 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?


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About the Author

Olivia Guy-Evans obtained her undergraduate degree in Educational Psychology at Edge Hill University in 2015. She then received her master’s degree in Psychology of Education from the University of Bristol in 2019. Olivia has been working as a support worker for adults with learning disabilities in Bristol for the last four years.

How to reference this article:

Guy-Evans, O. (2021, June 16). The 5 major classes of antidepressants. Simply Psychology.


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.

Petersen, A. (2019, August 28). New Concerns Emerge About Long-Term Antidepressant Use.

Dellwo, A. (2021, February 19). Long-Term Use of Antidepressants. Very Well Mind.

Guy-Evans, O. (2021, June 16). The 5 major classes of antidepressants. Simply Psychology.

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