LONG-TERM ANTIDEPRESSANT USE: EXPLORING NEW RESEARCH, EFFICACY, SIDE EFFECTS (PART 2)

Medically Reviewed by Dr. Sony Sherpa, (MBBS) - September 18, 2024

The following article forms part two of this discussion on the dangers associated with long-term antidepressant use, highlighting potential underlying mechanisms for adverse effects. Antidepressant withdrawal symptoms (discontinuation syndrome) are also covered, as well as recommendations for weaning off safely.

Part one discusses newer theories underlying depression, the efficacy of antidepressants in both short and long-term use, as well as the side effects of common antidepressants.

Long-Term Use Increases Adverse Effect Risk

Studies suggest that long-term antidepressant use has become increasingly prevalent in clinical practice around the globe, especially over the last two decades.^[1] Despite this trend, there are several major problems that have surfaced with respect to long-term use:

Long-Term Use May Promote Worse Depression. It is advised that antidepressants should only be prescribed for six months or less.^[2] Across many long-term trials, antidepressant use for more than six months tended to increase the occurrence of adverse effects^[3], particularly in the elderly.^[4] In some trials, a large percentage of patients experienced more frequent episodes of depression or an exacerbation of symptoms when using antidepressants for longer than three years. In bipolar disorder, long-term antidepressant use may invoke more rapid cycle switching.

Antidepressants May Promote Suicidal Ideation. Reports over the years have shown that some patients developed suicidal ideation while on antidepressants, particularly while on SSRIs.^[5] Studies investigating these reports show that children and young adults on SSRIs are generally more vulnerable to suicidality within the first three months of their initial prescription.^[6] This may be due to the delayed onset of antidepressant efficacy. Doctors usually monitor patients on antidepressants more closely within the first six months of treatment to ensure the medication agrees optimally with the patient. Adults may also be prone to developing suicidal ideation while on antidepressants, yet results remain mixed and inconclusive. It has been observed that long-term use (over three years) may increase the risk in susceptible adult patients.^[7] This could be a potentially under-recognized problem, as long-term antidepressant users are hardly monitored by their physicians.

Antidepressant Efficacy Wanes Over Time. It has been proposed that antidepressants become less effective over time due to increased tolerance and potential treatment resistance.^[8] Despite observations that the efficacy of antidepressants becomes reduced with very long-term use and the risk for adverse effects may increase, patients who receive long-term treatment are often monitored infrequently.

Antidepressants may be physically addictive. Many patients experience severe withdrawal effects when they attempt to get off antidepressants, the severity of which increases with long-term use. As a result, tapering off may require a longer time with respect to long-term use. According to the WHO global database for case reports pertaining to adverse drug effects (VigiBase), withdrawal effects appear to be more common with antidepressants than any other class of medication.^[9] Amongst surveys, many antidepressant users feel that they cannot wean off due to withdrawal despite worse side effects and medication-reduced efficacy. Furthermore, physicians often fail to inform their patients of potential side effects and withdrawal symptoms^[10] This lends itself to longer antidepressant prescriptions, unnecessary use, increased risk for adverse effects and more severe withdrawal.

Possible Underlying Mechanisms for Long-Term Adverse Effects

Further research has begun to reveal possible reasons why antidepressants may be ineffective in the long run, lead to withdrawal effects and even potentiate depressive symptoms. Some of these include:

Chronic Antidepressant Use and Possible Gut Dysbiosis. While short-term administration appears to abolish bacteria that may promote inflammation, dysbiosis and depressive symptoms, long-term use may promote antimicrobial resistance in these bacteria^[11]. Furthermore, long-term use could detract from essential gut bacteria required for optimal neurotransmission and brain health, lending to the observation that long-term use is commonly associated with a higher risk for adverse effects and recurrent depressive episodes.

Antidepressants Could Promote Depressive Behaviors. As a short-term intervention, studies show that dopamine transmission can be normalized as a result of antidepressant use, yet it depends on the patient’s needs as different types of antidepressants can increase or decrease dopamine expression. In the long term, many antidepressants can potentially exacerbate the abhorrent dopamine transmission witnessed in depression due to an increase in serotonin and norepinephrine synaptic activity. Despite being able to stabilize neurotransmission during the recovery phase, antidepressants are not able to resolve structural neurological changes associated with depression and particularly dopamine signaling.

Long-Term SNRIs May Enforce Stress-Induced Depression. Experimental studies show that chronic stress leads to damage in the locus coeruleus, particularly affecting noradrenergic signaling. Damage to these areas detracts from the effects of SNRIs and other antidepressants in animal studies due to low adrenergic receptor expression. Similarly, SNRIs promote a down-regulation of alpha and beta adrenergic receptors, which serves to normalize sensitivity to norepinephrine. However, long-term administration may result in effects similar to prolonged stress-induced damage and thus promote depression. This may help to explain the increased risk for side effects in the long-term use of these medications, as well as the improvements observed through complementary therapies that tackle stress management (e.g., psychotherapy, CBT).

Antidepressant Discontinuation Syndrome: Weaning Off, Withdrawal Symptoms and What to Expect

The longer one has been on antidepressants, the higher the likelihood of withdrawal symptoms. Despite average statistics suggesting that only 20% of those who wean off will experience discontinuation symptoms, the actual figures are probably much higher as withdrawal often resembles depression relapse.^[12]

Symptom Severity. Symptoms typically pertain to the type of medication and the patient’s depressive symptom set and can differ on an individual basis. Withdrawal effects tend to be noticeably worse for antidepressants with shorter half-lives^[13]. However, all types may induce discontinuation syndrome. Withdrawal symptoms are believed to pertain to neurotransmitter deficiencies and either increased or reduced receptor expression, resulting in less activity. This is likely why long-term use is associated with worse withdrawal effects.

Common Symptoms include:

• Irritability
• Flu-like symptoms
• Nausea
• Headaches
• Lethargy
• Dizziness
• Constipation or diarrhea
• Insomnia
• Anxiety or depressive mood
• Sensory symptoms

Medication-Specific Symptoms. Discontinuation of SSRIs and SNRIs may increase the risk for suicidal ideation and depression. Withdrawal from TCAs may promote movement problems, physical discoordination, and tremors. NMDA antagonists could induce severe fatigue, and MAOIs may induce psychosis and agitation when discontinued.

Withdrawal Symptom Onset After Short-Term Use. Withdrawal is rare for patients taking antidepressants for 6 weeks or less. Discontinuation symptoms are generally noticeable within one to seven days after stopping medication. In patients who have been on medication for six months or less, symptoms may be mild and only last for up to two weeks. If the patient has been on them for longer than six months yet less than two years, symptoms have been reported to last for up to one year. Physicians will often provide a regimen for tapering off medication if withdrawal symptoms are severe.

Long-Term Use Withdrawal Symptoms Are Persistent. Patients with a history of use longer than three years do not tend to stop taking antidepressants due to severe withdrawal symptoms. Hence, there is a lack of information regarding how long discontinuation symptoms may last in these cases. Similarly, tapering off may be more difficult and take a much longer time to achieve.^[14]

7 Suggestions for Safely Weaning Off Antidepressants

The following considerations are important for those wanting to wean off antidepressants. However, it is important to note that if you are on antidepressants, it is not recommended that you stop taking them straight away. Always speak to your doctor first before trying to wean off your medication.

1. Consult a Physician for Tapering Down. Before weaning off antidepressants, it is important to consult with a doctor who can frequently monitor the process. A skilled physician will be able to moderate the dosage if symptoms are too severe. It may also be highly beneficial to consult a dietician or nutritionist who can help to ensure optimal nutrition.
2. 5-HTP Supplementation may be pertinent for those who have made long-term use of any antidepressants that increase serotonin levels at the synapse. 5-HTP, or tryptophan, is the precursor to serotonin in the body. Three years or more of antidepressant use is known to promote 5-HTP deficiency, as well as cause excesses or deficits in serotonin receptor expression. Providing the body with more 5-HTP may help restore serotonin deficits and lessen the withdrawal side effects. However, it should be carried out with the help of a skilled physician.
3. Regular Exercise. There are numerous health benefits associated with exercise, the majority of which appear to be beneficial in improving upon various aspects of depression. These include lower body inflammation, protecting against hippocampal degeneration, increasing concentrations of BDNF, serotonin, and other neurotransmitters^[15], stress resilience, as well as promoting a stable mood. Many people with depression engage in little to no physical activity, while depressed patients who persevere with regular exercise show a significant reduction in symptom severity and sometimes even complete remission. In a couple of studies, the effect of regular exercise has been shown to be comparable to that of antidepressants with regard to treatment.^[16] Some authors go as far as to point out that a lack of physical activity may even be a primary cause of depression.^[17] Exercise is likely to be very important for those on antidepressants and even more so for those considering stopping.
4. Probiotics. There is increasing evidence to show that depression could be a symptom of gut dysbiosis and that probiotics can be an effective complementary treatment. The guts of depressed patients are noted to be out of balance, with particular bacterial strains promoting inflammation and depressive symptoms. Part of the initial therapeutic benefit seen with antidepressants pertains to their antimicrobial actions, which serve to lower the number of microbes related to depression. After prolonged use, these bacteria can become resistant to treatment, which may contribute to treatment-resistant depression. Normalizing the gut with optimal probiotic formulas and a nutritious diet high in prebiotic fiber can reduce “depressive” bacteria, lower inflammation, and help to prevent antidepressant withdrawal symptoms while weaning off^[18]. Beneficial gut bacteria are also known to produce the bulk of neurotransmitters in the body, especially serotonin and GABA, which may add to the antidepressant benefits of probiotics seen across studies.^[19]
5. Consuming a Healthy Diet. While probiotics can help to normalize the profile of the gut microbiome, they are entirely ineffective outside of a healthy diet. All the nutrients in our food (especially soluble fiber) provide a substrate for bacteria to survive upon and, in doing so, condition the gut microbiome. Healthy, nutrient-dense diets have been associated with a lesser risk of developing depression, while highly processed foods may promote both inflammation and depressive symptoms.
6. Homing in on Specific Antidepressant Foods and Nutrients. In a large-scale study that analyzed more than 1600 papers, it was revealed that the most “antidepressant” foods were plant-based foods, out of which leafy green vegetables, cruciferous vegetables, peppers, and lettuces scored the highest. Seafood and organ meats were the most antidepressant among animal foods, with mussels scoring highest in this review. Twelve nutrients were identified across studies that appear to have the most protective effects with regard to depression: B vitamins (especially B1, B6, B9, and B12), omega-3 fats, vitamins A and C, iron, magnesium, potassium, selenium and zinc.^[20]
7. Psychotherapy. Psychotherapy through talk therapy, combined with antidepressants, has shown to be effective in many cases. Often, psychotherapy has been found to yield better results than antidepressants alone. Also, in many cases, it has helped prevent relapses once the patient’s condition has improved. Cognitive behavioral therapy, or CBT, aids in identifying and modifying negative thoughts and related behavior. Negative thought patterns are a common challenge for those who experience depression.^[21]

Conclusion

Due to new insight into the development of depression, it is becoming increasingly understood that depression is a whole-body condition that can be caused by multiple factors. As antidepressants were initially designed to treat depression on the basis of neurotransmitter deficits, their efficacy has been called into question. Studies reveal that antidepressants may be useful for supporting recovery from depression on a short-term basis. Long-term use has proven to be less effective and increases the risk of adverse effects.

Having said that, in certain cases, continuing antidepressants long-term is medically necessary. Therefore, it is not recommended to stop or try to wean off the medication without talking to your doctor. Due to severe withdrawal symptoms, long-term antidepressant users ought to get assistance from a skilled physician when weaning off. Nutritional support, probiotics, and regular physical exercise appear to be some of the best recommendations for preventing withdrawal symptoms as well as improving upon depressive symptoms in general.

Please note that this article is strictly for informational purposes. For any changes in medication, it is vital to talk to your doctor first.

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