LONG-TERM ANTIDEPRESSANT USE: EXPLORING NEW RESEARCH, EFFICACY, SIDE EFFECTS (PART 1)

Antidepressants have been in use for more than half a century for treating depression, anxiety disorders, and recently, pain-related disorders. Despite remaining the standard treatment approach for depression, their efficacy has recently been called into question due to new research that undermines the original theory of depression. The side effects and dangers associated with long-term antidepressant use further emphasize the need for a better understanding of their use in clinical practice.

The following article forms part one of this discussion, exploring newer theories underlying depression, the efficacy of antidepressants in both short and long-term use, as well as the side effects of common antidepressants.

Part two discusses the dangers associated with long-term use and highlights potential underlying mechanisms for adverse effects. Antidepressant withdrawal symptoms (discontinuation syndrome) are also covered, as well as recommendations for weaning off safely.

The Serotonin Hypothesis of Depression is Outdated

Depression refers to a set of symptoms characterized by a persistent low mood and/or loss of motivation that are often accompanied by physical symptoms, including lethargy, fatigue and disrupted sleep. Its onset is associated with stressful major life events, trauma, injury, chronic illness and social isolation.

Lower Brain Serotonin Activity is Not Associated with Depression. The majority of antidepressants were designed to treat depressive symptoms based on the hypothesis that depression was a product of lower serotonin activity in the brain. This theory of depression has been used as a treatment model for more than 50 years. However, several scientific reviews in the last decade have highlighted that serotonin activity is not usually found to be different between healthy and depressed subjects. In fact, serotonin activity has been shown to be reduced more often as a result of long-term antidepressant use (two years or longer).^[1]

Brain Serotonin May Play a Role in Recovery. Despite these findings, serotonin may still be relevant to the treatment of major depressive disorder in some cases due to the efficacy of antidepressants as well as findings that show reduced levels of serotonin precursors in patients with recurrent depressive symptoms. Enhancing serotonin precursors may be pertinent to supporting the recovery process, particularly in patients with a long history of depression who are prone to deficiency.^[2]

Depression as a Multifactorial Condition

Much time has passed since the first antidepressants were formulated to treat depression. It is now understood that depression is characterized by more than just neurotransmitter imbalances. New research indicates that underlying mechanisms of depression involve neuroinflammation and inflammation in general, genetics, stress-related symptoms and the brain-gut (microbiome) axis. These factors have been shown to give rise to altered neurotransmitter activity, as discussed below.

Depression is Not Limited to the Brain. Increasingly more evidence supports the notion that depression is not limited to the brain but comprises a whole body health condition. Findings show that neuroinflammation contributes towards perpetuating depressive symptoms and that inflammation inside the CNS can be triggered by inflammation and other bodily processes in the periphery. This has been observed via vagus nerve stimulation, which mediates many immune functions, as well as vascular inflammation. Not surprisingly, depression very commonly presents as a condition secondary to other inflammatory diseases, including auto-immune disorders, metabolic disease, gastrointestinal conditions and cancer.

Other Neurotransmitters Implicated in Depression. Aside from serotonin, depression is associated with signaling alterations in norepinephrine, dopamine, glutamate and GABA. The differences seen across various types of depression are thought to be a result of unique neurotransmitter imbalances and their related causes. The most common mechanisms pertain to major life stressors and alterations in the brain’s reward pathway, both of which can be perpetuated by chronic low-grade inflammation. Common neurotransmitter alterations seen in depression are described below:

• Acetylcholine Genes. Studies assessing the genetics of depression have found that depressed subjects maintain higher levels of a polymorphism in the gene that regulates the expression of a specific acetylcholine receptor (A7 nAChR) in the dorsolateral prefrontal cortex, a key region for perpetuating the disease process. This polymorphism is associated with increased sensitivity and release of all the neurotransmitters associated with major depressive disorder due to increasing neuronal permeability to calcium.^[3]
• Glutamate and Neuronal-Excitability. Glutamate has recently been linked to depression. As a neurotransmitter, glutamate is involved in promoting optimal neurotransmission through enhancing neuronal excitability and thus mediating many cellular processes in the body as a whole. A variety of glutamate receptors were found to be upregulated in depressed patients and animals. Particularly NMDA receptors which are associated with heightened neuronal-excitability, toxicity and neuronal cell death. This suggests that glutamate signaling in depression is altered in related brain areas due to rises in glutamate followed by increased receptor expression. A higher expression of receptors indicates that more glutamate is required to achieve the same degree of neurotransmission, which can result in lower brain glutamate activity and reduced neurotransmission in depression-related brain areas. Chronic excessive dietary glutamate or stress hormones have been shown to induce heightened glutamate receptor expression and faulty glutamate signaling in the context of depression.^{[4] [5]}
• Norepinephrine and the Stress Response. Major life stressors are some of the most well-known triggers for depression. Further evidence has revealed a connection between stress-induced norepinephrine, neuroinflammation and depressive symptoms. Chronic stress is known to promote norepinephrine release in the locus coeruleus and neuroinflammation. Both of these can perpetuate the production of stress hormones and lead to a catch-22 cycle that perpetuates depression and anxiety. Heightened norepinephrine release in this brain area tends to increase its receptor expression level, making neurons less responsive towards norepinephrine and requiring higher concentrations to achieve the same effect. Alpha-1 norepinephrine receptors were shown to contribute towards increasing the stress response, while beta-adrenoceptors were shown to regulate the stress response. Receptors for glutamate (NMDA), dopamine and serotonin are also found in the locus coeruleus and are suggested to enhance norepinephrine signaling, as well as the stress response in the development of depression.^[6]
• Dopamine and the Reward Pathway. Depression is symptomatic of reduced feelings of pleasure (anhedonia) in response to ordinarily pleasurable experiences, such as eating or socializing. As a result, dopamine transmission is believed to be altered in depressed patients due to its primary role in the reward pathway. Animal studies reveal that dopamine’s function can be both negative or positive within the reward pathway and that its main functions pertain to goal-directed behavior. In the context of depression, dopamine transmission is diverted more toward promoting negative (depressed) behaviors. This is reflected by heightened dopamine firing within different areas of the reward pathway that trigger anhedonia. It also leads to reduced firing in areas associated with positive behavior and pleasure. These structural changes are thought to occur as a result of chronic stress, and stress is shown to promote heightened dopamine expression along anhedonia-related pathways in depressed subjects. Over time, this can increase dopamine receptor expression and further lower the response to dopamine, resulting in more severe symptoms. Differences in dopamine transmission may be able to explain the variation between major depressive disorder and bipolar disorder. Increases in serotonin signaling are also known to promote reductions in dopamine signaling within the positive components of the reward pathway and are strongly linked with both the feeling of sadness and the development of depression (if chronic). As seen with norepinephrine signaling, stress, glutamate and inflammation are believed to be involved in abhorrent serotonin and dopamine signaling, as well as the depression-related changes to the reward pathway.^[7]

Structural Brain Changes and Neuroplasticity. As mentioned above, depressed subjects show structural abnormalities in key brain areas involved in reward as well as anxiety. The abnormalities generally reveal strengthened firing of neural networks pertaining to depressive behavior and activity reductions in networks associated with pleasure and a good mood. As evidenced by animal and post-mortem human studies, those with long-term or recurrent depression are thought to incur brain damage, which helps to concretize these structural alterations and worsen the outcome. These changes are believed to be brought about by stress and/or inflammation. Depression and stress are both associated with reductions in the size of the hippocampus, lower BDNF (Brain-Derived Neurotrophic Factor) levels and impaired neurogenesis and neuroplasticity.

Inflammation, Reactive Astrogliosis and Neurotransmitter Imbalance. Perhaps primary to neurotransmission abnormalities would be neuroinflammation. Neurotransmitters are moderated at the synapse of neurons due to input from astrocytes. Astrocytes are a specialized type of glial cell that fulfill a supportive role in neurotransmission.^[8] Under inflammatory conditions, astrocytes become reactive, swollen and dysfunctional, leading to alterations in neurotransmission similar to those seen in depression and several other neurodegenerative disorders. This is known as astrogliosis.^[9] Inflammation can trigger reactive astrogliosis from either inside the central nervous system or from the body. Furthermore, resultant neurotransmitter imbalances can perpetuate inflammation due to their effects on immune cells.

Astrocytes Regulate Glutamate Signaling and Neuroinflammation. Of particular importance would be the regulation of glutamate signaling by astrocytes, as glutamate has been implicated in nearly all neurotransmitter imbalances pertaining to depression. Astrocytes maintain optimal glutamate levels at the synapse. Excess glutamate gets taken up by astrocytes and converted back into glutamine. Reactive inflammatory astrocytes are unable to moderate glutamate levels at the synapse, allowing for excesses to develop, increases in receptor expression, the imbalance of other neurotransmitters, reductions in neuroplasticity and eventual neuronal death. Astrocyte dysfunction, as well as deficiency, have been consistent findings in the brain tissue of deceased individuals who had major depressive disorder.^[10]

Gut-Brain Axis. The gut microbiome is now acknowledged as a major organ, influencing all other systems, including the brain. A healthy balance of bacteria serves to stabilize immune function, stress, metabolism and promote optimal neuronal health. Gut bacteria are essential for nutrient absorption and the production of nutrients that we would not get otherwise from the diet, including short-chain fats. Short-chain fats, such as butyrate, are known to be vital for balanced brain function. The microbiomes of depressed patients reveal lower diversity of bacteria that produce short-chain fats as well as increased intestinal permeability, which is known to promote systemic inflammation and neuroinflammation, leading to depressive symptoms.^[11]

How Effective Are Antidepressants?

Antidepressants are not a cure for depression. Antidepressants do not resolve underlying causes or prevent triggers of depression. They are usually prescribed as a short-term intervention that helps to stabilize neurotransmission during recovery from depression. Their effectiveness should be measured by how well they help the patient to manage their symptoms. Unlike other medications, it takes at least one to four weeks for antidepressants to work. Their delayed benefit and side effects often discourage their use. Many patients often battle to find an antidepressant that works for them with minimal or no side effects.

All Antidepressants Have a Similar Efficacy. In a large-scale study, it was shown that antidepressants of all kinds have very similar efficacy in terms of short-term symptom management. It was revealed that antidepressants were able to resolve symptoms in 40-60 out of every 100 people on average. Depending on the study, antidepressants were shown to be comparable to a placebo or better, with a placebo able to resolve symptoms in 20-40 people on average.^[12]

Short-Term Use is Usually More Beneficial than Very Long-Term Use. Antidepressants are usually prescribed to support recovery from depression. In those with frequent episodes of chronic depression, they may be prescribed for one or two years to prevent relapse. Roughly 23 out of 100 individuals will still experience relapse while on antidepressants for this time, compared to 50 out of 100 who used a placebo. After three years, antidepressants are often ineffective and may increase the risk of perpetuating depressive symptoms (see below).

Antidepressant Resistance and Non-Responsiveness. 30-40% of individuals that take antidepressants may be resistant to treatment. This can often be resolved by using another type of medication or a combination. Patients with pre-existing health conditions or who are subject to chronic stress may be more resistant to antidepressants than other depressed individuals. One study found that candidates with higher expression of inflammatory markers alongside glucocorticoid resistance were not likely to respond to antidepressant treatment and may experience a worsening of their symptoms early on. This may explain why depressed individuals with inflammatory health conditions such as cancer^[13] or post-stroke^[14] are less likely to respond to antidepressants.

Common Antidepressant Side Effects and Contraindications

Due to the side effects of antidepressants, many patients take time to find an antidepressant that works for them. Frequent side effects include gastrointestinal problems, insomnia, agitation and anxiety.^[15]

It is important for the patient to discuss their medical history with their doctor and for them to select an appropriate antidepressant that is not contraindicated. Antidepressants should also be mentioned to one’s physician when considering other medications, as they may interact negatively.

Common antidepressants are described below, alongside their side effects and contraindications.

The most common type of antidepressant is Serotonin Reuptake Inhibitors (SSRIs) which work by inhibiting the reuptake of serotonin, increasing its concentration at the synapse. They are considered the best pharmacological treatment option for depression due to their higher tolerability and lower side effects than other antidepressants.^[16]

• Side Effects include nausea, headaches, fatigue or withdrawal, disturbed sleep, headache, gastrointestinal symptoms, arrhythmias, diarrhea and sexual dysfunction. Uncommon side effects could include symptoms of impaired movement (extrapyramidal symptoms) such as those seen in Parkinsonism. However, these are rare and typically occur in elderly patients.
• Contraindications. SSRIs should never be used with other serotonergic agents due to the risk of serotonin syndrome. They are contraindicated in pregnant women and those with auto-immune diseases, severe allergies or asthma, as well as cataracts.^[17]

Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) work by promoting the reuptake of both serotonin and norepinephrine and increasing their concentrations at the synapse. Most of them promote serotonin increases first, followed by norepinephrine, and have a stronger SSRI effect. Others promote balanced reuptake of norepinephrine or greater norepinephrine reuptake, and these are known to treat different forms of depression as well as anxiety disorders.^[18]

• Side Effects of norepinephrine reuptake can induce profuse sweating, blood pressure fluctuation, arrhythmia, anxiety and tremors. Other side effects could include sexual dysfunction, dry mouth, incontinence, dizziness, insomnia, abdominal pain and constipation, depending on the type of SNRI. Mostly, side effects are similar to SSRIs.^{[19] [20] [21] [22]}
• Contraindications. SNRIs are contraindicated for use with MAOIs, other antidepressants and natural serotonin modulators. Some SNRIs are contraindicated in pregnancy and breastfeeding, if the patient has a history of severe allergy or anaphylaxis, heart conditions, epilepsy, or if the patient is taking antipsychotics or sedative medications.
• SNRIs May Increase Synaptic Dopamine. SNRIs are known to act faster than SSRIs and this may be due to the ability of some of them to increase dopamine concentrations. Some SNRIs were noted to improve dopamine levels in the prefrontal cortex^[23], which would disrupt depression-related brain circuits and help to improve depressive symptoms in the short term.

Tricyclic Antidepressants constitute an early class of SNRI that differs in chemical structure from classical SNRIs. Some of them are known to inhibit cholinergic, muscarinic and histaminergic receptors. They are not very often prescribed due to inducing worse side effects than conventional SNRIs^[24]. However, they may be useful in the treatment of comorbid pain-related disorders^[25].

• Side effects can include dry mouth, arrhythmias, urinary retention, constipation, seizures, dizziness or lightheadedness, very low blood pressure, blurred vision, weight gain and confusion.
• Contraindications. TCAs are contraindicated in individuals with heart conditions and epilepsy. Pregnant women should avoid TCAs due to an increased risk of birth defects.

NMDA Antagonists work by blocking the binding of glutamate to NMDA receptors, which appears to be implicated in several types of depression. They have been shown to exert better antidepressant effects than SSRIs in treatment-resistant patients^[26], to whom they are more commonly prescribed.

• Side effects vary depending on the medication but may include disassociation or similar perceptual alterations, dizziness, headaches, sedation and dry mouth.
• Contraindications vary depending on the type of NMDA antagonist used. Ketamine derivatives are often contraindicated for those with schizophrenia, microvascular complications and a high risk for aneurysms or bleeding. Other NMDA antagonists may be problematic for those with epilepsy, especially when coupled with other medications that can promote seizures.

MAO Inhibitors work by inhibiting monoamine oxidase, the enzyme responsible for the degradation of serotonin, dopamine and norepinephrine. This serves to increase the concentration of these neurotransmitters at the synapse. However, it also interferes with their optimal metabolism.

• Side effects include nausea, constipation or diarrhea, drowsiness or insomnia, dry mouth, blood pressure fluctuations and dizziness or lightheadedness. Longer-term use can cause weight gain, swelling, muscle pain, nutrient deficiencies and sexual dysfunction.
• Contraindications. Extreme adverse reactions can occur when taken with neurotransmitter precursors, antidepressants, or general anesthetics, some of which can result in serotonin syndrome, coma, or death.^[27]
• Used as a Last Resort. MAOIs are rarely prescribed nowadays due to dietary restrictions, poor outcomes, deleterious side effects and severe interactions with other medications. They may be used as a last resort if the patient is unresponsive to other treatment options and fails to manage symptoms otherwise.^[28]
• Long-Term Potential for Depression. Preliminary evidence suggests that monoamine oxidase is essential for regulating neurotransmission and that deficits or excesses can contribute to increasing mitochondrial oxidative stress^[29] and neuroinflammation. This can potentially cause depression in the long term, especially when coupled with prolonged increases in neurotransmitter receptors.

Other Potential Antidepressant Benefits

Aside from their intended benefits, a few other benefits have been discovered pertaining to short-term antidepressant use:

SSRIs/SNRIs and BDNF. Most antidepressants help to block the stress response, improve BDNF levels and facilitate neurogenesis and plasticity in the hippocampus. Some SSRIs only appear to increase BDNF transiently, which may be unrelated to their known benefits due to the longer wait time before they become effective. BDNF effects of SNRIs appear to be mediated via B3 adrenoceptors, which suggests that they will become less effective in the long run.

Potential Anti-Inflammatory Actions of Antidepressants. Aside from helping to promote stable neurotransmission during recovery from depression, it has been noted that antidepressants exert anti-inflammatory effects that may be partially responsible for their benefits.

Antimicrobial Effects. Antidepressants have been shown to exert antimicrobial effects and reduce the diversity of the gut microbiome. This is thought to contribute to both their adverse and beneficial effects. For similar reasons, some antibiotics have been associated with inducing antidepressant-like effects^[30].

Long-Term Use Increases Adverse Effect Risk

To be continued in part 2.

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