Antidepressants. What They Are and how They Work

Introduction. What are antidepressants?

The antidepressants address the entire spectrum of depressive symptoms, improving mood and energy, reducing anxiety and regulating the sleep. Depending on the type, antidepressants have different profile. Some of them have more mood enhancing and anti-anxiety effect while others work more stimulating.

The effect of antidepressants evolves over weeks. The patient doesn’t feel any causal connection between their intake and the resulting effect. Therefore, the antidepressants are not addictive.

The antidepressants are most commonly used for treatment of depression. However, due to their anxiety-reducing effect, they are also prescribed for anxiety disorders such as phobias, generalized anxiety disorder and panic attacks. Other uses for antidepressants include eating disorders, OCD, PTSD, and depression in bipolar disorder.

Antidepressants, historical note

The antidepressants have been developed in the late 50ties. In the early 1950s, during drug tests for tuberculosis treatment, the researchers noticed mood improvement of patients treated with Iproniazid. This medication inhibits an enzyme called Monoamine Oxidase (MAO) that breaks down neurotransmitters like norepinephrine, serotonin, and dopamine. As a result, the concentration of these neurotransmitters in the synaptic gap increases. Iproniazid was approved for the treatment of depression in 1958 but few years later has been taken from the market due to serious side effects.

The first effective and well tolerated antidepressant was Imipramine introduced into psychiatric treatment in 1957. Imipramine belongs to the group of tricyclic antidepressants. Today tricyclic antidepressants are rarely used because of more pronounced side effects compared with the newer antidepressants such as SSRIs or SNRIs.

The first modern antidepressant, and the first of the class called Selective Serotonin Reuptake Inhibitor (SSRI), was Fluoxetine. It has been discovered by Eli Lilly Company in 1972 and after intense clinical studies approved in 1986.   

The second modern antidepressant, Venlafaxine, which belongs to Serotonin–Norepinephrine Reuptake Inhibitor (SNRI) group, was introduced to the US market in 1993. Venlafaxine blocks the reuptake of serotonin and noradrenaline. In compare to other antidepressants Venlafaxine acts faster mostly due to norepinephrine reuptake inhibition.

Benefits and risks of antidepressants

Antidepressants need in average 3 to 4 weeks to develop the full efficacy. Most of the antidepressants have initially stimulating effect followed by mood improvement, increased energy level and reduction of anxiety. The initial overstimulation might be dangerous for patients experiencing severe depression or anxiety. It can “back-fire” increasing anxiety or triggering suicidal thoughts. Thus, the choice and the treatment with antidepressants should be monitored by an experienced psychiatrist.

Antidepressants do not induce euphoria. They are only effective in people with depression. Antidepressants work as a kind of scaffolding maintaining patient’s psychological balance. After restoring patient’s functionality, he/she has the means to implement life changes. Although antidepressants are effective in short and medium term, the long-term healing can be achieved by combining them with psychotherapy.

What are neurotransmitters and what they do?

Neurotransmitters are messenger molecules that transmit signals between neurons. The brain’s 100 billion neurons need to communicate quickly and effectively, which is done through electrical impulses and neurotransmitters. These molecules are produced in the brain and binding to receptors in the synapses, allowing the signal transmission between neurons. Despite their small size, neurotransmitters have a powerful impact on our performance. Without them, thoughts, feelings, and movements would not function properly. They control motivation, mood, energy, sleep, and desire, affecting out thinking and memory.

The serotonin hypothesis

The serotonin hypothesis dates back to 1969. Two scientists from Leningrad (now St. Petersburg) reported in depressed patients lower levels of a serotonin breakdown product in the brain fluid. Following this conclusion, they suggested that depression may stem from a serotonin deficiency.

The serotonin model became popular in medical textbooks and still exists in the popular opinion. However, later studies have failed to convincingly prove a serotonin deficit in depression. Depression is a complex condition, therefore the idea that an imbalance of a single neurotransmitter could be the only root cause is outdated. The development of new antidepressants with no influence on the serotonin receptor proved this hypothesis wrong.

How the antidepressants work?

Antidepressants influence the brain’s metabolism trough the neurotransmitters such as serotonin, norepinephrine, dopamine, and glutamate. Most antidepressants work by increasing the concentration of neurotransmitters in the so-called synaptic space. This happens by preventing the reuptake of neurotransmitters into “transmitter cells” (presynaptic neurons) after they have been released. This is also known as “no re-entry”. The increased concentration of the neurotransmitters exerts a stronger effect on the “receiving cell” (the post-synaptic neuron).

SSRIs as a model for antidepressant‘s course of action

SSRIs (Selective Serotonin Reuptake Inhibitors) can be used as a model for antidepressants mechanism of action. The nerve cell, called neuron, consists of a body and the axon. The latter can be compared to an electrical wire. There are several neurons between the source of impulse and its receiver, which means that the electric impulse must “jump” from one neuron to the other. The transport of the information along the axon happens “electrically” through voltage changes on the cell wall. The information travels as an electrical wave to the end of the axon. However, the axons are not connected directly. There is the mentioned synapse, a gap between the corresponding neurons. The impulse must be past to the next neuron chemically through the neurotransmitters, in case of SSRIs trough serotonin.

The electric impulse arriving in the first neuron stimulates the release of serotonin in the synaptic space which stimulates the second neuron. Afterwards serotonin is immediately taken back to the synapse of the first neuron. Premature or excessive reuptake, i.e. taking back the neurotransmiter into the neuron, lowers its concentration. The lower serotonin concentration slows the speed of the impulse traveling through the neural pathways. SSRIs block the excessive reuptake, leading to an increase of serotonin concentration in the synaptic space, and by doing so they speed up the flow of the information in the brain.

SSRI vs. SNRI: How are they different?

Serotonin plays a crucial role in regulating mood. When serotonin levels are too low, a person may experience depression, anxiety, suicidal thoughts, or obsessive-compulsive behaviours.

Norepinephrine is involved in the body’s fight-or-flight response. When a person feels threatened, norepinephrine naturally increases. In everyday life, norepinephrine also contributes to sleep, attention, memory, and mood regulation. People with low levels of norepinephrine may have trouble concentrating, or experience depression.

Both SSRIs (Selective Serotonin Reuptake Inhibitors) and SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors) increase serotonin concentration in brain areas associated with depression. Additionally, SNRIs also increase norepinephrine concentration in such areas. Higher norepinephrine concentration improves mood but also the energy level and concentration. There is no conclusive evidence that one of this group is consistently superior to the other. In clinical practice the psychiatrist may need to try different SSRI or SNRI to find the most effective antidepressant and the most effective dosage while avoiding the side effects.

Tricyclic antidepressants

The tricyclics are the eldest group among antidepressants. Such substances as imipramine, nortriptyline, amitriptyline, doxepin, trimipramine, and desipramine, are effective, but they have more side effects than SSRI and SNRIs. Tricyclics can be used for treatment of depressions resistant to treatment with other groups of antidepressants.

Monoamine Oxidase Inhibitors (MAO)

Monoamine Oxidase Inhibitors (MAOI) like tranylcypromine, phenelzine, and isocarboxazid, despite their strong anti-depressive effect, can be prescribed when other antidepressants don’t work. MAO Inhibitors block an enzyme dismantling neurotransmitters such as serotonin, norepinephrine, and dopamine increasing their concentration in the synaptic gap.

There are two groups of MAO inhibitors: irreversible and reversible. Irreversible MAOI have a longer lasting effect and interact with food containing tyramine such as cheese, red wine, or chocolate. Patients treated with irreversible MAOI have to follow a strict low-tyramine diet. Reversible MAO Inhibitors do not require such a diet.

Selegiline is a newer irreversible selective inhibitor of monoamine oxidase type B (MAO-B) that is applied as a patch and has fewer side effects. MAO-B is breaking down dopamine, which plays a crucial function for such cognitive functions as memorizing and concentration. MAO-B is effective in treating conditions with reduced dopaminergic neurotransmission including Parkinson’s disease.

MAO inhibitors might create severe side effects if combined with other antidepressants or alcohol. They can rapidly increase the serotonin concentration in the synaptic space causing life-threatening, so-called serotonin syndrome. In case the medication should be switched from irreversible MAO Inhibitors to other antidepressants a gap of three weeks should be maintained.

The less severe side effects of MAO inhibitors can be restlessness, insomnia, dry mouth, and digestive issues. In patients treated with MAO inhibitors regular blood and liver function controls are necessary.

Atypical antidepressants

Such newly developed antidepressants like Bupropion, Mirtazapine, Agomelatine, Nefazodone, Trazodone, and Vortioxetine, don’t belong to any of the above-mentioned categories. They have different course of actions and can be used alone or in combination with other antidepressants. Scientists assume that they are the predecessors of new groups of antidepressants which are already in the clinical trials, or which can be developed in the near future.

Herbal remedies

The most common herbal medication used in treatment for depression is an extract from St. John’s Wort. It has been clinically proved that this extract possesses a mild anti-depressive effect. St. John’s Wort contains various forms of hypericin and other flavonoids. It interacts with other medications among them with antidepressants. A common side effect of St. John’s Wort is sun allergy. Considering the weak effect and the side effects of St. John’s Wort, there are little indications for its use. For this reason, it hasn’t been approved by the FDA.

Ketamine

Ketamine has an immediate, short acting stimulating effect and it’s not a proper antidepressant. It’s used in anaesthesia inducing sedation, pain, and dissociation (trance-like state). Ketamine on the molecular level has antagonistic properties on glutamate receptors and acts on serotonin and dopamine systems. Ketamine is also influencing the neuroplasticity of the brain increasing the number of synapses in brain areas related to depression.

At the end of 2019 the drug Esketamine, has been approved by FDA as a nasal spray for therapy resistant depression. The biggest disadvantage of ketamine therapy is its short efficacy. After ketamine treatment most patients experience a depressive relapse after around one week.

The hype about Ketamine therapy is related to its immediate effect. The conventional antidepressants need weeks to take effect, so the rapid response of ketamine therapy is tempting. However, Ketamine is associated with promises that the substance cannot keep because of the substantial risk of relapse.

The therapy with ketamine is intended primarily for inpatient treatment in psychiatric centres. Ketamine can be used only for individuals who have already undergone at least two sufficiently long therapy attempts with approved antidepressants in sufficient dosages.

Choosing the proper medication

The treatment of severe depression or depression with anxiety requires a combination of two, sometimes three different substances. In people with severe anxiety and/or suicidal ideations the administration of a sedating medication, especially at the beginning of the treatment, prevents the risk of suicide or over-boarding anxiety. By choosing the right antidepressant and by titrating its dosage the side effects can be avoided.

Optimizing Treatment with Antidepressants

The initial step typically involves switching to a different antidepressant instead of combining two medications, as the evidence does not favour one strategy over the other. However, if combinations are considered, research suggests that combining SSRIs or SNRIs with Mirtazapin or Bupropion may be effective.

Changing the Antidepressant

When initial treatment optimization fails, switching to a different antidepressant is a viable option. However, selecting the new antidepressant should be based on factors such as the patient’s response history and potential side effects.

Combining Two Antidepressants

Combination of two antidepressants is another approach to consider in cases of treatment-resistant depression. Combining SSRIs or SNRIs with Mirtazapin or Bupropion has shown promise. However, the choice of combination should be made carefully, considering potential interactions and side effects.

Augmentation Therapy

This method involves adding a substance that doesn’t have acute antidepressant effects but enhances the efficacy of an antidepressant. This strategy may be preferred over switching antidepressants in cases of partial remission. Augmentation options include Lithium and atypical antipsychotics like Quetiapin, Aripiprazol, and Olanzapin, which are added to the existing antidepressant regimen.

Augmentation with Mood Stabilizers

As the name suggests this medication possess mood stabilizing effect reducing the mood swings. They could be added to the treatment with antidepressants to enhance their effectiveness. Mood stabilizers can also be used in the phase prophylaxis protecting the patients, especially those with recurrent depressive episodes, from relapses. The most effective mood stabilizers with such effect are Lamotrigine and Lithium.

Lithium Augmentation

Lithium augmentation has been supported by prospective studies in older patients, showing significant benefits compared to a placebo. For older patients, a target serum level of 0.4 mmol/l may be sufficient, and if there’s no response within four weeks, a change in strategy is recommended. Successful augmentation should continue for at least a year. Recent research also suggests potential pro-cognitive and anti-dementia effects of Lithium.

Augmentation with Lamotrigine

Lamotrigine is frequently used and effective in treatment of bipolar diorder especially as a prophylax. However, lamotrigine showed also its efficacy as an augmentation agent in treatment of refractory unipolar major depressive disorder. Studies revealed that lamotrigine was most effective in patient depressed for shorter periods of time who had failed fewer previous treatments with antidepressants. Lamotrigine seems to increased response in patients with comorbid anxiety disorders or chronic pain syndromes.

Augmentation with Atypical Antipsychotics

Atypical antipsychotics, particularly Aripiprazol and Quetiapin, can be used as augmentation strategies in cases of treatment-resistant depression. However, by their usea nticholinergic effects should be considered, as they can worsen cognitive function. Antipsychotics can be combined with antidepressant especially in cases of severe depression with psychotic futures or in cases of depression with OCD symptoms.

Augmentation with Stimulants

Stimulants, such as Methylphenidate, have been mentioned as augmentation strategies in treatment guidelines. However, the evidence for their use is inconsistent.

Adjuvant Medications

Antidepressants need several weeks to show positive effects. At the beginning of the treatment, they can even worsen the symptoms triggering more anxiety or sleep deprivation. Therefore, in the initial treatment phase a quick acting medication with calming and sleep regulating effect are necessary.

The most frequently used adjuvant medication are benzodiazepines. These drugs serve primarily as hypnotics (sleep inducing medication) and anxiolytics (anti-anxiety medication) in cases of severe insomnia or agitation. They are useful in the first days of treatment with antidepressants especially in patients with severe anxiety, sleeplessness, or suicidal thoughts. Because benzodiazepines show an immediate calming effect they help to “bridge” the gap until the antidepressant develops such effect on their own.