Basal Neurotransmission Levels - Personalized Prescribing

Summary:

The three primary neurotransmitters—serotonin, dopamine, and norepinephrine—play a crucial role in regulating a wide range of bodily and brain functions, including memory, learning, emotions, reward processing, heart function, muscle movement, stress response, and respiration. Regardless of the specific cause, it is well-established that individuals with mental illnesses often exhibit imbalances in one or more of these neurotransmitters. When neurotransmission is altered—whether increased or decreased—disruptions in the functions governed by these neurotransmitters can result, affecting well-being.

Most medications for mental health conditions work by adjusting the levels of these key neurotransmitters. Therefore, it is essential for healthcare providers to assess neurotransmitter levels in their patients to match them with the most effective medication.

Basal Neurotransmitter Levels:

Neurotransmitters are designed to maintain homeostasis within a specific range. They are synthesized, regulated along their pathway by auto-receptors, and metabolized, with genes controlling each step of this process. The genes responsible for synthesis, regulation, and metabolism generally come in three activity variants: normal, high, and low.

A person with a highly active synthesis gene, for example, will naturally have a higher baseline level of that neurotransmitter compared to someone with a low-activity variant. This variability also applies to regulatory and metabolic genes. Consequently, individuals are born with differing baseline levels of neurotransmission within the homeostatic range

Due to genetic variations, individuals are born with unique baseline levels of neurotransmitters, all within the range of homeostasis. One person might have typical serotonin levels but lower dopamine and very low norepinephrine, while another may have a different combination. While genetic variability can produce any combination of neurotransmitter levels, these differences fall within the definition of normal, and individuals with any baseline combination are entirely normal.

Humans encounter various stressors daily, including physical ones, like injury or infection, and nonphysical ones, such as financial worries or workplace conflicts. Acute stressors may temporarily disrupt neurotransmitter levels, but they are typically restored to homeostasis quickly.

In contrast, chronic stress often leads to a sustained reduction in neurotransmitter levels due to the upregulation of specific genes within these pathways. For example, a person with low baseline dopamine may experience even lower dopamine levels, similarly affecting serotonin and norepinephrine. Assessing an individual’s baseline neurotransmitter levels can provide insight into their neurotransmission status under chronic stress, offering a valuable profile of neurotransmitter dysregulation. This information may help guide treatment decisions aimed at restoring balance

Selective Serotonin Reuptake Inhibitors (SSRIs) increase serotonin levels by inhibiting the serotonin transporter (SERT), which normally recycles serotonin from the synapses back into the presynaptic neuron. By blocking SERT, these medications raise serotonin levels in the synapse. Each SSRI has distinct characteristics:

Citalopram, Escitalopram, Paroxetine, and Fluvoxamine: These are considered “pure” serotonergic SSRIs, meaning they have the highest selectivity for serotonin and thus primarily boost serotonin with minimal effects on other neurotransmitters.
Fluoxetine: This SSRI has an additional affinity for the serotonin 2C (5-HT2C) receptor, which may enhance energy and motivation, potentially helping with symptoms of fatigue and low motivation alongside low mood.
Sertraline: In addition to its serotonin reuptake inhibition, sertraline has some affinity for the dopamine transporter, making it suitable for patients who may have low levels of both serotonin and dopamine, addressing both mood and motivational aspects.

Each SSRI’s unique properties allow for a more tailored approach based on a patient’s specific neurotransmitter needs.

Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) elevate both serotonin and norepinephrine levels by blocking their respective transporters – serotonin transporter (SERT) and norepinephrine transporter (NET) which recycle these neurotransmitters from the synapse back into the presynaptic neuron. This blockage increases the concentration of both neurotransmitters in the synapse. Each SNRI has distinct properties:

Venlafaxine: Acts mainly as an SSRI at doses below 150 mg, enhancing serotonin without significantly affecting norepinephrine. At doses above 150 mg, it gains noradrenergic effects, although it is a weaker norepinephrine booster compared to duloxetine and levomilnacipran. Venlafaxine is noted for its high safety profile and lower risk of drug interactions relative to other SSRIs.
Desvenlafaxine: Similar to venlafaxine in action but does not rely on the cytochrome P450 system for metabolism, which can reduce potential interactions with other drugs.
Duloxetine: Has robust serotonin-enhancing effects and a stronger ability to increase norepinephrine levels than venlafaxine or desvenlafaxine. This makes it useful for conditions requiring both mood elevation and increased energy.
Levomilnacipran: Provides serotonin enhancement and has the highest norepinephrine-boosting effect among SNRIs, making it beneficial for patients needing both mood and motivation improvements with a significant focus on norepinephrine activity.

These varied effects enable more personalized SNRI selection based on individual neurotransmitter needs and symptom profiles.

Serotonin Partial Agonist Reuptake Inhibitors (SPARIs) increase serotonin by blocking the serotonin transporter (SERT) and by partially activating the serotonin autoreceptor, which regulates serotonin release. This combined action increases serotonin levels in the synapse. Each SPARI has unique characteristics:

Vortioxetine: Functions as a serotonin reuptake inhibitor and a partial agonist of the serotonin autoreceptor, making it suitable for cases where the autoreceptor is overactive. Additionally, it acts on serotonin 3 and 7 receptors, potentially aiding cognition and reducing nausea, providing broader therapeutic effects beyond mood enhancement.
Vilazodone: Works as both a serotonin reuptake inhibitor and an autoreceptor partial agonist, targeting cases of autoreceptor overactivity. It has difficulty crossing the blood-brain barrier and, unlike some other antidepressants, does not rely on cytochrome P450 for metabolism, reducing drug interaction risks.
Buspirone: Acts purely as an agonist of the serotonin autoreceptor, making it an option to pair with an SSRI when the patient has an overactive autoreceptor, helping enhance serotonin release without additional reuptake inhibition.

These distinct profiles allow SPARIs to be selected based on specific needs related to serotonin regulation and autoreceptor activity.

MAO-A inhibitors increase serotonin, norepinephrine, and to a lesser extent, dopamine, by inhibiting the enzyme monoamine oxidase A (MAO-A), which is responsible for breaking down these neurotransmitters in the presynaptic neuron. By blocking MAO-A, these inhibitors elevate the levels of these neurotransmitters in the synapse. Here’s an example:

Moclobemide: A reversible MAO-A inhibitor, moclobemide enhances serotonin and norepinephrine levels, with a modest increase in dopamine. As a reversible inhibitor, it has a lower risk of severe dietary restrictions and interactions compared to older, irreversible MAO inhibitors, making it safer for patients while still effectively boosting mood and energy.

This action makes moclobemide especially useful for patients with symptoms of low mood and energy where both serotonin and norepinephrine boosts are beneficial.

Tricyclic antidepressants (TCAs) enhance levels of serotonin, norepinephrine, or, in some cases, dopamine, depending on the specific drug. Although they are among the earliest antidepressants developed and are less commonly prescribed due to their side effects, some, like nortriptyline, are still in use today.

Nortriptyline: Primarily increases norepinephrine with some effect on serotonin. It is often used in cases where a stronger norepinephrine boost is needed, especially for patients who may not have responded well to newer medications. Nortriptyline can be effective for both depression and certain types of chronic pain.

Despite the development of newer antidepressants, nortriptyline remains a valuable option in specific cases due to its unique effects and efficacy in treating certain symptoms.

Norepinephrine/Dopamine Reuptake Inhibitors (NDRIs) increase levels of norepinephrine and dopamine by blocking the norepinephrine transporter (NET) and dopamine transporter (DAT). These transporters typically recycle norepinephrine and dopamine back into the presynaptic neuron, so by inhibiting them, NDRIs allow these neurotransmitters to remain in the synapse longer, enhancing their effects. An example of an NDRI is:

Bupropion: This medication boosts both norepinephrine and dopamine, making it effective for symptoms like low energy, lack of motivation, and concentration difficulties. Unlike many antidepressants, bupropion does not affect serotonin levels, which can make it a good option for patients sensitive to serotonin-related side effects, such as weight gain or sexual dysfunction.

Bupropion is frequently used in treating depression, certain types of anxiety, and even as a smoking cessation aid due to its effects on motivation and reward pathways.

Norepinephrine Reuptake Inhibitors (NRIs) increase norepinephrine levels by blocking the norepinephrine transporter (NET), which typically reabsorbs norepinephrine from the synapse back into the presynaptic neuron. By inhibiting NET, NRIs allow norepinephrine to remain in the synapse, thereby enhancing its effects. An example of an NRI is:

Atomoxetine: This medication primarily boosts norepinephrine, making it effective for increasing focus, alertness, and energy. Atomoxetine is commonly used in the treatment of ADHD, as it helps improve attention and reduce hyperactivity and impulsivity without affecting dopamine levels as much as stimulants do. It is also a good alternative for those who may not tolerate stimulant medications well.

Atomoxetine is especially useful for individuals requiring a norepinephrine boost without the dopamine effects associated with stimulants.

Serotonin 2A receptor antagonists (5-HT2A antagonists) work by blocking the serotonin 2A receptor, which, when over-activated, can contribute to symptoms such as anxiety, irritability, and sleep disturbances. By blocking this receptor, these drugs can help alleviate these symptoms, improving mood and sleep. Examples include:

Mirtazapine: A tetracyclic antidepressant that blocks the 5-HT2A receptor, mirtazapine is commonly used to treat depression and anxiety. It also has sedative effects, which can help with sleep disruptions.
Trazodone: Often used for its sedative properties, trazodone blocks the 5-HT2A receptor and is frequently prescribed for insomnia, particularly when depression or anxiety is also present.
Low doses of some antipsychotics: Certain antipsychotic medications, such as aripiprazole, brexpiprazole, and quetiapine, at low doses can block the 5-HT2A receptor. These medications are sometimes used as adjunctive treatments in depression or anxiety, particularly when there are issues with sleep or irritability.

These medications are particularly useful when patients experience symptoms related to serotonin dysregulation, helping to improve both mood and sleep.

Stimulants like amphetamine and methylphenidate are powerful enhancers of dopamine and norepinephrine activity. They achieve this by several mechanisms:

Blocking the dopamine transporter (DAT) and norepinephrine transporter (NET): This prevents the reuptake of dopamine and norepinephrine from the synapse, leading to higher levels of these neurotransmitters in the brain.
Inhibiting MAO-A (monoamine oxidase A): By inhibiting this enzyme, which normally breaks down neurotransmitters like dopamine and norepinephrine, stimulants help sustain higher levels of these neurotransmitters in the synapse.

These combined actions make stimulants highly effective in treating conditions like ADHD and narcolepsy, where boosting dopamine and norepinephrine improves focus, attention, and energy. Here are the key stimulants:

Amphetamines: These include medications like Adderall and Dexedrine, which strongly increase dopamine and norepinephrine levels. They are often prescribed for ADHD and sometimes for narcolepsy, offering rapid and significant symptom relief.
Methylphenidate: Commonly marketed under brand names like Ritalin and Concerta, methylphenidate works similarly by blocking the reuptake of dopamine and norepinephrine but is generally considered to have a milder effect compared to amphetamines. It is also used primarily for ADHD and narcolepsy.

Both drugs enhance dopamine and norepinephrine, improving cognitive function, alertness, and mood regulation, especially in individuals with attention deficit and related conditions.

Adrenergic receptor agonists, such as clonidine and guanfacine, were originally developed to treat high blood pressure but are also used for other purposes due to their ability to reduce norepinephrine (and to some extent dopamine) levels. They work by stimulating certain adrenergic receptors, particularly the alpha-2 adrenergic receptors in the brain, which leads to a reduction in sympathetic nervous system activity.

Clonidine: Primarily used as an antihypertensive, clonidine acts by stimulating alpha-2 receptors in the brainstem, which decreases the release of norepinephrine. This reduces sympathetic nervous activity, leading to a decrease in blood pressure and heart rate. Clonidine is also used off-label to treat ADHD, withdrawal symptoms, and anxiety due to its calming effects.
Guanfacine: Similar to clonidine, guanfacine stimulates alpha-2 receptors and reduces norepinephrine release, leading to lower blood pressure. It is often prescribed for ADHD and has a calming effect on the brain, improving focus and reducing hyperactivity. Like clonidine, it works by modulating norepinephrine levels.

These drugs can help manage conditions where reducing excessive sympathetic activity or lowering norepinephrine is beneficial, such as high blood pressure, ADHD, and certain anxiety disorders.

Low baseline serotonin:
- Scenario: A person with a low baseline serotonin level may experience an even further decline in serotonin under chronic stress, leading to increased symptoms of depression or anxiety.
- Recommended Medication: An SSRI (Selective Serotonin Reuptake Inhibitor) such as citalopram or paroxetine would be helpful because these drugs specifically target serotonin, boosting its levels and potentially alleviating mood and anxiety symptoms.

Normal to high serotonin, low dopamine, and very low norepinephrine:
- Scenario: A person with normal to high baseline serotonin but low dopamine and very low norepinephrine may not benefit from an SSRI, as boosting serotonin alone might not address their symptoms.
- Recommended Medication: Bupropion (a norepinephrine-dopamine reuptake inhibitor, NDRI) could be the best choice, as it directly targets dopamine and norepinephrine, boosting these neurotransmitters and addressing symptoms like low motivation and concentration, which are often linked to low dopamine and norepinephrine.

Low serotonin and low norepinephrine:
- Scenario: A person with both low baseline serotonin and low norepinephrine might experience significant depressive symptoms, with both mood and energy being affected.
- Recommended Medication: An SNRI (Serotonin-Norepinephrine Reuptake Inhibitor) like duloxetine or venlafaxine would be appropriate, as it boosts both serotonin and norepinephrine, which can improve mood and energy levels.

High dopamine levels and stimulant use:
- Scenario: An individual with naturally high dopamine levels may be at risk of exacerbating their symptoms if they take drugs that strongly increase dopamine, such as amphetamines or methylphenidate.
- Risk: Stimulants could dangerously elevate dopamine levels, leading to side effects such as psychosis, agitation, or mania.
- Recommended Approach: This person should avoid stimulant medications and may benefit from medications that target other neurotransmitter systems, such as SSRIs or SNRIs, depending on their specific symptoms.

Serotonin and dopamine imbalance due to genetic variability:
- Scenario: A person with low serotonin and low dopamine who is prescribed an SSRI might experience an increase in serotonin, which can alleviate depression, but simultaneously suffer from further reductions in dopamine, leading to symptoms like anhedonia (loss of pleasure) or lack of motivation due to postsynaptic genetic variations in the serotonin 2C receptor.
- Recommended Medication: In this case, a dopaminergic (e.g., bupropion) or adrenergic drug (e.g., atomoxetine) might be added to boost dopamine levels and counteract the potential decrease in dopamine caused by serotonin elevation.

Low serotonin and anxiety or sleep disruption:
- Scenario: A person with low baseline serotonin who takes an SSRI to treat depression might experience a reduction in depressive symptoms but could suffer from increased anxiety and sleep disruption due to genetic variability in the serotonin 2A receptor or hyperactivity of the HPA axis (hypothalamic-pituitary-adrenal axis).
- Recommended Medication: In such cases, medications that block the serotonin 2A receptor, such as mirtazapine or trazodone, or low doses of certain atypical antipsychotics like quetiapine or aripiprazole, can help mitigate these side effects by improving sleep and reducing anxiety.

These examples demonstrate how neurotransmitter imbalances or genetic variability can influence the response to antidepressant or anxiolytic medications, guiding the choice of the most suitable treatment to improve overall well-being and address specific symptoms.