How Does Moclobemide Work?

Moclobemide, best known by the brand name Manerix, is an antidepressant used to treat major depressive disorder in adults.

Moclobemide works differently from SSRIs, SNRIs and most other antidepressants. Instead of blocking a neurotransmitter transporter, it temporarily inhibits an enzyme called:

Monoamine Oxidase-A — MAO-A

MAO-A normally helps break down several important neurotransmitters, particularly:

Serotonin — 5-HT

Norepinephrine — NE

and:

Dopamine — DA

By inhibiting MAO-A, moclobemide slows the breakdown of these neurotransmitters and increases their availability for signaling.

The basic mechanism is:

1. Moclobemide
2. Reversibly inhibits MAO-A

• Serotonin breakdown decreases
• Norepinephrine breakdown decreases
• Dopamine breakdown decreases

1. More serotonin + norepinephrine + dopamine remain available
2. Their receptors receive altered or increased signaling
3. Mood, motivation, energy and emotional networks gradually adapt
4. Depressive symptoms may improve

The Canadian product monograph classifies moclobemide as a short-acting reversible inhibitor of monoamine oxidase-A (RIMA) and states that inhibition of serotonin, norepinephrine and dopamine deamination may account for its antidepressant activity.

How Does Moclobemide Work for Depression?

Depression should not be described simply as:

“Low serotonin”

or:

“Low norepinephrine.”

Major depressive disorder can involve dysregulation across multiple interacting systems responsible for:

• Mood
• Motivation
• Reward
• Energy
• Attention
• Cognitive function
• Stress response
• Emotional regulation
• Sleep
• Repetitive negative thinking Moclobemide changes the availability of three major monoamine neurotransmitters simultaneously.

The broader process is:

1. Moclobemide inhibits MAO-A
2. 5-HT + NE + DA degradation decreases
3. Monoamine signaling changes
4. Serotonin, adrenergic and dopamine receptors respond
5. Feedback systems and neural networks adapt
6. Depressive symptoms may improve

Therefore, moclobemide does not simply “replace a missing brain chemical.”

It changes the regulation and persistence of monoamine signaling.

What Is Monoamine Oxidase?

Monoamine oxidase, or:

MAO

is an enzyme located largely on the outer membrane of mitochondria inside cells.

Mitochondria are cellular structures involved in energy production, but they also provide a location for several important metabolic enzymes.

MAO helps metabolize monoamine neurotransmitters after they enter the intracellular environment.

There are two main forms:

MAO-A

and:

MAO-B

They overlap in function, but they differ in which substrates they preferentially metabolize.

What Does MAO-A Do?

MAO-A is particularly important for the metabolism of:

Serotonin

and:

Norepinephrine

It also contributes to:

Dopamine metabolism

Therefore:

1. Serotonin / norepinephrine / dopamine
2. MAO-A
3. Deaminated metabolites

Moclobemide interrupts this pathway.

1. Moclobemide
2. MAO-A inhibited
3. Monoamine degradation decreases
4. More neurotransmitter remains available for neuronal signaling

Experimental and clinical pharmacology studies consistently show that moclobemide increases monoamine availability, particularly serotonin, norepinephrine and dopamine.

What Is a RIMA?

Moclobemide is often described as a:

RIMA — Reversible Inhibitor of Monoamine Oxidase-A

Each part of this term matters.

Reversible

Moclobemide does not permanently disable the MAO-A enzyme.

Inhibitor

It reduces MAO-A activity.

Monoamine Oxidase-A

It preferentially targets the A form of monoamine oxidase.

At a 300 mg dose, the Canadian product monograph reports approximately:

80% inhibition of MAO-A

compared with approximately:

20–30% inhibition of MAO-B

and describes the MAO-A inhibition as reversible and lasting no more than about 24 hours.

Why Is Reversible MAO-A Inhibition Important?

Older MAO inhibitors such as:

• Phenelzine
• Tranylcypromine produce long-lasting inhibition of monoamine oxidase.

The enzyme remains unavailable until the body manufactures new enzyme.

Moclobemide behaves differently.

Moclobemide

binds MAO-A reversibly.

Therefore:

1. Moclobemide concentration rises
2. MAO-A inhibition increases

then:

1. Moclobemide concentration falls
2. MAO-A activity can recover relatively quickly

Research on moclobemide shows that MAO activity can largely recover within approximately 24 hours after the last dose.

This reversibility contributes to moclobemide’s different:

• Food-interaction profile
• Safety profile
• Duration of enzyme inhibition compared with older irreversible MAO inhibitors.

What Does Moclobemide Do to Serotonin?

Serotonin contributes to:

• Mood
• Anxiety
• Emotional regulation
• Repetitive thinking
• Sleep
• Appetite
• Stress responses MAO-A is an important enzyme for serotonin metabolism.

Therefore:

1. Moclobemide
2. MAO-A inhibited
3. Serotonin breakdown decreases
4. Serotonin availability increases
5. Serotonin receptors receive altered stimulation

This includes signaling through receptors such as:

• 5-HT1A
• 5-HT2A
• 5-HT2C
• Other serotonin receptors Moclobemide does not directly block SERT like an SSRI. Instead, it increases serotonergic activity by reducing serotonin degradation.

How Is Moclobemide Different From an SSRI?

An SSRI such as escitalopram or sertraline primarily works by blocking:

SERT — Serotonin Transporter

Therefore:

SSRI

1. SERT inhibited
2. Serotonin reuptake decreases
3. Serotonin remains in the synapse longer

Moclobemide works differently:

Moclobemide

1. MAO-A inhibited
2. Serotonin metabolism decreases
3. Serotonin availability increases

while also affecting:

Norepinephrine + dopamine

Therefore, both treatments can increase serotonergic transmission, but they act at different biological steps.

What Does Moclobemide Do to Norepinephrine?

Norepinephrine contributes to:

• Alertness
• Attention
• Mental energy
• Motivation
• Working memory
• Stress response MAO-A metabolizes norepinephrine.

Therefore:

1. Moclobemide
2. MAO-A inhibition
3. Norepinephrine breakdown decreases
4. Norepinephrine availability increases
5. Adrenergic receptor signaling changes

This may contribute to improvement in symptoms such as:

• Fatigue
• Reduced concentration
• Low mental energy
• Reduced motivation in some patients.

However, excessive noradrenergic activation can also contribute to:

• Restlessness
• Insomnia
• Anxiety
• Tremor
• Palpitations The therapeutic objective is therefore not simply:

“More norepinephrine.”

It is more appropriate norepinephrine signaling within relevant neural circuits.

What Does Moclobemide Do to Dopamine?

Dopamine contributes to:

• Motivation
• Reward
• Pleasure
• Task initiation
• Attention
• Reinforcement learning
• Movement MAO-A contributes to dopamine metabolism, although dopamine metabolism involves both MAO isoforms and varies by brain region.

Moclobemide can therefore:

1. Inhibit MAO-A
2. Reduce part of dopamine metabolism
3. Increase dopamine availability in some neural systems

Experimental studies demonstrate increases in cerebral dopamine along with serotonin and norepinephrine following moclobemide treatment.

This dopaminergic component distinguishes moclobemide from antidepressants that are predominantly serotonergic.

However:

Moclobemide is not a dopamine agonist and does not primarily block the dopamine transporter.

Its effect on dopamine occurs through reduced enzymatic degradation.

Why Might Moclobemide Affect Motivation and Pleasure?

Two neurotransmitters involved in these functions are:

Dopamine

and:

Norepinephrine

If moclobemide increases the availability of these neurotransmitters in relevant cortical and reward circuits, it may contribute to improvement in:

• Motivation
• Interest
• Energy
• Cognitive engagement
• Ability to experience reward The pathway is conceptually:

1. MAO-A inhibition
2. ↑ dopamine + norepinephrine availability
3. Reward and motivational circuitry receives altered monoamine signaling
4. Motivation or engagement may improve

However, depression-related anhedonia or low motivation cannot be assumed to result from one neurotransmitter alone.

Does Moclobemide Directly Bind Serotonin, Dopamine or Adrenergic Receptors?

Its principal action is enzyme inhibition, not direct receptor binding.

Preclinical pharmacology found little direct interaction with conventional serotonin, dopamine or adrenergic receptor sites and little direct inhibition of monoamine uptake mechanisms.

Therefore, the primary sequence is:

1. Moclobemide
2. MAO-A

rather than:

1. Moclobemide
2. Serotonin / dopamine / norepinephrine receptor

The receptors respond downstream because neurotransmitter availability has changed.

Why Does Moclobemide Take Time to Work?

MAO-A inhibition begins relatively quickly.

The Canadian monograph reports substantial MAO-A inhibition after therapeutic dosing, and older human pharmacology studies found approximately 80% inhibition within a few hours.

Yet depression does not necessarily improve immediately.

Why?

Because increased neurotransmitter availability is only the first step.

1. MAO-A inhibited
2. Monoamine availability changes
3. Receptors receive altered stimulation
4. Receptor sensitivity and feedback systems adapt
5. Intracellular signaling changes
6. Neural networks gradually adapt
7. Clinical antidepressant response develops

This is why rapidly increasing the dose does not necessarily make moclobemide work sooner. The Canadian monograph specifically notes that rapid dose escalation has not been shown to shorten the delay to therapeutic response and may increase adverse effects.

Why Can Moclobemide Feel Activating at First?

Increasing norepinephrine and dopamine signaling can sometimes initially produce:

• Restlessness
• Increased alertness
• Anxiety
• Insomnia
• Tremor
• Agitation The process may be:

1. Moclobemide starts
2. MAO-A inhibition
3. NE + DA availability increases
4. Arousal systems become more active
5. Temporary activation may occur

For another patient, the medication may not feel activating at all.

This variability illustrates why baseline neurotransmitter function and individual pharmacodynamics matter.

Why Can Moclobemide Cause Insomnia?

Both:

Norepinephrine

and:

Dopamine

contribute to wakefulness and alertness.

Therefore:

1. MAO-A inhibition
2. Noradrenergic + dopaminergic activity increases
3. Arousal remains elevated
4. Difficulty sleeping may occur

Insomnia and sleep disturbance are recognized adverse effects in Canadian moclobemide clinical-trial data.

How Is Moclobemide Different From an SNRI?

An SNRI such as duloxetine or levomilnacipran works primarily through:

SERT + NET inhibition

Therefore:

1. SNRI
2. Reuptake of serotonin + norepinephrine decreases

Moclobemide:

1. MAO-A inhibition
2. Breakdown of serotonin + norepinephrine + some dopamine decreases

Therefore, the end results partly overlap, but the mechanisms differ substantially.

SNRI

changes reuptake Moclobemide

changes metabolism

This distinction can influence:

• Side effects
• Drug interactions
• Food interactions
• Individual treatment response

How Is Moclobemide Different from Bupropion?

Bupropion primarily influences:

Norepinephrine + dopamine

through mechanisms involving their transporters.

Moclobemide affects:

Serotonin + norepinephrine + dopamine

by inhibiting their enzymatic degradation through MAO-A.

Therefore:

Bupropion

NDRI-related mechanism

→ ↑ NE + DA signaling

while:

Moclobemide

MAO-A inhibition

→ ↓ 5-HT + NE + DA breakdown

The two drugs should not be viewed as interchangeable simply because both affect catecholamine systems.

Importantly, current Canadian labeling contraindicates concomitant bupropion and moclobemide.

How Is Moclobemide Different from Traditional MAO Inhibitors?

Traditional MAOIs such as phenelzine and tranylcypromine generally produce:

Irreversible and broader MAO inhibition

Moclobemide produces:

Preferential + reversible MAO-A inhibition

The difference can be represented as:

Traditional irreversible MAOI

1. MAO enzyme permanently inhibited
2. New enzyme must be synthesized
3. Effect persists after the drug has left the blood

versus:

Moclobemide

1. MAO-A temporarily inhibited
2. Drug dissociates
3. Enzyme activity recovers relatively quickly

This is a major reason moclobemide has a less restrictive food-interaction profile than traditional irreversible MAO inhibitors.

Why Does Tyramine Matter with MAO Inhibitors?

Tyramine

is a naturally occurring compound found in certain aged or fermented foods.

Normally, monoamine oxidase in the intestine and liver helps metabolize tyramine before much reaches the circulation.

With powerful irreversible MAO inhibition:

1. Tyramine absorption increases
2. Norepinephrine release can increase dramatically
3. Blood pressure can rise sharply
4. Hypertensive reaction

This is the classic:

“Cheese reaction”

associated with older MAOIs.

Why Is the Tyramine Interaction Smaller with Moclobemide?

Moclobemide is:

Selective

and:

Reversible

Tyramine can compete with moclobemide at MAO-A, allowing more normal tyramine metabolism than occurs during irreversible MAO blockade.

This substantially reduces—but does not completely eliminate—the tyramine interaction.

The Canadian monograph therefore recommends taking moclobemide after meals.

Moclobemide should not be marketed as having zero food interaction; rather, the interaction is generally much less pronounced than with traditional irreversible MAO inhibitors.

Why Can Moclobemide Cause Serotonin Syndrome?

Moclobemide reduces the breakdown of serotonin.

Therefore:

1. Moclobemide
2. Serotonin degradation decreases

If another drug simultaneously causes a large increase in serotonin:

1. Additional serotonergic medication
2. Serotonin signaling increases further
3. Excessive serotonergic activity
4. Serotonin Syndrome

Symptoms may include:

• Agitation
• Confusion
• Sweating
• Fever
• Tremor
• Hyperreflexia
• Muscle twitching or clonus
• Rapid heart rate
• Gastrointestinal symptoms For this reason, current Canadian labeling contraindicates moclobemide with SSRIs, SNRIs and several other serotonergic medications.

How Is Moclobemide Metabolized?

Moclobemide is:

Extensively metabolized by the liver

primarily through oxidative pathways.

The Canadian product monograph identifies the polymorphic enzymes:

CYP2C19

and:

CYP2D6

as contributors to interindividual metabolic variability.

The simplified pharmacokinetic pathway is:

1. Moclobemide
2. Absorption
3. Hepatic first-pass metabolism
4. CYP2C19 + CYP2D6 and other oxidative pathways
5. Metabolites
6. Predominantly urinary elimination of metabolites

More than 95% of a dose is recovered in urine, but less than 1% is unchanged moclobemide, confirming that metabolism occurs before elimination.

Why Does Moclobemide Have Nonlinear Pharmacokinetics?

This is an important feature.

At lower doses, drug concentration rises relatively predictably.

At higher doses, metabolism can become increasingly saturated.

Therefore:

1. Moclobemide dose increases
2. Metabolic pathways become less able to increase clearance proportionally
3. Blood concentration can rise more than expected

The Canadian monograph describes nonlinear pharmacokinetics above approximately 200 mg in single-dose studies, with decreasing clearance and increasing half-life as dose increases.

This helps explain why:

Doubling a dose does not necessarily produce only twice the drug exposure.

Clinical titration is therefore important.

Why Does Moclobemide Bioavailability Increase During Treatment?

The Canadian monograph reports absolute bioavailability of approximately:

55% after a single dose

but approximately:

90% after repeated dosing.

This likely reflects partial saturation of first-pass metabolism.

Conceptually:

1. First dose
2. Substantial first-pass metabolism
3. Lower systemic bioavailability

After repeated dosing:

1. Metabolic capacity becomes more saturated
2. Greater proportion reaches systemic circulation

This is another reason moclobemide dosing is generally increased cautiously rather than rapidly.

How Long Does Moclobemide Stay in the Body?

Moclobemide itself has a relatively short plasma half-life.

The Canadian monograph reports approximately:

1.5 hours

after a single 100 mg dose.

However, a short plasma half-life does not mean its biological effect disappears at exactly the same time.

MAO-A inhibition can continue for longer than the measured plasma half-life.

Therefore:

Drug concentration

and:

enzyme inhibition

should not be treated as identical timelines.

Why Does Liver Function Matter?

Because moclobemide is extensively metabolized in the liver.

In people with significant liver impairment:

1. Hepatic metabolism decreases
2. Moclobemide clearance decreases
3. Drug concentration increases

In a study cited by the Canadian product monograph, liver cirrhosis produced approximately:

• A threefold increase in peak concentration
• A threefold increase in half-life
• A fourfold reduction in clearance following a single dose.

Therefore, liver function can be an important pharmacokinetic determinant.

Why Can the Same Moclobemide Dose Affect Two People Differently?

Two patients receiving the same dose may have very different experiences.

One may experience:

Improved mood + energy + motivation

Another:

Insomnia + anxiety + restlessness

Another:

Little therapeutic response

There are two broad reasons:

**Pharmacokinetics — PK -**How much moclobemide reaches the brain?

and:

Pharmacodynamics — PD- How does the brain respond once MAO-A is inhibited?

Moclobemide Pharmacokinetics — PK

PK asks: Does an appropriate amount of moclobemide reach the brain?

The pathway is:

1. Moclobemide dose
2. Gastrointestinal absorption
3. First-pass hepatic metabolism
4. CYP2C19 + CYP2D6 + other pathways
5. Moclobemide concentration
6. Medication reaches the brain

Important influences include:

• Dose
• Liver function
• CYP2C19 activity
• CYP2D6 activity
• Drug interactions
• Repeated dosing
• Nonlinear pharmacokinetics

Moclobemide Pharmacodynamics — PD

PD asks: What happens when moclobemide reaches MAO-A?

1. Moclobemide
2. MAO-A inhibition

• ↓ serotonin breakdown
• ↓ norepinephrine breakdown
• ↓ dopamine breakdown

1. ↑ monoamine availability
2. Serotonin + adrenergic + dopamine receptors respond
3. Mood, motivation, attention and emotional networks adapt
4. Depressive symptoms may improve

Therefore:

Normal moclobemide metabolism does not automatically mean an optimal pharmacodynamic response.

Moclobemide Needs Both Appropriate Exposure and Brain Compatibility

The complete pathway can be summarized as:

1. Moclobemide is taken
2. PK — Pharmacokinetics
3. Absorption
4. Hepatic first-pass metabolism
5. CYP2C19 + CYP2D6 + other oxidative pathways
6. Drug interactions + liver function
7. Appropriate moclobemide exposure
8. PD — Pharmacodynamics
9. MAO-A inhibition

• ↓ Serotonin breakdown
• ↓ Norepinephrine breakdown
• ↓ Dopamine breakdown

1. Greater 5-HT + NE + DA availability
2. Serotonin + adrenergic + dopamine receptor systems respond
3. Mood, motivation, energy and cognitive networks adapt
4. Depressive symptoms may improve

This creates two different personalized-prescribing questions:

PK asks:

Does an appropriate amount of moclobemide reach the brain?

PD asks: Is reversible MAO-A inhibition compatible with this patient’s underlying monoamine biology and symptom pattern?

Both can influence the final clinical outcome.

Does CYP2C19 Genotype Affect Moclobemide?

Yes, to some extent.

CYP2C19 contributes to moclobemide metabolism.

Therefore:

1. Reduced CYP2C19 activity
2. Moclobemide metabolism may decrease
3. Drug exposure may increase

The Canadian monograph reports that genetically or drug-induced slow metabolizers can have altered moclobemide concentrations; in the study cited there, exposure was approximately 1.5-fold greater in slow metabolizers.

More importantly, the Dutch Pharmacogenetics Working Group (DPWG) has specifically evaluated CYP2C19 and moclobemide.

The DPWG concluded that:

A CYP2C19–moclobemide gene-drug interaction exists

but:

No therapy adjustment is required

because increased exposure has not been shown to produce a clinically meaningful difference in effectiveness or adverse effects.

This is more precise than saying CYP2C19 is irrelevant.

It is:

Pharmacokinetically relevant

but currently:

Not dose-actionable under DPWG guidance.

Does CYP2D6 Genotype Affect Moclobemide?

The Canadian product monograph identifies CYP2D6, along with CYP2C19, as one of the polymorphic enzymes that can contribute to moclobemide metabolic variability.

However, moclobemide does not depend on CYP2D6 alone.

At present, there is no established CYP2D6-based moclobemide dosing recommendation comparable with the actionable CYP2D6 guidance available for medications such as atomoxetine.

Therefore:

CYP2D6 may influence exposure

but:

CYP2D6 genotype should not independently determine moclobemide dose.

Can Moclobemide Affect Other CYP Enzymes?

Yes.

Moclobemide is not simply a drug that is metabolized by CYP enzymes—it can also inhibit drug-metabolizing enzymes.

The Canadian product monograph specifically identifies clinically relevant inhibition of:

CYP2C19

and:

CYP2D6-related metabolism

in certain interaction settings. For example, moclobemide can increase concentrations of CYP2C19 substrates and can interfere with metabolism of CYP2D6-dependent thioridazine.

Therefore:

1. Another medication
2. Normally metabolized by CYP enzyme
3. Moclobemide inhibits that pathway
4. Other drug concentration may increase

This is why pharmacogenomics alone is insufficient—drug-drug interactions must also be incorporated into PK interpretation.

What Is the Role of the MAOA Gene?

MAOA

encodes:

Monoamine Oxidase-A

which is moclobemide’s principal pharmacodynamic target.

The biological relationship is therefore direct:

1. MAOA gene
2. MAO-A enzyme expression/function
3. Moclobemide inhibits MAO-A
4. 5-HT + NE + DA metabolism changes
5. Clinical response

Functional variation in MAOA has been studied extensively in neuroscience and psychiatry, including regulatory variants such as the:

MAOA-uVNTR

Because moclobemide acts directly on MAO-A, differences affecting MAO-A expression or function are biologically interesting.

However:

There is currently no validated MAOA genotype-based moclobemide prescribing guideline.

An MAOA result therefore should not be interpreted alone as:

“Moclobemide will work”

or:

“Moclobemide will fail.”

What About SLC6A4 Genetics?

SLC6A4

encodes:

SERT — Serotonin Transporter

Moclobemide does not directly inhibit SERT.

However, once MAO-A inhibition increases serotonin availability:

1. Serotonin
2. SERT regulates serotonin clearance
3. Serotonin receptors respond

Therefore, SLC6A4 could influence the broader serotonergic environment through which moclobemide acts.

Variants such as:

5-HTTLPR

and:

rs25531

are biologically interesting but are not validated moclobemide prescribing markers.

What About SLC6A2?

SLC6A2

encodes:

NET — Norepinephrine Transporter

Again, moclobemide does not directly block NET.

Instead:

1. Moclobemide reduces norepinephrine metabolism
2. Norepinephrine availability changes
3. NET helps determine extracellular norepinephrine clearance

Therefore, SLC6A2 may contribute to the downstream pharmacodynamic environment, but no validated SLC6A2-based moclobemide dosing or selection guideline currently exists.

What About SLC6A3 and Dopamine?

SLC6A3

encodes:

DAT — Dopamine Transporter

DAT regulates dopamine clearance, particularly in regions such as the striatum.

Moclobemide increases dopamine availability by reducing enzymatic metabolism rather than directly blocking DAT.

Therefore:

1. Moclobemide
2. ↓ dopamine metabolism

while:

DAT determines part of dopamine reuptake

These two systems interact to influence extracellular dopamine availability.

SLC6A3 is therefore biologically relevant but is not an established moclobemide response marker.

What About COMT?

COMT — Catechol-O-Methyltransferase

is another enzyme involved in the metabolism of:

• Dopamine
• Norepinephrine particularly in some cortical regions.

Therefore:

Moclobemide inhibits MAO-A

while:

COMT remains another route of catecholamine metabolism

The commonly studied:

COMT rs4680 — Val158Met

affects COMT activity and may influence baseline catecholamine signaling.

This makes COMT a biologically plausible downstream modifier of moclobemide response.

However:

There is no validated COMT-guided moclobemide prescribing recommendation.

Can Pharmacogenomic Testing Predict Whether Moclobemide Will Work?

Not with certainty.

Moclobemide response involves several layers.

PK — Drug exposure

Potentially influenced by:

• CYP2C19
• CYP2D6
• Liver function
• Drug interactions

PD — Brain response

Potentially influenced by:

• MAOA
• SLC6A4
• SLC6A2
• SLC6A3
• COMT
• Serotonin receptors
• Adrenergic receptors
• Dopamine receptors
• Baseline monoamine function The DPWG provides the clearest currently recognized pharmacogenetic conclusion: CYP2C19 affects moclobemide pharmacokinetics, but no dose adjustment is recommended because a clinically meaningful effect on efficacy or toxicity has not been demonstrated.

For pharmacodynamic genes such as MAOA, evidence remains investigational.

Why Might Moclobemide Work Very Well for One Person but Poorly for Another?

Two people can both have major depressive disorder while displaying very different neurobiological and symptom patterns.

One may primarily experience:

Low mood + repetitive negative thinking

Another:

Low motivation + loss of pleasure

Another:

Fatigue + poor concentration

Another:

Anxiety + hyperarousal + insomnia

Moclobemide simultaneously changes:

Serotonin Norepinephrine

and:

Dopamine

For one patient, this may move signaling toward a more favourable range.

For another, the same mechanism may produce:

• Excessive activation
• Insomnia
• Anxiety
• Limited therapeutic benefit Therefore:

A diagnosis of depression alone does not identify whether a serotonin-norepinephrine-dopamine mechanism is optimal for a particular patient.