Why some people tolerate antidepressants less well

Medikamente

Neurobiological, psychological, and clinical reasons

Antidepressants can be an important support for many people. At the same time, there are patients who develop severe side effects even at low doses or who subjectively feel worse while taking the medication.

These reactions are not a sign of weakness, lack of motivation, or "refusal of treatment." In most cases, they can be explained clinically and neurobiologically.

1. Different nervous systems react differently

Not every nervous system processes neurotransmitter changes in the same way.

People with:

high stress sensitivity

early childhood trauma

chronic hyperarousal

high inner vigilance

often react more sensitively to medications that affect serotonergic or noradrenergic systems.

A rapid increase in serotonin or noradrenaline can then lead to:

inner restlessness

sleep disturbances

increased anxiety

a feeling of loss of control

especially at the beginning of treatment.

2. Activating vs. Sedating Effect Profiles

Antidepressants differ significantly in their activating or sedating nature.

Problems arise when:

an activating medication is used when there is already high levels of inner tension

a sedating medication is used when there is pronounced lack of motivation

Examples of possible consequences:

Increased anxiety with activating substances

Emotional flattening with strongly sedating drugs

The choice of medication should therefore be based not only on the diagnosis but also on the individual's level of tension.

3. Trauma, Attachment, and Loss of Control

In people with traumatic experiences, antidepressants can unconsciously trigger something that is difficult to put into words: 👉 the feeling of losing inner control.

Typical statements:

"I don't recognize myself anymore."

"It feels strange."

"I'm afraid of what the medication will do to me."

Here, it's not so much the pharmacological effect alone that matters, but rather the significance of the change in one's inner state.

4. Bipolar Spectrum and Hidden Vulnerabilities

Not all depressive symptoms are purely unipolar.

In people with:

bipolar spectrum disorder

cyclothymia

pronounced emotional reactivity

antidepressants can:

increase inner restlessness

significantly disrupt sleep

increase emotional instability

In such cases, antidepressants are not generally contraindicated, but require special caution, combinations, or alternative strategies.

5. ADHD and Neurotransmitter Dynamics

In adults with ADHD, serotonergic medications sometimes have paradoxical effects.

Possible effects:

Emotional blunting

Increased irritability

Impaired concentration

Here, the focus is often less on serotonin and more on dopaminergic and noradrenergic systems.

Undiagnosed ADHD is a common cause of "unexplained" medication intolerance.

6. Metabolism, Genetics, and Drug Metabolism

Individual differences in drug metabolism (e.g., via CYP enzymes) affect:

Drug levels

Side effect profile

Tolerability

Some people metabolize medications:

very slowly → side effects even at low doses

very quickly → minimal effect despite correct administration

This explains why standard dosages are not suitable for everyone.

7. Expectations, Anxiety, and Early Side Effects

Another factor is the early phase of treatment.

Antidepressants can initially cause:

restlessness

changes in sleep patterns

vegetative symptoms

before the antidepressant effect takes hold.

Without sufficient information, this can quickly lead to:

uncertainty

fear of "worsening"

premature discontinuation

Not every early side effect means that a medication is unsuitable—but every side effect should be taken seriously.

My Clinical Perspective

If antidepressants are poorly tolerated, it is rarely due to a lack of compliance. It is usually due to a less than optimal match between:

nervous system

life history

internal tension

substance profile

Good psychiatric treatment takes precisely these factors into account—and considers alternatives, combinations, and adjustments.

Key Takeaway

Antidepressant intolerance is not a personal failure. It is an indication that the nervous system needs to be considered in a more nuanced way.

Individualized psychiatry means treating not just the diagnosis – but the person behind it.