SSRIs.
SSRIs present a puzzle worth understanding rather than memorising: the biochemical effect is immediate but the clinical benefit takes weeks, while the side effects arrive on day one. That mismatch explains most of what goes wrong in the first month of treatment.
The mechanism in one sentence
SSRIs block the presynaptic serotonin transporter, leaving more serotonin in the synapse for longer.
Serotonin released into the synapse is normally recovered by a reuptake transporter. SSRIs block that transporter, so serotonin persists and receptor stimulation increases. This happens within hours, which is why nausea, agitation and sexual side effects appear almost immediately. The therapeutic response is thought to depend on slower downstream adaptation, including receptor downregulation and changes in neuroplasticity, which take weeks. Patients therefore experience the costs before the benefit, and that is the single most important thing to warn them about.
Members of the class
| Drug | What sets it apart |
|---|---|
| Sertraline | Commonly first-line; relatively few interactions. |
| Fluoxetine | Very long half-life with an active metabolite, so withdrawal effects are mild and washout is long. |
| Citalopram and escitalopram | Dose-dependent QT prolongation, hence maximum dose limits. |
| Paroxetine | Short half-life and more anticholinergic; prominent discontinuation symptoms. |
| Fluvoxamine | Potent CYP1A2 inhibitor, so interaction-heavy. |
What the class is used for
- Depression
- Generalised anxiety, panic disorder and social anxiety
- Obsessive compulsive disorder, often at higher doses
- Post-traumatic stress disorder and some eating disorders
Side effects, derived from the mechanism
Each entry below follows from the mechanism above rather than being a separate fact. Read the middle column as the answer to the question, why would that happen.
| Effect | Why it follows |
|---|---|
| Nausea and GI upset | Most serotonin in the body is in the gut, so raising synaptic serotonin there disturbs motility. Usually settles within a fortnight. |
| Sexual dysfunction | Increased serotonergic tone inhibits sexual response centrally. Often persistent rather than transient, and a common reason for stopping. |
| Early agitation and increased anxiety | Serotonin rises before the adaptive changes occur, which is why the first two weeks can feel worse and require specific warning. |
| Hyponatraemia | Through inappropriate ADH secretion; the risk is highest in older adults and in the first weeks. |
| Bleeding risk | Platelets take up serotonin and use it in aggregation. Blocking the transporter depletes platelet serotonin, which compounds with NSAIDs and anticoagulants. |
| Discontinuation symptoms | Abrupt cessation of a short half-life agent produces dizziness, electric-shock sensations and flu-like symptoms; fluoxetine largely avoids this. |
Contraindications and cautions
- Concurrent MAOI use, and within the required washout period
- Caution with other serotonergic drugs, including tramadol, triptans and St John’s wort
- Caution in those with bleeding risk or on anticoagulants
The part you cannot derive
Serotonin syndrome requires serotonin to be raised by more than one route. It presents with the triad of altered mental state, autonomic instability and neuromuscular hyperactivity, and clonus is the sign that most reliably distinguishes it from neuroleptic malignant syndrome, which produces rigidity and develops far more slowly.
Exam traps
Side effects precede benefit
A patient who stops at week one because they feel worse has experienced expected pharmacology, not treatment failure.
Fluoxetine’s half-life cuts both ways
It protects against discontinuation symptoms and requires a long washout before starting an MAOI.
Citalopram has a dose cap for a cardiac reason
QT prolongation is dose-dependent, which is why maximum doses are lower in older adults.
Members of this class that get confused
Within a class, the members differ on one property at a time, and that property is what exam questions are usually built on. These pairs split cleanly.
- Sertraline vs Fluoxetine — Fluoxetine has an unusually long half-life with an active metabolite lasting days, so it rarely causes discontinuation symptoms but needs a long washout before an MAOI.
Test yourself on this
Reading a mechanism and being able to retrieve it under time are different skills, and only the second one is examined. These are free and need no account.
- CNS pharmacology practice questions — 10 questions with explanations
- Serotonin syndrome versus NMS
- CYP450 inducers and inhibitors
- Half-life and steady state calculator — free calculator with a worked example
Common questions
Why do SSRIs take weeks to work?
Reuptake blockade happens within hours, but the clinical benefit depends on slower downstream adaptation such as receptor downregulation and neuroplastic change. Side effects follow the fast mechanism, which is why they arrive first.
Why do SSRIs increase bleeding risk?
Platelets have no way of making serotonin and take it up from plasma using the same transporter the drug blocks. Depleted platelet serotonin impairs aggregation, which compounds with NSAIDs or anticoagulants.
What is the difference between serotonin syndrome and NMS?
Serotonin syndrome develops within hours and features clonus and hyperreflexia; neuroleptic malignant syndrome develops over days and features lead-pipe rigidity. The speed of onset and the muscle findings are what separate them.
Other drug classes
Beta blockers · ACE inhibitors · Statins · Anticoagulants · Diuretics · Opioids · All drug classes
Study aid only. This page is written for learning and examination practice. It is not medical advice, not clinical decision support, and must never be used to make a decision about a real patient. Always verify against your local formulary, the product literature and a qualified pharmacist. See our medical disclaimer.
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