3 Clinical psychopharmacology3.4 Therapeutics
3.4.4.2 With prescribed psychotropics
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Written by Resident Doctor Committee · Published
Withdrawal, rebound and recurrence
Withdrawal can follow correctly prescribed treatment. Physical adaptation is not addiction, which involves impaired control and compulsive use despite harm.
Rebound is a rapid, exaggerated return of a symptom the drug had suppressed.
Recurrence is the return of the underlying disorder.
What raises the risk
Elimination half-life sets the risk: drugs cleared quickly, such as paroxetine and venlafaxine, carry the highest risk because plasma levels fall fast after the last dose.
Anticholinergic properties raise the risk through cholinergic rebound after muscarinic receptors adapt, whereas slow elimination and partial agonism protect.
Another centrally acting drug, such as an antipsychotic, taken alongside an antidepressant makes discontinuation symptoms more likely when the antidepressant stops.
A fixed milligram cut is proportionally larger at low doses, so the final steps of a taper should be smaller.
Antidepressant discontinuation syndrome
Symptoms begin within days of stopping a short half-life drug such as paroxetine.
Cluster | Symptoms |
|---|---|
Sensory | Paraesthesia, electric shock-like "brain zaps" |
Vestibular | Dizziness, vertigo, imbalance |
Gastrointestinal | Nausea, diarrhoea, abdominal upset |
Sleep | Insomnia; vivid or disturbing dreams from rebound of REM sleep suppressed during treatment |
Affective | Irritability, anxiety, hyperarousal; suicidal ideation with paroxetine |
General | Flu-like symptoms, sweating, headache |
Mechanism: serotonergic signalling falls temporarily and reversibly while receptors remain adapted to chronic reuptake blockade.
Comparing antidepressants
Drug | Risk | Reason |
|---|---|---|
Paroxetine | Highest among selective serotonin reuptake inhibitors | Short half-life, no active metabolite, non-linear kinetics from CYP2D6 autoinhibition, anticholinergic rebound |
Venlafaxine | High | Cleared quickly; missed doses cause symptoms |
Fluoxetine | Lowest | Long half-life, extended by the active metabolite norfluoxetine |
Agomelatine | No discontinuation syndrome | Unlike most antidepressants |
Tranylcypromine | Dependence | A phenylcyclopropylamine structurally related to amphetamine |
Fluoxetine bridging: when discontinuation symptoms block withdrawal of a shorter-acting antidepressant, switching to fluoxetine helps because it and norfluoxetine clear over weeks, so levels fall gradually by themselves.
Discontinuation or relapse
Feature | Discontinuation | Depressive or anxiety relapse |
|---|---|---|
Paraesthesia, shock sensations, dizziness, vivid dreams | Present | Absent |
Restarting the original drug | Symptoms settle quickly, often within about a day | Improves only over weeks |
In bipolar disorder, abruptly stopping a short half-life antidepressant can mimic a switch to hypomania; nausea, dizziness, paraesthesia, shock sensations, vivid dreams and onset within days point to discontinuation.
Benzodiazepines and other anxiolytics
Course length: UK guidance limits benzodiazepines for anxiety to 2 to 4 weeks, with 4 weeks the maximum for the whole course.
Withdrawal after long-term use is hyperexcitable: perceptual hypersensitivity, insomnia, anxiety, tachycardia, poor appetite and muscle tension.
Seizures are real but uncommon, and follow abrupt or high-dose withdrawal.
Switching to long-acting diazepam smooths the taper; lorazepam converts at about 1:10 of the whole daily dose, so lorazepam 1 mg is about diazepam 10 mg.
Buspirone is a 5-HT1A partial agonist with no action at the GABA-A chloride channel complex, so it has no recognised withdrawal syndrome; it does not prevent benzodiazepine withdrawal.
Antipsychotics
Phenomenon | Features |
|---|---|
Cholinergic rebound | Gastrointestinal upset, sweating, agitation, insomnia, especially after clozapine or olanzapine |
Withdrawal movement disorders | Dyskinesia, akathisia, dystonia |
Supersensitivity psychosis | Rapid psychotic worsening, possibly from dopamine receptor adaptation |
Depot injections keep releasing drug for weeks or months, which delays both withdrawal and relapse.
Lithium, anticonvulsants and stimulants
Lithium stopped rapidly raises the risk of early recurrence, particularly mania; planned withdrawal takes at least 4 weeks, preferably up to 3 months.
Anticonvulsant mood stabilisers are reduced according to indication and seizure risk, not stopped abruptly.
Stimulants, when stopped, can cause fatigue, altered sleep and appetite, and low mood alongside returning symptoms of attention deficit hyperactivity disorder.