Antidepressant Withdrawal and Akathisia: What the Evidence Shows

SSRIs, SNRIs, and other antidepressants are among the most widely prescribed medications in the world. The harms associated with their long-term use and discontinuation are documented in the peer-reviewed literature but remain systematically understated in prescribing guidelines and rarely discussed with patients. This page summarizes what the evidence currently shows on antidepressant withdrawal, SSRI-induced akathisia, and related iatrogenic injury.

How common withdrawal is, and how severe

A 2019 systematic review by Davies and Read, published in Addictive Behaviors, examined the incidence, severity, and duration of antidepressant withdrawal effects and concluded that current clinical guidelines significantly understate the problem. The review found that antidepressant withdrawal is common (56% of patients) and often severe (46% of those affected), and that prevailing guidelines describing withdrawal as mild and brief are not supported by the evidence. UK and US guidelines have historically described discontinuation reactions as self-limiting and typically resolving within one to two weeks. The literature does not support that characterization.

What akathisia is and why it matters

Akathisia is a drug-induced state of profound inner restlessness and psychological torment. It is most often associated with antipsychotics but is also caused by SSRIs, SNRIs, and other medications affecting dopamine signaling. Akathisia is routinely misidentified by clinicians as worsening of the underlying psychiatric condition, which can lead to dose increases that worsen the akathisia.

A 2024 clinical study (Akgoz, Kara et al., Behavioural Pharmacology) investigated the frequency and risk factors for akathisia in patients prescribed SSRIs and SNRIs and characterized the condition as an underestimated extrapyramidal side effect of antidepressants. A 1998 review by Lane (Journal of Psychopharmacology) established that SSRIs can induce akathisia through serotonergically-mediated inhibition of dopamine pathways and described predisposing factors and the clinical consequences of failure to recognize SSRI-induced akathisia.

Akathisia, suicidality, and violence

A 1991 case series by Rothschild and Locke in the Journal of Clinical Psychiatry described three patients who made serious suicide attempts during fluoxetine treatment and developed severe akathisia on retreatment. All three reported that akathisia, not depression, had precipitated their suicide attempts. Symptoms resolved with discontinuation or propranolol. This was an early signal that SSRI-induced akathisia can precipitate suicidality in patients not previously suicidal.

A 2016 BMJ meta-analysis by Sharma and colleagues, based on clinical study reports obtained from the European and UK drug regulators, found that antidepressants approximately doubled the risk of suicidality and aggression in children and adolescents compared to placebo (odds ratios 2.39 and 2.79). The effect in adults did not reach statistical significance in the trial-report data analyzed, though the authors noted that data quality and completeness varied substantially across the reports.

A 2011 forensic study by Lucire and Crotty in Pharmacogenomics and Personalized Medicine examined eight individuals who committed homicide while taking antidepressants, none of whom had prior histories of violence. All had CYP450 polymorphisms that caused dangerously elevated drug levels and severe akathisia. The paper established a pharmacogenetic mechanism by which a standard prescription can drive catastrophic behavior.

A 2003 review by Leong and Silva in the Journal of Forensic Sciences documented that the association between antipsychotic-induced akathisia and violent behavior was not formally recognized until nearly 25 years after antipsychotics were introduced. The underlying mechanism (drug-induced akathisia as a driver of violent behavior) generalizes from antipsychotics to other akathisia-inducing classes including SSRIs.

Protracted withdrawal and the mitochondrial picture

For a meaningful fraction of patients, withdrawal symptoms persist for months or years after stopping the medication. Mechanistic research suggests one reason: SSRIs and benzodiazepines directly impair mitochondrial function. A 2012 paper in Toxicological Sciences demonstrated that sertraline induces mitochondrial permeability transition, ATP depletion, and inhibition of respiratory complexes I and V in isolated rat liver mitochondria. A 2023 study in Antioxidants found that several common antidepressants, including SSRIs, significantly inhibited mitochondrial Complex I and Complex IV in pig brain mitochondria at high concentrations, with escitalopram the strongest inhibitor of Complex I-linked respiration among the drugs tested. These findings are consistent with patient reports of persistent fatigue, cognitive impairment, and nervous system dysregulation that outlast the drug itself.

Informed consent

Severe withdrawal, akathisia, and in some cases iatrogenic suicidality or aggression are documented in the peer-reviewed literature. They are systematically understated in prescribing guidelines and rarely communicated to patients before treatment begins. Informed consent in psychiatric prescribing should include this evidence.

What the Foundation is doing

The Fuller Research Foundation funds research into iatrogenic injury from psychiatric medications and into whether ketogenic dietary intervention and mitochondrial support can aid recovery. The Foundation is a 501(c)(3) nonprofit (EIN 33-3097190).