Which medications are known to provoke sudden anger, irritability, or rage reactions?

Medications Known to Provoke Rage and Irritability

Corticosteroids are the most well-documented medication class that can provoke sudden anger, irritability, and rage reactions, particularly at high doses or with chronic use. 1, 2

Corticosteroids (Prednisone, Methylprednisolone, Dexamethasone)

Corticosteroids lower central and peripheral serotonin levels, which directly contributes to depression, aggression, irritability, violence, and even psychosis. 1, 2 This mechanism explains why patients on chronic high-dose corticosteroids (such as prednisone) can present with severe depression, irritability, violence, and psychotic symptoms. 2

• The mood disturbances and aggressive behavior induced by corticosteroids are dose-dependent, with high-potency steroids carrying greater risk. 2
• These psychiatric side effects can emerge during treatment or persist with chronic use. 1, 2
• Children using systemic corticosteroids may present with symptoms mimicking ADHD, oppositional defiant disorder, or conduct disorder due to serotonin depletion. 1

Management Approach

• Sertraline and other SSRIs have been successfully used to treat steroid-induced mood disorder, irritability, and even psychotic symptoms by upregulating serotonin levels. 2
• The treatment addresses the underlying serotonergic mechanism rather than requiring antipsychotics in many cases. 2

CNS Stimulants (Amphetamines, Lisdexamfetamine)

Misuse and abuse of CNS stimulants can cause anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation. 3

• Overdose or high-dose stimulant use produces sympathomimetic effects including psychomotor agitation, confusion, and hallucinations. 3
• These effects occur through activation of dopaminergic and noradrenergic pathways that can trigger impulsive aggression. 4
• Paradoxically, when used appropriately in therapeutic doses for ADHD, stimulants may actually reduce aggressive behavior in some populations (brain-injured patients, violent adolescents with conduct disorders). 5

Substances of Abuse Associated with Rage

Alcohol, anabolic steroids, cocaine, and amphetamines are strongly associated with aggression through alterations in dopamine, norepinephrine, GABA, and serotonin neurotransmission. 4

• These substances cause impulsive aggression rather than predatory (planned) aggression. 4
• The aggression is typically unplanned and occurs without apparent motive. 4
• Voluntary intoxication with these substances is rarely accepted as a legal defense for violent behavior. 4

Benzodiazepines

Benzodiazepines can induce behavioral disinhibition and paradoxical rage reactions, particularly in patients with underlying aggression or dementia. 5

• While benzodiazepines can reduce agitation in some populations, they may paradoxically increase aggressiveness in others. 5
• Short-acting benzodiazepines carry particular risk for disinhibition. 5
• This paradoxical effect is more common in patients with delirium, mania, or pre-existing impulse control problems. 6

Antipsychotic Medications

Traditional antipsychotic agents have been associated with increased aggressiveness in mentally retarded subjects in at least one study. 5

• The mechanism may involve akathisia (inner restlessness) that manifests as agitation and aggressive behavior. 5
• Atypical antipsychotics (clozapine, risperidone, olanzapine) appear less likely to cause this effect and may actually reduce aggression. 5

Medications with Modest Evidence for Rage Induction

Antihistamines (Diphenhydramine, Hydroxyzine)

• These agents have sedative effects but can cause paradoxical excitation and agitation in some patients, particularly children and elderly individuals. 6

Clonidine

• While used to treat aggression, clonidine showed only marginal benefits and can cause irritability in some patients with autism or conduct disorder. 5

Critical Clinical Pitfalls

Do not overlook medication-induced causes when evaluating new-onset aggression or rage. 1, 2 Specifically:

• Always obtain a complete medication history including over-the-counter products, supplements, and corticosteroid use (topical, inhaled, or systemic). 1
• Consider that patients may be using multiple medications simultaneously without awareness of interactions. 1
• Recognize that treating secondary psychiatric symptoms (depression, ADHD-like symptoms) caused by corticosteroids with SSRIs or stimulants may create additional complications. 1
• Evaluate whether aggressive behavior emerged temporally related to medication initiation or dose escalation. 2

The serotonin-lowering effect of corticosteroids is particularly important because it can create a cascade of psychiatric symptoms that may be misdiagnosed as primary psychiatric disorders rather than medication side effects. 1, 2