Precision Psychopharmacology: Irritability and Rage

Although EEG biomarkers cannot diagnose psychological disorders, they can help inform drug selection. When symptoms have sudden onset or there are two or more treatment failures, an EEG could provide clues about what the initial assessment missed or a mismatch between a patient's brain function and prescribed drugs. Physicians should exercise caution when prescribing drugs known to exacerbate EEG biomarkers associated with their patients' symptoms.

Client F

This case involves a 28-year-old male who presented with progressive irritability and explosive anger episodes that emerged following sequential trials of two antidepressants and subsequently a psychostimulant. Prior to pharmacological intervention, the patient exhibited baseline tension and emotional reactivity, though aggressive behaviors remained infrequent.

Electroencephalographic evaluation revealed significant frontal and central high beta activity with concurrent spindling excessive beta patterns, indicative of elevated cortical excitability and dysregulated arousal mechanisms. The EEG further demonstrated increased frontal theta activity and reduced sensorimotor rhythm, findings consistent with compromised inhibitory gating and increased vulnerability to emotional dysregulation.

Family observations during medication trials noted the patient became energized yet emotionally unstable, displaying rapid escalation from minor frustrations to verbal outbursts and physical agitation.

Comprehensive assessment identified frontal alpha asymmetry and disorganized resting state alpha activity, corresponding with chronic affective instability and impaired modulation of approach motivated anger responses.

As medication dosages increased, these preexisting neurophysiological vulnerabilities showed marked potentiation. The patient reported subjective experiences of feeling excessively activated and primed for aggressive responses. This manifested behaviorally as hostile verbal exchanges with colleagues and two documented episodes of property damage within his home environment. Growing concern about potential loss of behavioral control prompted patient initiated medication discontinuation.

The clinical presentation of intensified rage responses, heightened emotional reactivity, and deteriorating self-regulatory capacity following administration of activating medications aligned closely with the observed EEG profile demonstrating excessive arousal states, reduced frontal inhibitory function, and pronounced vulnerability to paradoxical activation responses.

Six Cortical Hyperarousal Patterns

We will examine six distinct electroencephalographic patterns associated with cortical hyperarousal states and their clinical implications for aggressive behavior, emotional dysregulation, and paradoxical responses to psychotropic medications.

These neurophysiological markers include excess frontal and central high beta activity linked to behavioral disinhibition, spindling excessive beta patterns predicting paradoxical activation, elevated frontal theta activity associated with explosive aggression, frontal alpha asymmetry correlating with anger driven approach behaviors, diminished sensorimotor rhythm indicating weak inhibitory gating, and poorly organized alpha rhythms reflecting emotional instability.

Each pattern represents a specific vulnerability in arousal regulation and inhibitory control systems that can be significantly exacerbated by activating medications such as stimulants and certain antidepressants. Understanding these EEG biomarkers provides critical insight into why certain individuals experience severe irritability, rage episodes, or aggressive outbursts when treated with medications that increase catecholaminergic activity or cortical arousal.

The convergent evidence from ADHD, substance use disorder, and intermittent explosive disorder research demonstrates that these patterns transcend specific diagnostic categories and instead represent transdiagnostic markers of arousal dysregulation that directly inform medication selection and predict treatment related adverse effects.

Excess Frontal and Central High Beta Activity Associated with Antisocial and Aggressive Behavior

Research examining the neurophysiological correlates of aggressive behavior has identified excessive beta power as a significant biomarker. Adults presenting with ADHD symptoms who engaged in delinquent behavior demonstrated significantly elevated beta power across frontal, central, and parietal regions compared to their nondelinquent ADHD counterparts. Researchers have concluded that excessive beta power represents a risk factor for delinquent behavior in adults with ADHD symptomatology, particularly in a hyperaroused, behaviorally disinhibited subgroup (Meier et al., 2015).

This pattern of elevated beta power extends beyond ADHD populations and serves as a marker of disinhibitory, externalizing risk, as evidenced by findings that alcohol dependent adults exhibit increased resting beta power compared with controls, consistent with hyperexcitability and behavioral disinhibition characteristic of externalizing disorders (Rangaswamy et al., 2002).

These converging findings support the understanding that prominent high beta activity at rest identifies a hyperaroused, disinhibited phenotype where administration of activating medications such as stimulants or activating antidepressants may further potentiate irritability or aggressive acting out behaviors (Meier et al., 2015; Rangaswamy et al., 2002).

Spindling Excessive Beta and Paradoxical Activation Responses

The phenomenon of spindling excessive beta, characterized by frontocentral spindle like high frequency beta activity, has emerged as a distinct EEG phenotype associated with insomnia and impulsivity/hyperactivity, suggesting an arousal system abnormality that transcends specific diagnostic categories (Arns et al., 2015). The spindling excessive beta graphic below is courtesy of Dr. Ronald Swatzyna.

Subsequent replication research confirmed that individuals exhibiting spindling excessive beta demonstrated increased impulse control problems and elevated false positive responses on behavioral inhibition tasks, establishing this pattern as a transdiagnostic marker of impulse control difficulties (Krepel et al., 2021).

A comprehensive deep learning study further elucidated that spindling excessive beta probability and frontocentral beta power were associated with poor sleep maintenance and reduced daytime impulse control, while also serving as treatment prediction markers, with these patterns predicting remission to methylphenidate in ADHD and remission to antidepressant medication in depression in a drug specific manner (Meijs et al., 2025).

These findings establish spindling excessive beta as both a biomarker of hyperarousal and poor inhibitory control and a treatment prediction marker for stimulants and antidepressants (Arns et al., 2015; Krepel et al., 2021; Meijs et al., 2025).

In clients presenting with strong spindling excessive beta patterns, aggressive paradoxical activation responses to stimulants or activating antidepressants would align with expected neurophysiological vulnerabilities.

Related research in stimulant prediction has demonstrated that quantitative EEG and event related potential measures predicted both clinical gains and acute side effects of stimulants in pediatric ADHD with high accuracy, with side effect risk specifically linked to EEG spectral patterns including fast oscillatory activity (Ogrim & Kropotov, 2019).

Additionally, both slow and fast EEG oscillations, including beta frequencies, have shown predictive value for methylphenidate response in ADHD populations (Sari Gokten et al., 2019).

Elevated Frontal Theta Activity and Under Controlled Impulsivity with Explosive Aggression

Comprehensive reviews of electroencephalographic findings in ADHD consistently identify elevated frontal and central theta activity and increased theta/beta ratios as robust neurophysiological markers linked to inattention and executive dysfunction (Loo & Makeig, 2012).

In neurotypical adults, elevated frontal theta/beta ratios correlate with reduced trait attentional control and greater deterioration of attention under stress conditions, indicating compromised top down control mechanisms (Putman et al., 2014). Clinical investigations in ADHD populations similarly demonstrate that theta/beta elevations at midline sites correspond with executive dysfunction severity and overall ADHD symptom burden (summarized in Loo & Makeig, 2012).

The relationship between these EEG patterns and aggressive behavior becomes particularly evident in intermittent explosive disorder, where EEG abnormalities including low frequency alterations over frontal sites have been documented in individuals experiencing uncontrollable, impulsive aggressive attacks (Koelsch et al., 2008).

Synthesizing findings across ADHD and intermittent explosive disorder research reveals that elevated frontal theta and high theta/beta ratios identify neural systems already compromised in attentional and inhibitory control capacities (Loo & Makeig, 2012; Putman et al., 2014; Koelsch et al., 2008).

When stimulants or activating antidepressants are introduced to such systems, they may increase behavioral drive without adequately enhancing control mechanisms, precipitating rage episodes or explosive outbursts.

Frontal Alpha Asymmetry and Anger Related Aggressive Approach Behaviors

Frontal alpha asymmetry, typically calculated as right minus left alpha power with higher values indicating greater relative left frontal activation due to the inverse relationship between alpha power and cortical activity, has emerged as a critical marker of anger related neural processes.

Research by Zinner and colleagues (2008) demonstrated that state anger can be associated with either left or right frontal activation depending on contextual factors, while confirming that asymmetrical frontal cortical activity remains closely tied to anger experience and its regulation, with distinct patterns predicting anger expression versus withdrawal responses.

Earlier foundational work from Harmon Jones and colleagues established that relative left frontal activation, manifested as reduced left alpha power, correlates with state anger and behavioral aggression, particularly when anger involves approach motivated states (Harmon Jones et al., 2003).

These investigations support understanding pronounced frontal alpha asymmetry, especially patterns reflecting anger related frontal activation, as marking individuals whose approach drive in anger contexts can be particularly strong.

When pharmacological agents increase approach system activation, as occurs with certain antidepressants and stimulants, this can further facilitate anger expression and aggressive behaviors in individuals exhibiting such asymmetry patterns (Zinner et al., 2008; Harmon Jones et al., 2003).

Low Sensorimotor Rhythm and Weak Inhibitory Gating with High Reactivity

Experimental evidence regarding the sensorimotor rhythm provides clear documentation that this rhythm indexes inhibitory gating within thalamocortical motor sensory circuits.

Sterman and Bowersox characterized the sensorimotor rhythm as a functional gate mechanism representing a thalamic inhibitory gate that reduces excitability in afferent and efferent sensorimotor pathways when the rhythm is present, based on converging animal and human data (Sterman & Bowersox, 1981).

Lubar and Bahler trained epileptic patients to increase 12 to 14 Hz sensorimotor rhythm over the Rolandic area, hypothesizing this rhythm related to motor inhibitory processes, and demonstrated that sensorimotor rhythm biofeedback training was associated with meaningful reductions in seizure frequency (Lubar & Bahler, 1976).

If adequate sensorimotor rhythm reflects effective inhibitory gating and motor calm, then low or poorly developed sensorimotor rhythm suggests weak gating mechanisms and heightened excitability.

In neural systems with compromised sensorimotor rhythm, medications that boost catecholamines or otherwise increase cortical activation may more readily produce over-reactivity, agitation, or aggressive outbursts (Sterman & Bowersox, 1981; Lubar & Bahler, 1976).

Poorly Organized Alpha Rhythms and Emotional Instability with Inhibitory Control Problems

The alpha rhythm is associated with emotional regulation. Pavlenko and colleagues (2009) showed that alpha rhythm features in healthy adults correlate with emotional stability versus anxiety, with more robust alpha organization associated with greater emotional stability and altered alpha patterns associated with heightened anxiety states.

Knyazev's comprehensive integrative review concluded that motivation, emotion, and inhibitory control are tightly mirrored in brain oscillatory patterns, with alpha oscillations including their synchrony and organizational features playing key roles in inhibitory processes and regulation, while disturbances in these oscillatory patterns including alpha abnormalities are linked to increased anxiety, impulsivity, and dysregulated emotional responding (Knyazev, 2007).

Therefore, poor alpha organization or unstable alpha patterns indicate both state and trait emotional instability along with impaired inhibitory control mechanisms (Pavlenko et al., 2009; Knyazev, 2007).

In clients presenting with such neurophysiological backgrounds, medications that acutely shift arousal and monoaminergic tone can magnify emotional lability, sometimes manifesting as severe rage or marked irritability rather than the intended mood improvements.

The Psychopharmacology of Paradoxical Rage and Hyperarousal

Understanding the Neurobiological Rationale for Treatment Selection

Client F's paradoxical escalation of rage and aggressive outbursts on both antidepressants and psychostimulants provides a clear pharmacologic signal that catecholaminergic activation and early SSRI activation may be aggravating an already hyperadrenergic, poorly gated arousal system. In such neurophysiological profiles, therapeutic agents that dampen central noradrenergic drive or enhance cortical inhibitory tone typically prove more effective as initial interventions than medications that further raise synaptic serotonin, dopamine, or norepinephrine concentrations.

Alpha-2A Adrenergic Agonists as First-Line Interventions

The most practical first step typically involves an α2A-adrenergic agonist, with guanfacine extended-release representing the primary choice because it reduces presynaptic norepinephrine release and, crucially, strengthens prefrontal cortical network firing by inhibiting cAMP-HCN channel signaling at postsynaptic α2A receptors. This mechanism translates across species and links directly to improvements in top-down control under stress conditions (Arnsten, 2020; Wang et al., 2007).

In child and adolescent populations with externalizing symptoms where hyperarousal and oppositionality are prominent features, randomized trials demonstrate that guanfacine XR reduces hyperactivity/impulsivity while also lowering oppositional behaviors and irritability, effects that often correspond with reductions in aggressive episodes.

Clonidine, acting through the same receptor family, represents a reasonable alternative when sedation and autonomic dampening are desired therapeutic effects (Scahill et al., 2015; Politte et al., 2018).

In Client F's medication history, where stimulants worsened affective lability and anger, shifting from catecholamine-enhancing agents to an α2A agonist is both mechanistically coherent and empirically defensible (Arnsten, 2020; Scahill et al., 2015).

Beta-Adrenergic Blockade for Adrenergic Surge Phenomena

When rage episodes retain a strong adrenergic or surge phenotype characterized by tachycardia, diaphoresis, and tremulousness, adding a centrally acting β-adrenergic antagonist can further blunt the peripheral-central feedback loop that sustains explosive outbursts.

Propranolol, which readily crosses the blood-brain barrier, has repeatedly demonstrated reductions in violent and assaultive behavior in controlled trials among neurologically injured and chronically aggressive patients. Systematic reviews in acquired brain injury support β-blockade for agitation and aggression while calling for more high-quality trials, and a recent randomized, double-blind pilot combining propranolol with clonidine showed safety and improvement in sympathetic hyperactivity features, reinforcing the rationale for adrenergic dampening when arousal drives the behavior (Greendyke et al., 1986; Fleminger et al., 2006; Nordness et al., 2023).

Small modern crossover data in autism spectrum disorder also report clinically meaningful reductions in severe, chronic aggression at higher propranolol doses, albeit with the usual caveats about sample size and monitoring requirements (London et al., 2024).

Mood-Stabilizing Anticonvulsants for Impulsive Aggression

For patients whose aggression is predominantly impulsive, characterized by sudden, affect-laden, poorly premeditated acts, mood-stabilizing anticonvulsants are supported by randomized evidence.

Divalproex/valproate has reduced impulsive aggression in cluster B personality pathology and in intermittent explosive disorder through its multimodal actions including enhanced GABAergic signaling, dampening of high-frequency neuronal firing via sodium-channel effects, and epigenetic modulation at therapeutic concentrations. These mechanisms can stabilize cortical excitability without the activating liability of stimulants or the akathisia risk of some serotonergic antidepressants (Hollander et al., 2003; Hollander et al., 2005; Romoli et al., 2019).

Oxcarbazepine represents another option with a double-blind, placebo-controlled trial showing benefit in adults with clinically significant impulsive aggression. As a sodium-channel-modulating agent, it can reduce paroxysmal reactivity with a side-effect profile distinct from valproate (Mattes, 2005).

Reserved Use of Atypical Antipsychotics

When aggression is severe, persistent, or accompanied by broader irritability and affective dyscontrol, short-term use of an atypical antipsychotic, most often low-dose risperidone, can be justified by randomized evidence demonstrating robust reductions in aggression and related disruptive behaviors. However, this choice carries well-known metabolic and extrapyramidal liabilities and is best reserved for refractory cases or as a time-limited bridge while anti-adrenergic or mood-stabilizing strategies take effect (McCracken et al., 2002).

Medications to Avoid or Approach with Caution

In alignment with avoiding what worsened Client F's presentation, it is reasonable to defer or minimize further trials of SSRIs/SNRIs and amphetamine-class stimulants at the outset, because early SSRI activation can include irritability, agitation, and aggression in a subset of patients.

Meta-analytic evidence suggests that irritability risk is disproportionately associated with amphetamine-derived stimulants compared with methylphenidate, even though stimulants often reduce aggression in other contexts (Sharma et al., 2016; Stuckelman et al., 2017).

Benzodiazepines also deserve particular caution as paradoxical disinhibition and worsened agitation are documented, particularly in brain-injured or highly aroused patients, making them a poor fit for the Client F pattern except in carefully titrated, short-term, clearly indicated scenarios (Curtin et al., 2020).

Recommended Pharmacologic Sequencing Strategy

Taken together, a pharmacologic sequence for a Client F-like presentation would begin with α2A-agonist monotherapy such as guanfacine XR to improve prefrontal control and autonomic stability. If adrenergic storm features dominate, clinicians should add or swap to propranolol for additional autonomic dampening. When impulsive aggression persists despite these interventions, layering in a mood-stabilizing anticonvulsant such as divalproex or oxcarbazepine becomes appropriate.

Brief, low-dose risperidone should be reserved for severe or refractory aggression, always with careful medical monitoring and dose titration to minimize adverse effects (Arnsten, 2020; Greendyke et al., 1986; Hollander et al., 2003; McCracken et al., 2002; Nordness et al., 2023; Politte et al., 2018; Scahill et al., 2015).

Key Takeaways

1. Client F’s EEG hyperarousal profile (frontal high‑beta/SEB, low SMR, elevated frontal theta) signals risk for paradoxical agitation and aggression on stimulants and activating antidepressants.

   
   

2. First‑line psychopharmacology should reduce noradrenergic drive and strengthen prefrontal control—prefer alpha‑2A agonists (guanfacine ER; clonidine as an alternative) via cAMP–HCN inhibition.

   
   

3. When outbursts have an adrenergic‑surge signature, a lipophilic beta‑blocker (propranolol) can blunt central and peripheral sympathetic amplification.

   
   

4. For persistent impulsive aggression, use mood‑stabilizing anticonvulsants (divalproex/valproate or oxcarbazepine), with lithium reserved for severe trait‑level aggression.

   
   

5. Pair medication with neurofeedback that uptrains SMR (12–15 Hz), downtrains excess high‑beta, and organizes resting alpha to strengthen inhibitory gating and reduce hyperarousal.

Glossary

akathisia: subjective inner restlessness with an urge to move, often accompanied by motor agitation; typically an extrapyramidal adverse effect.

alpha: oscillatory EEG activity around 8–12 Hz linked to relaxed wakefulness, sensory gating, and cortical organization.

alpha asymmetry: see frontal alpha asymmetry.

alpha‑2A (α2A) adrenergic agonist: drug that stimulates postsynaptic α2A receptors in prefrontal cortex and presynaptic autoreceptors, reducing norepinephrine release and cAMP‑HCN signaling to strengthen top‑down control while dampening arousal (e.g., guanfacine).

atypical antipsychotic: second‑generation antipsychotic (e.g., risperidone) with serotonin‑dopamine antagonism that can reduce irritability/aggression but carries metabolic and extrapyramidal risks.

benzodiazepine: GABA-A​ positive allosteric modulator producing anxiolysis and sedation; in a subset, may cause paradoxical disinhibition.

beta: oscillatory EEG activity roughly 13–30 Hz associated with cortical activation and arousal.

beta spindling (spindling excessive beta, SEB): rhythmic, spindle‑like bursts of high‑frequency beta over frontocentral regions, often interpreted as a hyperarousal/impulse‑control vulnerability marker.

beta‑adrenergic antagonist (β‑blocker): drug that blocks β‑adrenergic receptors to blunt sympathetic effects; lipophilic agents (e.g., propranolol) cross the blood–brain barrier and may reduce aggression driven by adrenergic surge.

blood–brain barrier (BBB): specialized endothelial interface that regulates passage of substances from blood into the central nervous system.

cAMP (cyclic adenosine monophosphate): intracellular second messenger; in prefrontal pyramidal neurons, higher cAMP facilitates opening of HCN and related channels, weakening persistent firing and executive control.

catecholamine: class of neurotransmitters that includes dopamine, norepinephrine, and epinephrine, central to arousal and stress responses.

clonidine: centrally acting α2‑adrenergic agonist (less α2A‑selective than guanfacine) that reduces noradrenergic tone; often more sedating.

dopaminergic: pertaining to dopamine signaling (release, receptors, or downstream effects).

EEG biomarker: quantifiable EEG feature (e.g., band power, ratio, or pattern) associated with traits, symptoms, or treatment response.

epigenetic modulation: drug‑induced changes to gene expression without altering DNA sequence (e.g., valproate’s histone deacetylase inhibition).

excitatory/inhibitory (E/I) balance: relative strength of glutamatergic excitation versus GABAergic inhibition within neural circuits.

extrapyramidal symptoms (EPS): drug‑induced movement disorders such as dystonia, parkinsonism, akathisia, and tardive dyskinesia.

frontal alpha asymmetry: difference in alpha power between left and right frontal sites (alpha inversely indexes activity), linked to approach/withdrawal tendencies, anger, and mood regulation.

frontal theta: increased theta‑band power over frontal regions, often associated with reduced executive control and inhibitory capacity.

frontostriatal circuits: loops connecting prefrontal cortex with striatum and thalamus that support action selection, motivation, and impulse control.

GABA (gamma‑aminobutyric acid): principal inhibitory neurotransmitter in the mammalian brain.

GABAergic signaling: inhibition mediated by GABA receptors (GABAA_AA​, GABAB_BB​); increased tone tends to reduce cortical excitability.

guanfacine (extended‑release): once‑daily α2A‑adrenergic agonist that reduces noradrenergic drive and strengthens prefrontal network functioning; used for hyperarousal/impulsivity.

HCN channel (hyperpolarization‑activated cyclic nucleotide‑gated channel): cation channel opened by hyperpolarization and facilitated by cAMP; when active in prefrontal dendritic spines, it destabilizes persistent firing and working memory.

high beta: faster beta activity (~22–30 Hz) often linked to hyperarousal and cortical hyperexcitability.

hyperarousal: state of heightened sympathetic and cortical activation with increased reactivity and vigilance.

inhibitory gating: neural mechanisms that reduce sensory/motor excitability to maintain stability; robust sensorimotor rhythm (SMR) reflects stronger gating.

lipophilic: fat‑soluble; more likely to cross lipid membranes such as the BBB.

lithium: classic mood stabilizer that reduces impulsive aggression through multiple mechanisms (e.g., second‑messenger modulation), requiring serum monitoring.

mood stabilizer (anticonvulsant): antiseizure agent used to reduce affective/behavioral volatility by decreasing neuronal hyperexcitability (e.g., valproate, oxcarbazepine).

noradrenergic: pertaining to norepinephrine signaling.

noradrenergic drive: overall tone/level of norepinephrine activity influencing arousal and stress responsiveness.

oxcarbazepine: sodium‑channel–modulating anticonvulsant that can dampen paroxysmal reactivity and impulsive aggression.

paradoxical disinhibition: unexpected increase in agitation, impulsivity, or aggression following a sedative or anxiolytic (e.g., benzodiazepine).

paroxysmal reactivity: sudden, episodic surges of dysregulated physiological or behavioral activation.

prefrontal cortex (PFC): frontal lobe region supporting working memory, planning, and top‑down regulation of emotion and behavior.

propranolol: nonselective, lipophilic β‑blocker that crosses the BBB; used off‑label to reduce adrenergically driven aggression and autonomic surges.

risperidone: atypical antipsychotic with D2/5‑HT2A antagonism; effective for severe irritability/aggression but associated with metabolic and EPS risks.

sensorimotor rhythm (SMR): ~12–15 Hz rhythm over sensorimotor cortex associated with motor inhibition and thalamocortical gating.

serotonergic: pertaining to serotonin signaling.

sodium‑channel modulation: reduction of high‑frequency neuronal firing by inhibiting voltage‑gated sodium channels (mechanism for several anticonvulsants).

SSRI activation: early treatment phenomenon with selective serotonin reuptake inhibitors characterized by jitteriness/insomnia, increased energy, and in some cases irritability or aggression.

sympathetic hyperactivity: excessive activation of the sympathetic nervous system (e.g., tachycardia, diaphoresis, tremor) that can amplify aggressive outbursts.

theta: oscillatory EEG activity ~4–7 Hz linked to attention, executive control, and state regulation.

theta/beta ratio: index of slow‑to‑fast EEG power; frontal elevations are associated with diminished attentional/inhibitory control.

top‑down control: regulation of subcortical and sensory processes by prefrontal executive systems to guide goal‑directed behavior.

valproate (divalproex sodium): mood‑stabilizing anticonvulsant that increases GABAergic tone, modulates sodium channels, and exerts epigenetic effects; used to reduce impulsive aggression.

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About the Author

Fred Shaffer earned his PhD in Psychology from Oklahoma State University. He earned BCIA certifications in Biofeedback and HRV Biofeedback. Fred is an Allen Fellow and Professor of Psychology at Truman State University, where has has taught for 50 years. He is a Biological Psychologist who consults and lectures in heart rate variability biofeedback, Physiological Psychology, and Psychopharmacology. Fred helped to edit Evidence-Based Practice in Biofeedback and Neurofeedback (3rd and 4th eds.) and helped to maintain BCIA's certification programs.

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