Norepinephrine, Anxiety and Aggression

Introduction

Many of us have experienced the fight-or-flight response to stressful situations such as exams, important business meetings or public speeches. Many stage performers are plagued by “stage fright”, aka performance anxiety, manifesting itself as rapid heartbeat, sweating, butterflies in the stomach, urge to urinate, shaky hands and legs, nausea and dry mouth. This is the main action of the sympathetic nervous system (SNS) whose neurons release norepinephrine (noradrenaline) in response to fear, which further triggers the release of epinephrine (adrenaline) from the adrenal medulla, which in turn triggers changes in different parts of the body such as increased heart rate, vasoconstriction, sweating, bladder contraction, etc. The purpose of this sympathetic response is to prime our body for fighting or fleeing, which helped our ancestors to survive. However, in modern times, this response often reduces our social functioning: the fight response leads to angry confrontations, and the flight response leads to social withdrawal, both of which are typical in autism. The heart-pressure medication Propranolol reduces the adrenalin action and has been used off-label to reduce performance anxiety and aggressive behaviors. The first report of the Propranolol use in the treatment of aggression appeared in 1977. Since then, dozens of papers have reported the use of beta-blockers in the treatment of aggression in patients who failed to respond to antipsychotics, tranquilizers, lithium, or anticonvulsants. Besides reducing aggression, Propranolol has been shown to improve social functioning, verbal fluency and working memory in autistic patients. It has been also used off-label to treat hypersexuality due to its testosterone reduction properties.

Mechanism of NE action

Norepinephrine (NE) is the primary neurotransmitter of the sympathetic nervous system. It is formed from the amino acid L-tyrosine, which is first converted to L-dopa through tyrosine hydroxylase and then to dopamine by dopa-decarboxylase and then to NE through β-hydroxylation inside storage vesicles of adrenergic neurons. NE is released by these neurons in response to fear. It then activates postsynaptic β-adrenergic receptors, which are coupled to the stimulatory G proteins, Gs. Upon their activation, Gs-proteins stimulate adenylyl cyclase to form cAMP from ATP. Increased cAMP activates a cAMP-dependent protein kinase (PKA) that phosphorylates L-type calcium channels, which causes increased calcium entry into the cell (excitation). Depending on the cell location in the body, the above cascade leads to different attributes of the fight-or-flight response.

There are also pre- and postsynaptic α2 adrenergic receptors. Activation of postsynaptic α2 adrenergic receptors decreases adenylyl cyclase activity through the inhibitory G protein, Gi, which is the opposite action to β-adrenergic receptors. Activation of presynaptic α2 adrenergic receptors reduces the release of NE from the presynaptic neuron. Because β- and α2-adrenoreceptors have the opposite effect on the NE activity, their combined net effect depends on their relative ratio in a specific tissue.

NE and aggression

Limbic regions of the brain, such as the frontal neocortex and hypothalamus, are known to contain significant levels of adrenergic receptors and to modulate behavior. High levels of NE have been associated with aggression [R, RR].  Substances that enhance central NE function, such as tricyclic antidepressants, MOA inhibitors and presynaptic α2 antagonists, have been shown to increase fighting in rodents [R, R]. Total β-adrenoreceptor concentration in the cerebellum cortex of aggressive Alzheimer’s disease (AD) patients has been found to be 25% higher than that of age-matched nonaggressive AD patients and healthy controls [R], suggesting a possible link between aggression and β-adrenoreceptors. Among these receptors, blocking β2 but not β1 receptors reduced aggression in mice, triggered by tricyclic antidepressant Desipramine [R].

Along with social dysfunction and restricted behaviors, autism is often accompanied by impulsivity, anxiety, and aggression that resemble states of sympathetic autonomic arousal, suggesting a possible involvement of NE. Autistic children demonstrate rapid heart rate and elevated sweating compared with children without ASD [R, R] – markers that are associated with aggression [R].

Hypoglycemia triggers the release of another fight-or-flight hormone, epinephrine (adrenalin), from the adrenal glands, which signals the liver and kidneys to produce more glucose. It is also associated with adverse behaviors such as aggression, social withdrawal and depression [R, R, R]. These behaviors have been shown to be dependent on β2-receptor-mediated pathway [R]. Blocking β2 receptors blocks sympathetic manifestations of hypoglycemia.

Treatments

  • Propranolol is a nonselective beta (both β1 and β2) blocker. Originally approved as a high-blood-pressure medication, it has been successfully used off-label to treat “stage fright” in stage performers and violent behaviors in psychiatric and autistic patients [R, R, R, R]. Small studies showed that Propranolol also improves verbal fluency, conversational reciprocity and working memory in autistic patients [R, R, R]. These effects may be due to reduced hyperarousal. As patients become less anxious and defensive, more social and adaptive behaviors appear. There is an ongoing clinical trial of Propranolol on social interaction, language tasks, anxiety, and adaptive behaviors in autistic children and young adults [R]. Some rare side effects include abnormally low heart rate (bradycardia), fatigue, reduced exercise capacity, and sexual dysfunction. The last side effect is due to the Propranolol’s ability to significantly reduce free and total testosterone [R], which is why this drug is often used off label to treat hypersexuality [R].

Summary of clinical trials [R]: From the eight single-dose clinical trials, Propranolol led to significant improvements in cognitive performance – verbal problem solving, social skills, mouth fixation, and conversation reciprocity; and changes in neural correlates – improvement in semantic networks and functional connectivity. The remaining eight case series and single case reports showed improvements in EBAD, anxiety, aggressive, self-injurious and hypersexual behaviors. Additionally, Propranolol significantly improved similar behavioral domains (aggression and self-injury) for those with acquired brain injury.

Case report 1 [R]: A 20-year-old man diagnosed as having moderate intellectual disability and generalized epilepsy … with severe aggression, both verbal and physical, occurring with little or no provocation over the past 3 years. These episodes would last up to several hours and often led to food refusal… After the onset of his aggression, it was difficult to engage him in any activities, including basic self-care… He was seizure-free for the past 4 years on Carbamazepine 1,000 mg/d and Diazepam 10 mg/d, and he had never exhibited postictal aggression in the past. He had already received trials of Olanzapine (up to 15 mg/d for 6 weeks) and Chlorpromazine (up to 400 mg/d for 3 months) without significant improvement… He was given a trial of Propranolol, starting at 20 mg/d and increased by 20 mg every week. At 40 mg/d, there was a significant reduction in his aggression, and his food intake was better. On further increasing the dose to 60 mg/d, his mother reported that he was essentially “normal,” with no significant episodes of aggression. Over the next year, Olanzapine and Chlorpromazine were tapered and stopped, and he remained stable. He has been well on Carbamazepine 1,000 mg/d, Propranolol 60 mg/d, and Diazepam 10 mg/d for the past 3 months with no recurrence of either seizures or aggression, and it is now possible to engage him in household tasks and speech therapy.

Case report 2 [R]: A 25-year old man with ASD was admitted to the hospital due to “getting angry at home” for over a month… Discussions between the patient and his mother became increasingly heated, and the patient began to exhibit behavior that ranged from verbal insults to destruction of doors and windows in their shared home. His previously fluent speech began to include stuttering and echolalia, which were mild prior to his exacerbation. His past medications included Clomipramine, Risperidone, and Pemoline (a dopaminergic stimulant), but he had been stable off of medication prior to this exacerbation. When initially evaluated, the patient … displayed impulsive and inappropriate behaviors that included shouting jokes into the telephone handset, pacing the hallways, knocking on other patients’ doors, and initiating loud conversations with inappropriate laughter. When playing board games, he would exhibit aggressive outbursts and sweep the game pieces off the board when he lost. Throughout his hospital stay, he stuttered during single sentences and experienced episodes of noticeable echolalia. A basic metabolic panel, lipid panel, and electrocardiogram obtained on admission were normal. Monotherapy with the beta blocker Propranolol 20 mg twice daily was started for behavioral and verbal control and its known benefit in the treatment of neuroleptic-induced akathisia, which was a possible contributor to the patient’s agitation from prior antipsychotic use. Two days later, he impulsivity subsided, and he participated in group activities on the unit without disruption. Four days into treatment, he developed friendships on the unit, held quiet conversations, and engaged in board games without anger. He tolerated emotional conversations…, and the frequency of stuttering and echolalia decreased. He denied any side effects… With the behavioral improvement on Propranolol and stable vital signs, the patient was safely discharged without additional medications.

Case report 3 [R]: A 13-year-old boy with a history of autism was presented to the outpatient psychiatric clinic for hypersexual behaviors that started at the onset of puberty. The behaviors affected his functioning both at school and home. A trial of low-dose Propranolol, 0.3 mg/kg/d (10 mg twice a day), targeting hypersexual behavior led to remarkable clinical improvement. The behaviors remained stable on this dose of Propranolol for 1 year.

  • Guanfacine, a selective α2A receptor agonist, and Clonidine, a nonselective α2 receptor agonist, have been used off-label to treat oppositional and aggressive behaviors mainly in children with ADHD [RRR, R]. Both Guanfacine and Clonidine suppress the NE release from sympathetic nerve endings in different organs including prefrontal cortex, which helps to eliminate irrelevant attention and behavioral reaction to stressors and improve task-specific focus [R], which is why they have been approved and used as nonstimulant ADHD drugs. Both drugs have a pronounced sedative effect (Clonidine is even used off-label as a sleep-aid medication) as opposed to Propranolol, which maintains clarity of thoughts. At high doses, Clonidine can actually cause aggression due to its blockade of adenosine receptors [R]. Guanfacine and Clonidne must not be combined with Propranolol because all three reduce blood pressure.
  • Calcium channel blockers such as Verapamil, Nifedipine and Diltiazem, inhibit NE release from the sympathetic nerve endings [RR, R]. Activating L-type calcium channels has been shown to trigger self-injurious biting in mice, which was inhibited by pretreating the mice with dihydropyridine L-type calcium channel antagonists such as Nifedipine, Nimodipine, or Nitrendipine [R]. Verapamil diminished aggressive behavior in male Siamese fighting fish [R]. There have been no published reports on use of calcium channel blockers to control aggression in humans. The number of articles on the use of calcium channel blockers in the treatment of anxiety disorders is low. Three reports (two open, one double-blind) described some success in the treatment of panic disorder with Verapamil, Diltiazem, or Nimodipine and one open-label study described unsuccessful treatment of anxiety and phobia with Nifedipine in patients with various anxiety disorders [R].
  • Among supplements, lithium decreases NE availability and increases tryptophan uptake. Tryptophan reduces tyrosine absorption and also increases serotonin. It should not be combined with SSRI’s. Taurine and L-theanine reduce NE release [R, RR, R]. Magnesium inhibits NE release by blocking N-type calcium channels [R]. St John’s wort inhibits dopamine β-hydroxylase (DBH) [RR, R], which converts dopamine into NE. Blocking DBH reduces NE but also increases dopamine, which can worsen or cause mania [R]. St. John’s wort should not be combined with SSRI’s because of its MAO inhibition. Avoid things that increase NE such as B6, folate, caffeine, tyrosine, phenylalanine, L-dopa, acetyl-L-carnitine, phosphatidylserine, Atomoxetine (Strattera), Bupropion (Wellbutrin), Amphetamine, Modafinil, tricyclic antidepressants, Yohimbine, Ginkgo Biloba [R], Curcumin, Ginseng, etc.

Summary

Norepinephrine is the key neurotransmitter responsible for acute anxiety and anger related to the fight-or-flight response. Poor feedback control of NE action is the cause of “bad temper”. Activation of beta (and more specifically β2) adrenergic receptors by NE is responsible for aggression. It can be successfully treated by the non-selective beta-blocker Propranolol, which is a blood pressure medication often used off-label by stage performers for performance anxiety. Guanfacine can also reduce impulsivity by reducing the NE release from presynaptic fibers. Adding lithium orotate (5-10mg), magnesium, taurine (500mg before bed) and tryptophan (500mg before bed) can further reduce anxiety and aggression and improve sleep.

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