Anxiogenic

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An anxiogenic or panicogenic substance is one that causes anxiety. This effect is in contrast to anxiolytic agents, which inhibits anxiety. Together these categories of psychoactive compounds may be referred to as anxiotropic compounds.

Contents

Experimental Studies

Anxiogenic effects can be measured by, for example, the hole-board test in rats and mice. [1] A number of agents are used to provoke anxiety (anxiogens) or panic (panicogens) in experimental models.

Mechanisms of Action

Anxiogenic substances typically work through affecting levels of neurotransmitters such as dopamine, epinephrine, gamma-aminobutyric acid (GABA), norepinephrine (NE), and serotonin in the central nervous system (CNS). Some substances may alter functioning in the HPA axis, the neuroendocrine system that mediates responses to stress, where dysfunction has been linked to anxiety and panic disorders. [2]

Some substances, such as caffeine [3] and sodium lactate, [4] are largely reported to have anxiogenic effects only if they are consumed or taken by people with pre-existing anxiety or panic disorders.

Anxiogenic Substances

Psychoactive Substances

A psychoactive substance is one that alters the functioning of the nervous system to produce changes in cognition and behaviour and include commonly consumed substances such as caffeine and nicotine. Though not typically the desired response, several of these compounds may have anxiogenic side effects.

Caffeine

Caffeine, found in tea and coffee, acts as an adenosine receptor antagonist. Adenosine receptors are involved in mood regulation among other functions, with its antagonists linked to general anxiogenic effects, and specific receptors, such as the A2A receptor disorders. [5]

However, research suggests that for caffeine to have notable anxiogenic effects when consumed, a person needs to have a pre-existing anxiety or panic disorder, and to consume a large amount of caffeine (5 cups or more). [3]

Nicotine

Nicotine, found in tobacco products, binds to nicotinic acetylcholine receptors (nACHRs), that may affect the function of pathways implicated with stress brains and anxiety, such as the serotonergic or GABAergic pathways. [6]

Though nicotine is typically associated with a reduction in levels of anxiety, animal studies have found that at higher dosages, nicotine may have anxiogenic effects compared to its typical anxiolytic effects at lower dosages. [7]

Adrenergic Agents

Adrenergic agents affect the levels of norepinephrine and epinephrine in the nervous system. NE is a neurotransmitter associated with the regulation of various cognitive functions including stress responses, arousal, vigilance, and anxiety.

Yohimbine is an adrenergic agent that increases the levels of NE through inhibiting the absorption of NE by blocking the receptors on noradrenergic neurons. Research suggests that it can lead to a mildly anxious state or worsen panic, anxiety, and related symptoms in PTSD patients. [8]

Serotonergic Agents

Serotonergic agents affect the neurotransmission pathways that involve serotonin, a neurotransmitter associated with mood regulation. Serotonin agonists can bind to and activate serotonin receptors, increasing the levels of serotonin in the CNS and resultingly increasing the occurrence of behaviours associated with anxiety. [9] Research supports the resulting anxiogenic effects of agents such as LY-293,284 and mCPP [9] in the CNS.

Antibiotics

Fluroquinolones (FQs), such as ciprofloxacin, levofloxacin, and moxifloxacin, are a type of antibiotic that have been linked to increased levels of anxiety and panic attacks, [10] psychotic symptoms, [11] and depression [10] [11] in both mice and humans, with adverse neuropsychiatric reactions estimated to occur in 1–4.4% of patients, across a range of mild to more severe cases. [11] However, some of these effects may be resolved by the patient ceasing the course of antibiotics, instead of through therapeutic action. [11]

The mechanism behind this action is unclear however, [11] with some researchers suggesting that FQs may act as low-affinity GABA-A antagonists, [12] and others positing that its interactions with N-methyl-D-aspartate (NMDA) receptors, which have been associated with fear, anxiety, and depression, may be responsible for the anxiogenic effects. [13]

Sodium Lactate

Sodium lactate given intravenously has been proven to cause panic attacks in people with a panic disorder but not in people with no such history. [4]

Miscellaneous

Other substances that may have anxiogenic effects include:

The GABAA receptor negative allosteric modulator flumazenil can cause panic attacks in certain people.[ medical citation needed ]

Anxiolytic Substances

Anxiolytic substances have the opposite effect to anxiogenic substances in that they reduce levels of anxiety. Some of these are used in psychopharmacotherapy as antidepressants to treat a range of mental health conditions, including various types of anxiety disorders, panic disorders, and depression. Typical antidepressants prescribed in psychiatry today include selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines.

Though these substances are typically used to decrease anxiety through affecting levels of neurotransmitters, some may have anxiogenic effects.

SSRIs

SSRIs are a commonly prescribed type of antidepressants that are used to treat anxiety and depression in the long term by increasing levels of serotonin in the CNS through blocking the reabsorption of serotonin. However, SSRIs are ineffective in the short-term treatment of acute panic attacks or acute anxiety.

Clinical research suggests that SSRIs may have a biphasic response, with research suggesting that citalopram may have immediate anxiogenic effects from one dosage but long-term anxiolytic effects after three dosages in mice, [14] supporting clinical findings of exacerbated anxiety preceding the beneficial effects from SSRIs. Other research suggests that at low doses, paroxetine induces an anxiogenic-like response in rats [15]

Benzodiazepines

Benzodiazepines are a class of depressant drugs used to treat anxiety disorders by acting as GABA receptor agonists and affecting the levels of GABA within the CNS.

However, studies suggest that benzodiazepines may be anxiogenic in the long term. [16] Different benzodiazepines have different effects, such as β-CCM [17] which has been linked to anxiogenic effects, unlike Ro 15-17888. [17]

See also

Related Research Articles

An anxiolytic is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiety disorders and their related psychological and physical symptoms.

<span class="mw-page-title-main">Benzodiazepine</span> Class of depressant drugs

Benzodiazepines, colloquially called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, insomnia, and seizures. The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955 and was made available in 1960 by Hoffmann–La Roche, who soon followed with diazepam (Valium) in 1963. By 1977, benzodiazepines were the most prescribed medications globally; the introduction of selective serotonin reuptake inhibitors (SSRIs), among other factors, decreased rates of prescription, but they remain frequently used worldwide.

<span class="mw-page-title-main">Psychopharmacology</span> Study of the effects of psychoactive drugs

Psychopharmacology is the scientific study of the effects drugs have on mood, sensation, thinking, behavior, judgment and evaluation, and memory. It is distinguished from neuropsychopharmacology, which emphasizes the correlation between drug-induced changes in the functioning of cells in the nervous system and changes in consciousness and behavior.

<span class="mw-page-title-main">Panic attack</span> Period of intense fear

Panic attacks are sudden periods of intense fear and discomfort that may include palpitations, sweating, chest pain or chest discomfort, shortness of breath, trembling, dizziness, numbness, confusion, or a feeling of impending doom or of losing control. Typically, symptoms reach a peak within ten minutes of onset, and last for roughly 30 minutes, but the duration can vary from seconds to hours. Although they can be extremely frightening and distressing, panic attacks themselves are not physically dangerous.

<span class="mw-page-title-main">Alprazolam</span> Benzodiazepine medication

Alprazolam, sold under the brand name Xanax, is a fast-acting, potent tranquilizer of moderate duration within the triazolobenzodiazepine group of chemicals called benzodiazepines. Alprazolam is most commonly used in management of anxiety disorders, specifically panic disorder or generalized anxiety disorder (GAD). Other uses include the treatment of chemotherapy-induced nausea, together with other treatments. GAD improvement occurs generally within a week. Alprazolam is generally taken orally.

Colloquially known as "downers", depressants or central depressants are drugs that lower neurotransmission levels, or depress or reduce arousal or stimulation in various areas of the brain. Depressants do not change the mood or mental state of others. Stimulants, or "uppers", increase mental or physical function, hence the opposite drug class from depressants are stimulants, not antidepressants.

<span class="mw-page-title-main">Azapirone</span> Drug class of psycotropic drugs

Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics. They are commonly used as add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs).

Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certain medications such as benzodiazepines, opioids, stimulants, antiepileptics and antidepressants, as well as the recreational misuse of drugs such as alcohol, opioids and benzodiazepines. The higher the dose used, the greater the duration of use, and the earlier age use began are predictive of worsened physical dependence and thus more severe withdrawal syndromes. Acute withdrawal syndromes can last days, weeks or months. Protracted withdrawal syndrome, also known as post-acute-withdrawal syndrome or "PAWS", is a low-grade continuation of some of the symptoms of acute withdrawal, typically in a remitting-relapsing pattern, often resulting in relapse and prolonged disability of a degree to preclude the possibility of lawful employment. Protracted withdrawal syndrome can last for months, years, or depending on individual factors, indefinitely. Protracted withdrawal syndrome is noted to be most often caused by benzodiazepines. To dispel the popular misassociation with addiction, physical dependence to medications is sometimes compared to dependence on insulin by persons with diabetes.

Cross-tolerance is a phenomenon that occurs when tolerance to the effects of a certain drug produces tolerance to another drug. It often happens between two drugs with similar functions or effects—for example, acting on the same cell receptor or affecting the transmission of certain neurotransmitters. Cross-tolerance has been observed with pharmaceutical drugs such as anti-anxiety agents and illicit substances, and sometimes the two of them together. Often, a person who uses one drug can be tolerant to a drug that has a completely different function. This phenomenon allows one to become tolerant to a drug that they have never used before.

<span class="mw-page-title-main">Clorazepate</span> Benzodiazepine medication

Clorazepate, sold under the brand name Tranxene among others, is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. Clorazepate is an unusually long-lasting benzodiazepine and serves as a prodrug for the equally long-lasting desmethyldiazepam, which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.

<span class="mw-page-title-main">Benzodiazepine withdrawal syndrome</span> Signs and symptoms due to benzodiazepines discontinuation in physically dependent persons

Benzodiazepine withdrawal syndrome is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines as prescribed develops a physical dependence on them and then reduces the dose or stops taking them without a safe taper schedule.

GABA gamma-aminobutyric acid (GABA) is a key chemical messenger or a neurotransmitter in the central nervous system, that significantly inhibits neuronal transmission. GABA calms the brain and controls several physiological processes, such as stress, anxiety, and sleep. GABAA receptors are a class of ionotropic receptors that are triggered by GABA. They are made up of five subunits that are assembled in various configurations to create distinct receptor subtypes. The direct influx of chloride ions causes rapid inhibitory responses. GABAB receptors are another type of metabotropic receptor that modifies intracellular signaling pathways to provide slower, sustained inhibitory responses. At synapses, GABAA receptors facilitate rapid inhibitory neurotransmission, whereas GABAB receptor which comprise GABA B1 and GABA B2 subunits—control neurotransmitter release and cellular excitability over a longer period of time. These unique qualities help explain the various ways that GABAergic neurotransmission controls brain communication and neuronal function.

<span class="mw-page-title-main">Deramciclane</span> Drug used to treat anxiety disorders

Deramciclane (EGIS-3886) is a non-benzodiazepine-type anxiolytic drug to treat various types of anxiety disorders. Deramciclane is a unique alternative to current anxiolytics on the market because it has a novel chemical structure and target. It acts as an antagonist at the 5-HT2A receptor, as an inverse agonist at the 5-HT2C receptor, and as a GABA reuptake inhibitor. The two serotonin receptors are G protein-coupled receptors and are two of the main excitatory serotonin receptor types. Their excitation has been implicated in anxiety and mood. Deramciclane does not affect CYP3A4 activity in metabolizing other drugs, but it is a weak inhibitor of CYP2D6. Some studies also show the drug to have moderate affinity to dopamine D2 receptors and low affinity to dopamine receptor D1. Researchers are looking for alternatives to benzodiazepines for anxiolytic use because benzodiazepine drugs have sedative and muscle relaxant side effects.

<span class="mw-page-title-main">ELB-139</span> Chemical compound

ELB-139 (LS-191,811) is an anxiolytic drug with a novel chemical structure, which is used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic.

<span class="mw-page-title-main">GABA reuptake inhibitor</span> Drug class

A GABA reuptake inhibitor (GRI) is a type of drug which acts as a reuptake inhibitor for the neurotransmitter gamma-Aminobutyric acid (GABA) by blocking the action of the gamma-Aminobutyric acid transporters (GATs). This in turn leads to increased extracellular concentrations of GABA and therefore an increase in GABAergic neurotransmission. Gamma-aminobutyric acid (GABA) is an amino acid that functions as the predominant inhibitory neurotransmitter within the central nervous system, playing a crucial role in modulating neuronal activity in both the brain and spinal cord. While GABA predominantly exerts inhibitory actions in the adult brain, it has an excitatory role during developmental stages. When the neuron receives the action potential, GABA is released from the pre-synaptic cell to the synaptic cleft. After the action potential transmission, GABA is detected on the dendritic side, where specific receptors collectively contribute to the inhibitory outcome by facilitating GABA transmitter uptake. Facilitated by specific enzymes, GABA binds to post-synaptic receptors, with GABAergic neurons playing a key role in system regulation. The inhibitory effects of GABA diminish when presynaptic neurons reabsorb it from the synaptic cleft for recycling by GABA transporters (GATs). The reuptake mechanism is crucial for maintaining neurotransmitter levels and synaptic functioning. Gamma-aminobutyric acid Reuptake Inhibitors (GRIs) hinder the functioning of GATs, preventing GABA reabsorption in the pre-synaptic cell. This results in increased GABA levels in the extracellular environment, leading to elevated GABA-mediated synaptic activity in the brain.

<span class="mw-page-title-main">Benzodiazepine dependence</span> Medical condition

Benzodiazepine dependence defines a situation in which one has developed one or more of either tolerance, withdrawal symptoms, drug seeking behaviors, such as continued use despite harmful effects, and maladaptive pattern of substance use, according to the DSM-IV. In the case of benzodiazepine dependence, the continued use seems to be typically associated with the avoidance of unpleasant withdrawal reaction rather than with the pleasurable effects of the drug. Benzodiazepine dependence develops with long-term use, even at low therapeutic doses, often without the described drug seeking behavior and tolerance.

<span class="mw-page-title-main">Panic disorder</span> Anxiety disorder characterized by reoccurring unexpected panic attacks

Panic disorder is a mental and behavioral disorder, specifically an anxiety disorder characterized by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear that may include palpitations, sweating, shaking, shortness of breath, numbness, or a feeling that something terrible is going to happen. The maximum degree of symptoms occurs within minutes. There may be ongoing worries about having further attacks and avoidance of places where attacks have occurred in the past.

An anxiotropic agent is one that modifies anxiety, a human emotion that has homologous processes in animals. In psychopharmacology anxiotropic agents consist of two categories of psychoactive drugs: anxiolytics that reduce anxiety and may be used therapeutically, and anxiogenic compounds that increase anxiety.

Caffeine-induced anxiety disorder is a subclass of the DSM-5 diagnosis of substance/medication-induced anxiety disorder.

References

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  2. ↑ Juruena, M. F.; Eror, F.; Cleare, A. J. (2020). "The Role of Early Life Stress in HPA Axis and Anxiety". Anxiety Disorders. Advances in Experimental Medicine and Biology. pp. 141–153.
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  5. ↑ Calker, D.; Biber, K.; Domschke, K.; Serchov, T. (2019). "The role of adenosine receptors in mood and anxiety disorders". Journal of Neurochemistry. 151 (1): 11–27. doi:10.1111/jnc.14841. PMID   31361031.
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