Caffeine-induced anxiety disorder

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Caffeine-induced anxiety disorder is a subclass of the DSM-5 diagnosis of substance/medication-induced anxiety disorder.[1]

Consumption of caffeine has long been linked to anxiety.[2] The effects of caffeine and the symptoms of anxiety both increase activity within the sympathetic nervous system. Caffeine has been linked to the aggravation and maintenance of anxiety disorders, and the initiation of panic or anxiety attacks in those who are already predisposed to such phenomena.[3] Caffeine usage surpassing 200 mg has been shown to increase the likelihood for anxiety and panic attacks in a population. Excessive amounts of caffeine can result in symptoms from general anxiety to obsessive-compulsive and phobic symptoms. Anxiety symptoms caused by caffeine are often mistaken for serious mental disorders including bipolar disorder and schizophrenia, leaving patients medicated for the wrong issue.[4]

DSM-5 classification[edit]

Diagnostic criteria[edit]

Caffeine-induced anxiety disorder is a subclass of the DSM-5 diagnosis of substance/medication-induced anxiety disorder. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, or DSM-5, is the current authority for psychiatric diagnosis in the United States. Substance/medication-induced anxiety disorder falls under the category of anxiety disorders in the DSM-5, and not the category of substance-related and addictive disorders, even though the symptoms are due to the effects of a substance.[5]

Diagnosis according to the DSM-5 is dependent on various criteria. Patients must present symptoms of either panic attacks or anxiety. There must also be evidence that the panic or anxiety symptoms are a direct result of the use of the intoxicating substance. In caffeine-induced anxiety disorder, such symptoms would be due to the consumption of caffeine. The DSM-5 makes the distinction that the substance must be physiologically capable of leading to the anxiety and panic symptoms. This establishes the relationship between the abused chemical agent and the observed clinical effects. Caffeine has been proven to act as an antagonist on adenosine receptors, which acts as a stimulant and therefore fulfills this criteria. Symptoms must also not have a more likely clinical cause, such as another type of anxiety disorder, come before the ingestion of the intoxicating substance, or last for an extended amount of time after stopping the use of the substance. Diagnosis also requires that the panic attacks or anxiety due to the use of the intoxicating substance cause a certain amount of disturbance in the patient or lead to deficiency of varying types of daily performance.[5]

Diagnostic features[edit]

In addition to the criteria above, it is important to recognize that the diagnostic criteria for substance/medication-induced anxiety disorder are not met if the symptoms of panic come before the intoxication by the substance. In caffeine-induced anxiety disorder, a diagnosis will not be made if symptoms of anxiety or panic precede the ingestion of caffeine. Also, if symptoms persist for more than one month after substance intoxication, the diagnosis cannot be made. Persistence and continuation of symptoms beyond the initial consumption of caffeine suggest an alternate diagnosis that would better explain the long-lasting symptoms. A caffeine-induced anxiety disorder diagnosis should be made, rather than a substance abuse or intoxication diagnosis, when symptoms panic attacks or anxiety predominate.[6]

Prevalence[edit]

Although exact rates of prevalence are not available, general population data shows a 0.002% prevalence over a year-long period and higher prevalence within clinical populations.[6]

Caffeine[edit]

Caffeine structure

Caffeine is a methylxanthine, and is hydrophobic.[7] The structure of caffeine allows the molecule to pass freely through biological membranes including the blood-brain barrier. Absorption in the gastrointestinal tract reaches near completion at about 99% after only 45 minutes. Half-life of caffeine for most adults is between 2.5 and 4.5 hours when consumption is limited to less than 10 mg/kg. However, during neonatal development, half-life for the fetus is significantly longer and decreases exponentially after birth to reach a normal rate at about 6 months.[7] Cytochrome P-450, a hemeprotein, acts in liver microsomes to metabolize caffeine into dimethylxanthines, monomethylxanthines, dimethyl uric acids, monomethyl uric acids, trimethylallantoin, dimethylallantoin, and derivatives of uracil. Most caffeine is metabolized by 3-methyl demethylation, forming the metabolite of paraxanthine. Many metabolites, in addition to caffeine, act within the body and are partly responsible for the physiological response to caffeine.[7]

Mechanism of caffeine action[edit]

Caffeine acts in multiple ways within the brain and the rest of the body. However, due to the concentration of caffeine required, antagonism of adenosine receptors is the primary mode of action.[8] The following mechanisms are ways in which caffeine may act within the body, but depending on necessary caffeine concentration and other factors may not be responsible for the clinical effects of the substance.

Mobilization of intracellular calcium[edit]

At very high concentrations of about 1–2 mM, caffeine lowers the excitability threshold in muscle cells, leading to prolonged contraction. The introduction of such high doses of caffeine allows calcium to enter the muscle cell through the plasma membrane and sarcoplasmic reticulum more readily. Influx of calcium through the membranes in muscle cells requires at least 250 μM of caffeine. Normally, other toxic effects of caffeine begin to occur in concentrations over 200 μM, however average consumption averages lead to concentrations less than 100 μM. This means that calcium influx and mobilization are most likely not the cause of caffeine's effect on the central nervous system, and are therefore not the cause of caffeine-induced anxiety disorder.[8]

Inhibition of phosphodiesterases[edit]

Methylxanthines such as caffeine inhibit the action of cyclic nucleotide phosphodiesterase, which normally acts to break down cAMP. Cyclic adenosine monophosphate, or cAMP, is a second messenger important in many cellular processes and is a critical factor in signal transduction. The inhibition of the phosphodiesterase would lead to a buildup of cAMP, increasing the activity of the second messenger throughout the cell. Though this mechanism is possible, it only occurs after levels of caffeine have reached a toxic level, and therefore it is unlikely to explain the mechanism of caffeine in the brain.[8]

Antagonism of adenosine receptors[edit]

There are four well-known adenosine receptors found in the body, A1, A2A, A2B, and A3. The endogenous agonist for these receptors is adenosine, which is a purine nucleoside that is important for processes such as energy transfer in the form of adenosine triphosphate (ATP) and adenosine monophosphate (AMP) and signal transduction in the form of cyclic adenosine monophosphate (cAMP). A2B and A3 receptors require concentrations of caffeine that do not occur at normal physiological levels or with normal levels of caffeine consumption in order to be antagonized, and will therefore not be considered as a possible mechanism for caffeine-induced anxiety.[7]

Caffeine acts as an antagonist of adenosine A1 and A2A receptors. Adenosine is a normal neuromodulator that activates adenosine g-protein coupled receptors. The actions of A1 and A2A receptors oppose each other but are both inhibited by caffeine due to its function as an antagonist.[7]

A2A receptors are coupled to Gs proteins which activate adenylate cyclase and some voltage gated Ca2+ channels. A2A receptors are located in dopamine rich brain regions. A2A receptor mRNA was found in the same neurons as the dopamine receptor D2 within the dorsal striatum, nucleus accumbens and tuberculum olfactorium. A2A receptors are not found in neurons that express the dopamine receptor D1 receptors and Substance P. Within the striatum, part of the basal ganglia, activation of A2A receptors by adenosine increases GABA release, an inhibitory neurotransmitter. When caffeine binds to the receptor, less inhibitory neurotransmitter is released, supporting caffeine's role as a central nervous system stimulant.[7]

A1 receptors are paired with the G-proteins of Gi-1, Gi-2, Gi-3, Go1, and Go2. The g-proteins of A1 receptors continue to inhibit adenylate cyclase, some voltage gated Ca2+ channels, and activate some K+ channels, and phospholipase C and D. A1 receptors are primarily located in the hippocampus, cerebral and cerebellar cortex, and particular thalamic nuclei. Adenosine acts on A1 receptors to decrease opening of N-type Ca2+ channels in some hippocampal neurons, and therefore decrease the rate of firing since Ca2+ is necessary for neurotransmitter release. Caffeine's antagonistic action on the A1 receptor thus decreases the action of adenosine, allowing increased Ca2+ entry through N-type channels and higher rates of neurotransmitter release.[7]

Other actions of caffeine[edit]

Though antagonism of adenosine receptors is the primary mechanism of caffeine, Introduction of the methylxanthine into the body also increases the rate of release and recycling of some monoamine neurotransmitters such as noradrenaline and dopamine. Caffeine also has an excitatory effect on mesocortical cholinergic neurons by acting as an antagonist on adenosine receptors that normally inhibit the neuron.[7]

Genetics and variability of caffeine consumption[edit]

While many factors contribute to individual differences in a person's response to caffeine, such as environmental and demographic factors (i.e. age, drug use, circadian factors, etc.), genetics play an important role in individual variability. This inconsistency in responses to caffeine can take place either at the metabolic or at the drug-receptor level.[6] The effects of genetic factors can occur either directly by changing acute or chronic reactions to the drug or indirectly by altering other psychological or physiological processes.[6]

Some of these processes include wakefulness, stimulation, and mood and cognition enhancement. Low doses can result in psychological effects of "mild euphoria, alertness, and enhanced cognitive performance";[6] higher doses produce physiological side effects of nausea, anxiety, trembling, and jitteriness.

There are individuals who are prone to caffeine's anxiogenic effects whilst others are susceptible to its caffeine-induced sleep disturbances and insomnia. Studies with twins have shown that genetics influence individual differences in response to caffeine. Homozygous twins have been found to react in more consistent ways to the caffeine than heterozygous twins.[8]

Behavioral effects[edit]

Caffeine's benefits are "related to its mild psychostimulant properties".[9] Caffeine's widespread appeal is due primarily to its effect to increase alertness and cognitive arousal and diminish fatigue. In most people, caffeine has positive benefits like the alleviation of fatigue and heightened cognitive arousal. Caffeine also produces a wide range of other symptoms, including upregulation of the cardiovascular system ranging "from moderate increases in heart rate to more severe cardiac arrhythmia".[9] However, what is less widely known is that caffeine can induce anxiety-like symptoms in individuals, particularly when consumed in excess. Studies show that consuming caffeine in "excess produces persisting insomnia, nervousness, and mood fluctuations".[9]

Additionally, studies show that caffeine consumption results in "subsequent dysregulation" of HPA axis function,[10] which presents in anxiety-related behavior. When undergoing stress, the body activates a system-wide response mechanism known as the HPA axis. This stress signal begins at the level of the hypothalamus in the brain and undergoes subsequent amplifications throughout the body. This system succeeds in elevating blood levels of stress hormones, which results in the body shutting down secondary bodily processes, increasing hyperawareness, and readying the body for response to the perceived threat. Studies show that activation of this pathway is associated with "anxiety-related disorders such as panic disorder, post-traumatic stress disorder and generalized anxiety disorder".[10]

In cases of prolonged consumption of excess amounts of caffeine, studies show that individuals exhibit a reduced response to HPA axis activation by the hormone ACTH and a generalized increase in basal levels of stress hormone corticosterone. This led researchers to conclude that "caffeine consumption decreases adrenal gland sensitivity to ACTH. A blunted HPA response to psychological stress has been seen in humans with panic disorder compared to healthy controls following administration of a psychosocial test".[10]

Populations most susceptible[edit]

Various populations exhibit varying degrees of susceptibility to anxiety-like symptoms when consuming caffeine. Most notably, those who suffer from preexisting anxiety-related disorders, those who suffer from ADHD, and adolescents are at greatest risk for experiencing caffeine-induced anxiety-like symptoms. Adolescents, particularly, are at increased risk for developing anxiety disorders and anxiety-related symptoms. Studies show that adolescents who consume caffeine chronically demonstrate "transient and sustained neurochemical and behavioral responses".[10] This means that when caffeine is consumed regularly in excess amounts, adolescents display "more lasting effects on behavioral reactivity to psychologically stressful events"[10] and are at increased "vulnerability to the development of psychiatric disorders"[10] in the long term.

Long-term health effects[edit]

When consumed in moderation, caffeine can have many beneficial effects. However, over the course of several years, chronic caffeine consumption can produce various long-term health deficits in individuals, "including permanent changes in brain excitability".[11] As previously stated, long-term effects are most often seen in adolescents who regularly consume excess amounts of caffeine. This can affect their neuroendocrine functions and increase the risk of anxiety-disorder development.

Treatment[edit]

For individuals prescribed anti-anxiety medications such as Alprazolam (Xanax), caffeine can introduce further problems by increasing rates of cytotoxicity and cell death by necrosis. This leads to these medications being essentially ruled out as viable treatments for caffeine-induced anxiety.[12] Due to caffeine's negative interaction with anti-anxiety medications such as benzodiazepines, treatments for caffeine-induced anxiety disorder tend to focus on abstinence from or a reduction of caffeine intake and behavioral therapy. Some doctors may recommend a continuance of caffeine consumption but with the provision that the patient actively takes note of physiological changes that happen after caffeine intake. The goal of this approach is to help patients better understand the effects of caffeine on the body and to distinguish threatening symptoms from normal reactions.[13]

References[edit]

  1. ^ Addicott MA (September 2014). "Caffeine Use Disorder: A Review of the Evidence and Future Implications". Current Addiction Reports. 1 (3): 186–192. doi:10.1007/s40429-014-0024-9. PMC 4115451 Freely accessible. PMID 25089257.
  2. ^ http://www.psychology.org.nz/wp-content/uploads/NZJP-Vol251-1996-7-Hughes.pdf
  3. ^ Winston, Anthony P.; Hardwick, Elizabeth; Jaberi, Neema (October 2005). "Neuropsychiatric effects of caffeine". Advances in Psychiatric Treatment. 11 (6): 432–439. doi:10.1192/apt.11.6.432. ISSN 2056-4678.
  4. ^ Torres, Francis M. (April 2009). "Caffeine - Induced Psychiatric Disorders" (PDF). Journal of Continuing Education Topics & Issues. Retrieved 22 February 2016.
  5. ^ a b American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders (DSM-5). American Psychiatric Publishing. pp. 226–230. ISBN 978-0-89042-555-8.
  6. ^ a b c d e Yang, Amy; Palmer, Abraham A.; de Wit, Harriet (June 9, 2010). "Genetics of caffeine consumption and responses to caffeine". Psychopharmacology. 211 (3): 245–257. doi:10.1007/s00213-010-1900-1. PMC 4242593. PMID 20532872.
  7. ^ a b c d e f g h Fredholm, B. B.; Bättig, K.; Holmén, J.; Nehlig, A.; Zvartau, E. E. (1999-03-01). "Actions of caffeine in the brain with special reference to factors that contribute to its widespread use". Pharmacological Reviews. 51 (1): 83–133. ISSN 0031-6997. PMID 10049999.
  8. ^ a b c d Nehlig, Astrid; Daval, Jean-Luc; Debry, Gérard (June 2, 1992). "Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic, and psychostimulant effects". Brain Research Reviews. 17 (2): 139–170. doi:10.1016/0165-0173(92)90012-B. PMID 1356551.
  9. ^ a b c "Psychiatric emergencies (part II): psychiatric disorders coexisting with organic diseases". European Review (in Italian). Retrieved 2016-04-01.
  10. ^ a b c d e f O’Neill, Casey E.; Newsom, Ryan J.; Stafford, Jacob; Scott, Talia; Archuleta, Solana; Levis, Sophia C.; Spencer, Robert L.; Campeau, Serge; Bachtell, Ryan K. (2016-05-01). "Adolescent caffeine consumption increases adulthood anxiety-related behavior and modifies neuroendocrine signaling". Psychoneuroendocrinology. 67: 40–50. doi:10.1016/j.psyneuen.2016.01.030. PMC 4808446. PMID 26874560.
  11. ^ Tchekalarova, Jana D.; Kubová, Hana; Mareš, Pavel (2014). "Early caffeine exposure: Transient and long-term consequences on brain excitability". Brain Research Bulletin. 104: 27–35. doi:10.1016/j.brainresbull.2014.04.001. PMID 24727007.
  12. ^ Saha, Biswarup; Mukherjee, Ananda; Samanta, Saheli; Saha, Piyali; Ghosh, Anup Kumar; Santra, Chitta Ranjan; Karmakar, Parimal (2009-09-01). "Caffeine augments Alprazolam induced cytotoxicity in human cell lines". Toxicology in Vitro. 23 (6): 1100–1109. doi:10.1016/j.tiv.2009.05.018. PMID 19490937.
  13. ^ "Information on caffeine induced anxiety on MedicineNet.com". MedicineNet. Retrieved 2016-03-31.